HTA. Supporting Informed Decisions. Canadian Agency for Drugs and Technologies in Health

Transcription

1 Canadian Agency for Drugs and Technologies in Health Agence canadienne des médicaments et des technologies de la santé t e c h n o l o g y r e p o r t HTA Issue 120 July 2009 Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses Supporting Informed Decisions

2 Until April 2006, the Canadian Agency for Drugs and Technologies in Health (CADTH) was known as the Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Publications can be requested from: CADTH Carling Avenue Ottawa ON Canada K1S 5S8 Tel.: Fax: or downloaded from CADTH s website: Cite as: Assasi N, Blackhouse G, Xie F, Gaebel K, Marshall J, Irvine EJ, Giacomini M, Robertson D, Campbell K, Hopkins R, Goeree R. Anti-TNF-α drugs for refractory inflammatory bowel disease: Clinical- and cost-effectiveness analyses [Technology report number 120]. Ottawa: Canadian Agency for Drugs and Technologies in Health; Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Ontario, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada or any provincial or territorial government. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CADTH. CADTH is funded by Canadian federal, provincial, and territorial governments. Legal Deposit 2009 National Library of Canada ISBN: (print) ISBN: (online) H0479 July 2009 PUBLICATIONS MAIL AGREEMENT NO RETURN UNDELIVERABLE CANADIAN ADDRESSES TO CANADIAN AGENCY FOR DRUGS AND TECHNOLOGIES IN HEALTH CARLING AVENUE OTTAWA ON K1S 5S8

3 Canadian Agency for Drugs and Technologies in Health Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses Nazila Assasi, MD PhD 1,2 Gord Blackhouse, MSc 1,2 Feng Xie, PhD 1,2 Kathryn Gaebel, MSc 1,2 John Marshall, MD MSc FRCPC AGAF 2,3 E. Jan Irvine, MD FRCPC MSc 4 Mita Giacomini 2 Diana Robertson, MLIS 1,2 Kaitryn Campbell, MLIS 1,2 Rob Hopkins, MA MBA 1,2 Ron Goeree, MA 1,2 July PATH Research Institute, St. Joseph s Healthcare, Hamilton, Ontario, Canada 2 McMaster University, Hamilton, Ontario, Canada 3 Hamilton Health Sciences, Hamilton, Ontario, Canada 4 University of Toronto / St. Michael s Hospital, Toronto, Canada

4 Reviewers These individuals kindly provided comments on this report. External Reviewers Charles N. Bernstein, MD Professor of Medicine Head, Section of Gastroenterology Director, University of Manitoba IBD Clinical and Research Centre Bingham Chair in Gastroenterology Research University of Manitoba Winnipeg, MB Zahra Musa, BSc MHA Health Economics Research Coordinator British Columbia Cancer Agency Vancouver, BC CADTH Peer Review Group Reviewers Michelle L. McIsaac, MA Economics Health Economist University of Sydney Camperdown, NSW Australia Theresa Longobardi, PhD Economics Assistant Professor Department of Internal Medicine University of Manitoba Winnipeg, MB Kenneth Croitoru, MDCM FRCPC Professor of Medicine University of Toronto, Mount Sinai Hospital Toronto, ON John M. Fardy, MD MSc FRCPC Professor of Medicine (Gastroenterology) Memorial University of Newfoundland St. John s, NL Industry: The following manufacturers were provided with an opportunity to comment on an earlier version of this report: AMGEN Canada Inc., Schering Plough Canada Inc., and Abbott Laboratories Ltd. All comments that were received were considered when preparing the final report. This report is a review of existing public literature, studies, materials, and other information and documentation (collectively the source documentation ) that are available to CADTH. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured, or represented in any way by CADTH, and CADTH does not assume responsibility for the quality, propriety, inaccuracies, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH takes sole responsibility for the final form and content of this report. The statements and conclusions in this report are those of CADTH and not of its Panel members or reviewers. Authorship Nazila Assasi, the clinical research lead for the project, contributed to the development of the study protocol, the screening questionnaires, the data abstraction forms, and the Review Manager database. She conducted the clinical review and wrote the clinical review portion of the report. i Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical and Cost-Effectiveness Analyses

5 Gord Blackhouse was responsible for the analysis and write-up of the Crohn s disease economic section, the write-up of the review of published economic analyses, the analysis and write-up of the budget impact analysis, the responses to reviewers comments, and the editing of the report. Feng Xie was responsible for the analysis and write-up of the ulcerative colitis economic model, the responses to reviewers comments, and the editing of the report. Kathryn Gaebel wrote a section of the report, assisted with the economic analysis, responded to reviewers comments, and edited the report as required. John Marshall reviewed and revised the protocol and report, and reviewed and discussed reviewers comments. Jan Irvine reviewed the findings, performed data extraction, provided interpretation of analyses and economic models, and provided feedback on the report and review comments and queries. Mita Giacomini provided advice on approaches to address health system and ethical issues, and on the editing and revision of drafts. Diana Robertson kept the databases up to date using alerts and performed updates of the grey literature searches. She obtained full-text literature, generated the bibliographies, and checked the format and accuracy of the references in the report. Kaitryn Campbell designed and ran the literature search and wrote research methods for the literature search. Rob Hopkins performed the meta-analysis and reviewed the final report. Ron Goeree contributed to the design and execution of the study and to the writing of the final report. Conflicts of Interest Dr. John Marshall has received speaker fees, has participated in advisory boards, and has had clinical trial participation with Schering Canada, Abbott Laboratories, and UCB. Dr. Charles N. Bernstein is part of the advisory board and is a consultant for Axcan Pharma. He is part of the advisory board for Abbott Pharmaceuticals Canada and Shire Pharmaceuticals Canada. He receives research funding from UCB Canada. Kenneth Croitoru is part of the regional advisory boards for Schering Canada, Abbott Laboratories, and UCB. Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses ii

6 iii Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical and Cost-Effectiveness Analyses

7 EXECUTIVE SUMMARY The Issue The volume of reimbursement requests to the publicly funded drug plans in Canada for infliximab and adalimumab from patients with Crohn s disease (CD) or ulcerative colitis (UC) who are not responding to conventional therapy is increasing. These anti-tumour necrosis factor alpha (anti-tnf-α) drugs are not listed as a general benefit in several jurisdictions. Therefore, reimbursement may be based on pre-set criteria or on case-by-case reviews. There is interest in some jurisdictions in improving this process and developing reimbursement criteria or updating existing criteria. Findings from this health technology assessment (HTA) may serve in some jurisdictions as a platform for a pilot reimbursement program of anti-tnf-α drugs being used by patients with CD or UC who are not responding to conventional anti-inflammatory treatments. Objectives The aim of this HTA is to evaluate the comparative clinical-effectiveness of anti-tnf-α drugs in patients with CD or UC with an inadequate response to conventional therapy and to determine the economic value of anti-tnf-α drugs compared with that of conventional therapy and surgical interventions. Conventional therapy includes 5-aminosalicylic acid (5-ASA) derivatives, immunosuppressant drugs (azathioprine, cyclosporine, mercaptopurine, and methotrexate) and corticosteroids. For each diagnosis, a set of common research questions was developed. How do anti-tnf-α drugs (adalimumab, etanercept, and infliximab) compare with each other, in terms of clinical- and cost-effectiveness for adult patients with refractory CD or UC, including luminal and fistulizing forms of the disease? How do anti-tnf-α drugs (adalimumab, etanercept, and infliximab) compare with conventional therapy (including 5-ASA derivatives [5-ASA, olsalazine, sulfasalazine], immunosuppressant drugs [azathioprine, cyclosporine, mercaptopurine, methotrexate], and corticosteroids) for patients with refractory CD in terms of clinical- and cost-effectiveness? What are the benefits and harms that are associated with dose escalation with anti-tnf-α drugs? What potential exists that patients who have been exposed to an anti-tnf-α drug could benefit or be harmed by switching to another anti-tnf-α drug? What is the optimal timing of anti-tnf-α treatment (early versus later in the course of the disease), and is there a subgroup of patients who will benefit most from early aggressive treatment? Is there a subgroup of patients who have CD or UC that respond to maintenance immunosuppressive therapy alone (after anti-tnf-α drug induction)? What is the harm associated with the formation of neutralizing antibodies to these agents? What is the effect of neutralizing antibody formation on dosing requirements? Are there interventions that can prevent the formation of neutralizing antibodies? What is the effect of anti-tnf-α drugs on clinical response, hospitalizations, surgery, clinical remission, and death? Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical and Cost-Effectiveness Analyses iv

8 Methods A systematic review was undertaken to address the clinical research questions. Relevant clinical trials, cohort studies, and registries that focus on infliximab, adalimumab, or etanercept for CD or UC were identified using a search strategy that was developed by an information specialist. Clinical outcomes were described qualitatively. When deemed appropriate, clinical outcomes were pooled. Otherwise, a systematic review of existing economic evaluations of adalimumab, infliximab, and etanercept in CD and UC was undertaken. The search strategy was developed by an information specialist. Results from the economic literature were described qualitatively. Two primary economic evaluations were completed to present findings for CD and UC. The health services impact impact of anti-tnf-α treatment of inflammatory bowel disease (IBD) was assessed by estimating the prevalence of those who qualify for treatment in Canada, estimating the current public expenditures on anti-tnf-αs for IBD, and reviewing ethical, legal, and equity issues of anti-tnf-α treatment of IBD. Results Clinical-Effectiveness Review Crohn s Disease No head-to head trials comparing the effectiveness of infliximab with adalimumab or with etanercept in CD were identified, nor were there any studies directly comparing the anti-tnf-α drugs with conventional therapy in refractory CD. Infliximab and adalimumab showed a consistent superiority to placebo for the induction and maintenance of clinical remission and for reduction of rates of surgery and hospitalization in refractory CD. Infliximab also led to higher response and remission rates in patients with UC compared with placebo. There was no compelling evidence of a clinically important effect in the treatment of CD with etanercept. Ulcerative colitis No head-to-head trials comparing the effectiveness of infliximab with adalimumab or etanercept in UC were found. No publications of randomized studies were identified on which to base an assessment of the effectiveness of adalimumab and etanercept in the treatment of refractory UC. Patients with IBD who start to lose their response to anti-tnf-α treatment could benefit from dose escalation. In terms of optimal timing to start the treatment of CD using anti-tnf- drugs, the results from three studies indicate that earlier is better for improving the rate of remission. The results of this review show that the presence of antibodies against anti-tnf-α drugs could result in impaired effectiveness. Concomitant immunomodulators could prevent the formation of antibodies against infliximab, particularly in the patients who were treated with episodic treatment. Economic Analysis Crohn s Disease The incremental cost-utility ratio (ICUR) of adalimumab therapy compared with usual care was estimated to be $193,305 per quality-adjusted life-year (QALY). The ICUR of infliximab therapy compared with adalimumab therapy was estimated to be $451,165. The cost per QALY of infliximab therapy compared with usual care was estimated to be $222,955. The adalimumab v Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical and Cost-Effectiveness Analyses

9 strategy has the highest probability of being cost-effective at willingness-to-pay values greater than or equal to $208,000. Ulcerative colitis The cost-utility of a strategy that consisted of first-line 5 mg infliximab treatment followed by second-line adalimumab treatment was $358,088 per QALY compared with usual care. The same strategy based on an assumption of 10 mg/kg led to less favourable cost-utility results. Compared to a strategy involving 5mg/kg of infliximab and adalimumab, usual care is likely to be the most cost-effective strategy unless society is willing to pay more than $370,000 for a QALY. Health Services Impact Based on the findings of a Crohn s and Colitis Foundation of Canada report, the numbers of individuals who were diagnosed with UC and CD in Canada were estimated to be 88,500 and 112,000 respectively. Current total public expenditures on anti-tnfs for the treatment of IBD were estimated to be $46,979,043. Based on trends in expenditures over the last three years, total public expenditures on anti-tnfs for IBD are projected to be $94,832,652 in fiscal year Conclusions Although infliximab and adalimumab have been shown to provide clinical benefit, the costs associated with these treatments could be perceived as high. Based on the incremental cost-utility findings from our primary economic evaluations, adalimumab and infliximab for the treatment of IBD may not be perceived to be a cost-effective use of health care resources. Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses vi

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11 TABLE OF CONTENTS EXECUTIVE SUMMARY...iv ACRONYMS AND ABBREVIATIONS...x 1 INTRODUCTION Background and Setting in Canada Overview of Technology ISSUE OBJECTIVES Crohn s Disease Ulcerative Colitis CLINICAL REVIEW Methods Literature searches Selection criteria Selection method Data extraction strategy Strategy for validity assessment Data analysis methods Results Quantity of research available Study characteristics Data analyses and synthesis Discussion ECONOMIC ANALYSIS Review of Economic Studies Methods Results Primary Economic Evaluation Crohn s disease Ulcerative colitis HEALTH SERVICES IMPACT Population Impact Methods Results Budget Impact Analysis Current Canadian expenditures for anti-tnf-α treatment Estimating future public expenditures for anti-tnf-α drugs for inflammatory bowel disease Planning, Implementation, Utilization, and Legal or Regulatory Considerations Results Discussion...60 Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses viii

12 7 DISCUSSION Summary of Results Strengths and Weaknesses of this Assessment Generalizability of Findings Knowledge Gaps CONCLUSIONS REFERENCES...64 APPENDICES available from CADTH s web site APPENDIX 1: Search Strategy for clinical review APPENDIX 2: Level 1 (Title and Abstract) Screening for Clinical Review APPENDIX 3: Level 2 (Full Text) Screening for Clinical Review APPENDIX 4: Clinical Review Data Abstraction Form APPENDIX 5: Quality Score for the Randomized Controlled Trials Included in Clinical Review (Jadad Scale) APPENDIX 6: Newcastle-Ottawa Quality Assessment Scale for the Cohort Studies included in Clinical Review APPENDIX 7: Selected Reports for Clinical Review APPENDIX 8: Excluded Studies from the Clinical Review and Reasons for Exclusions APPENDIX 9: Characteristics of the included studies APPENDIX 10: Pooled Analyses for the clinical data APPENDIX 11: Crohn s Disease Activity Index* APPENDIX 12: Disease Activity Index (DAI or MAYO Scoring System) for assessment of ulcerative colitis activity APPENDIX 13: Search Strategy for the economic review APPENDIX 14: Selected Reports for the economic review APPENDIX 15: List of excluded studies from the economic review and reasons for exclusion APPENDIX 16: Full summary of the eight economic studies APPENDIX 17: Comparative summary of the economic analyses reviewed APPENDIX 18: Graphical representation of the Crohn s Disease model structure and movement between health states. APPENDIX 19: Response and Remission Rates for Crohn s Disease APPENDIX 20: Initial treatment costs used in the Crohn s Disease model for infliximab and adalimumab APPENDIX 21: Treatment Costs for Maintenance anti-tnf therapy APPENDIX 22: Non anti-tnf outpatient drug costs APPENDIX 23: Parameters and distributions used in probabilistic sensitivity analysis APPENDIX 24: Incremental Cost-Utility ratios in Crohn s Disease varying patient weight APPENDIX 25: Cost per QALY using sensitivity analysis on structural uncertainty for Crohn s Disease APPENDIX 26: Simplified Markov model schematic for Ulcerative Colitis APPENDIX 27: Non-time dependant parameters used in the Ulcerative Colitis model APPENDIX 28: Time-dependent parameters used in the Ulcerative Colitis model* APPENDIX 29: One-way deterministic sensitivity analyses results on variability for Ulcerative Colitis APPENDIX 30: One-way deterministic sensitivity analyses results on uncertainty for Ulcerative Colitis APPENDIX 31: Planning, Implementation, Utilization, Legal, Regulatory, Ethical and Psychosocial Issues Abstraction Form ix Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses

13 ACRONYMS AND ABBREVIATIONS 5-ASA ATA ATI CADTH CD CDAI CEAC CI CMG HTA IBD ICUR OCCI RCT RR TNF-α UC WTP 5-aminosalicylic acid antibodies against adalimumab antibodies against infliximab Canadian Agency for Drugs and Technologies in Health Crohn s disease Crohn s disease activity index cost-effectiveness acceptability curve confidence interval case-mixed group health technology assessment inflammatory bowel disease incremental cost-utility ratio Ontario Case Costing Initiative randomized controlled trial relative risk tumour necrosis factor alpha ulcerative colitis willingness-to-pay threshold values Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses x

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15 1 INTRODUCTION 1.1 Background and Setting in Canada Inflammatory bowel disease (IBD) refers to ulcerative colitis (UC) and Crohn s disease (CD), which are chronic inflammatory diseases of the gastrointestinal tract of unknown etiology. 1 CD is characterized by patchy, transmural inflammation, which may affect any part of the gastrointestinal tract. It may be defined by location (terminal ileal, colonic, ileocolic, upper gastrointestinal) or by pattern of disease (inflammatory, fistulating, or stricturing). 2,3 UC is characterized by diffuse mucosal inflammation that is limited to the colon. The extent can be divided into distal and more extensive disease. Distal disease refers to colitis that is confined to the rectum (proctitis) or rectum and sigmoid colon (proctosigmoiditis). UC can extend to the descending colon (left side colitis) or the entire colon (pancolitis). 2,3 Perianal fistulas and anal fissures are rare in UC. 2 The most consistent clinical manifestation of UC is the presence of blood and mucus that are mixed with stool, accompanied by lower abdominal cramping, which is most intense during bowel movements. The often subtle presentation in CD can lead to a delay in diagnosis. The gastrointestinal symptoms depend on the location, extent, and severity of involvement. In patients with ileocolonic involvement, abdominal pain is usually postprandial and may present in the periumbilical area, especially in children. Gastroduodenal CD presents with early satiety, nausea, emesis, epigastric pain, or dysphagia. Extensive small bowel disease causes diffuse abdominal pain, anorexia, diarrhea, and weight loss, and may result in lactose malabsorption. Colonic CD may mimic UC with a presentation of diarrhea with blood and mucus that is associated with crampy lower abdominal pain. Perianal disease is common, as are anal tags, deep anal fissures, and fistulae. Increasing abdominal cramping, distension, and emesis that are accompanied by borborygmi are signs of progression of the inflammatory process to localized stenosis with partial or complete obstruction. 4 Refractory IBD is persistent acute symptomatic disease despite anti-inflammatory therapy or as chronically active disease requiring continuous treatment for relief of symptoms. 5 Patients with IBD usually need continual medication and long-term follow-up. The medical management of IBD involves acute treatment of all inflammatory symptoms, followed by maintenance of remission. 5-aminosalicylic acid (5-ASA) agents, steroids, immunomodulatory therapy, biological therapy, antibiotics, and nutritional therapy are used alone or in combination to induce remission in active IBD. 6 The therapeutic approach is determined based on the severity of the symptoms and the degree of intestinal involvement. The most common treatments that are used in the maintenance of remission include 5-ASA agents, immunomodulatory therapy, and biological therapy. 6 Surgical management may be needed in poorly controlled or recurrent acute IBD cases. Canada has one of the highest incidences of IBD in the world. It is estimated that 200,500 Canadians have IBD. 7 The prevalence of UC in Canada has been estimated to be per 100,000 people, with 11.8 new cases per 100,000 people each year. 8 CD, which is more common in Canada, affects about per 100,000 people. The incidence is 13.4 per 100,000 people each year. 8 Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses 1

16 Assuming that 5% of IBD cases are those of moderate-to-severe disease refractory to conventional treatment, 9-11 then each year in Canada, approximately 8,500 patients will need a biological therapy. 1.2 Overview of Technology Biological therapies have changed the therapeutic approach to IBD, particularly for patients with severe and refractory disease. In the Drug Effectiveness Review Project drug class review of targeted immune modulators, three biologicals (etanercept, infliximab, adalimumab) are categorized as anti-tumor necrosis factor alpha (anti-tnf- ) drugs. 12 Etanercept (Enbrel, Amgen Canada Inc. and Wyeth Canada) is a recombinant fusion protein. Infliximab (Remicade, Schering Canada Inc) and adalimumab (Humira, Abbott Canada) are recombinant monoclonal antibodies that bind to human TNF Infliximab is a chimeric monoclonal antibody. Adalimumab consists entirely of human amino acid sequences. TNF is a key inflammatory cytokine and mediator of intestinal inflammation. The expression of TNF is increased in IBD. It has been shown that infliximab and adalimumab induce and maintain clinical response and remission in patients with active IBD and in patients with fistulizing disease The efficacy and effectiveness of etanercept in the treatment of IBD remain unclear because of a limited number of randomized controlled trials (RCTs) that focus on the assessment of this drug. It has been shown that during long-term treatment with infliximab, the development of anti-infliximab antibodies may contribute to an increased risk of infusion reactions and a decreased response to treatment. 21,22 Infliximab and adalimumab are increasingly being used in patients with IBD who have inadequate response to conventional therapy. The aims of this treatment are to improve symptom control and to reduce the need for hospitalization and surgery. In Canada, infliximab is approved for the treatment of all IBD indications including CD induction dosing (approval date June 6, 2001), 23 CD maintenance dosing (approval date February 2004), 24 fistulizing CD (approval date November 14, 2005), 25 pediatric CD (approval date October 26, 2006), 26 UC with inadequate response to conventional therapy (approval date March 10, 2006), 27 and UC maintenance therapy (approval date January 10, 2007). 28 Adalimumab is approved for CD (approval date July 5, 2007) 29, but not UC. Etanercept is not approved for CD or for UC. According to the Canadian Association of Gastroenterology and the Canadian Expert Drug Advisory Committee, infliximab is recommended for patients with moderate to severe CD who have continuing symptoms despite the use of conventional therapies, for those who cannot tolerate conventional therapy (including corticosteroids and immunosuppressive drugs), or for those who have fistulizing CD. 30,31 The Canadian Association of Gastroenterology guidelines indicate that patients who receive infliximab should also receive concomitant immunosuppressant therapy to reduce the formation of antibodies to infliximab, decrease the likelihood of infusion reaction, and increase the overall response. 31 Adalimumab may offer potential advantages over infliximab in terms of the elimination of infusion reactions and a possible reduction in the requirement for dose escalation over time. 32 The Canadian Expert Drug Advisory Committee recommends adalimumab for patients with moderate to severe active CD 2 Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses

17 who are refractory to or who experience contraindications to an adequate course of 5-ASA and corticosteroids and other immunosuppressive therapy. 33 The estimated annual drug costs for IBD patients who are on maintenance therapy with anti- TNF-α drugs vary from $23,000 to $38, ISSUE The volume of reimbursement requests to the publicly funded drug plans in Canada for infliximab and adalimumab from patients with CD or UC who are not responding to conventional therapy is increasing. These anti-tnf-α drugs are not listed as a general benefit in several jurisdictions. Therefore, reimbursement may be based on pre-set criteria or on case-bycase reviews. There is interest in improving this process and developing reimbursement criteria or updating existing criteria. As a result, more information is needed. In patients with CD, there is a need to determine when these anti-tnf-α drugs should or should not be used (earlier versus later in the disease course). In patients with UC, anti-tnf-α drugs are increasingly being used for maintenance therapy, but information is missing on their role for that purpose. There is a need to determine what distinguishes mild, moderate, and severe CD. There is also a need to determine whether disease severity or other prognostic factors are relevant for policy decisions. There is a need to determine if evidence is available regarding infliximab on the benefit- torisk ratio that is associated with dose escalation. There is also a need to determine if a maximum effective dose exists and whether there is benefit in switching to adalimumab. The impact of this drug on surgery also needs to be determined. There is a need to determine if a maximum dose of adalimumab exists. The impact of this drug on surgery also needs to be determined. There is a need to determine the effects of neutralizing antibodies to anti-tnf-α drugs on dosing requirements and harm risk. There is also a need to determine whether there are interventions to prevent the formation of such antibodies. Does maintenance treatment after infliximab induction prevent the formation of neutralizing antibodies? Findings from this health technology assessment (HTA) may serve in some jurisdictions as a platform for a pilot reimbursement program of anti-tnf-α drugs in patients with refractory IBD. As a result, this HTA project includes an intra-class (infliximab versus adalimumab or etanercept) and an inter-class (anti-tnf-α drugs versus conventional therapy) comparison. 3 OBJECTIVES The aims of this HTA are to evaluate the comparative clinical-effectiveness of anti-tnf-α drugs in patients with CD or UC who have an inadequate response to conventional therapy (including 5-ASA derivatives, immunosuppressant drugs [azathioprine, cyclosporine, mercaptopurine, and methotrexate] and corticosteroids) and to determine their economic value compared with that of conventional therapy and surgical interventions. Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses 3

18 Two sets of research questions are proposed for this HTA, each based on the specific IBD indication. For each set of questions, the report will be stratified to address the comparative clinical- (including benefit and harm) and economic-effectiveness for each indication. 3.1 Crohn s Disease How do anti-tnf-α drugs (adalimumab, etanercept, and infliximab) compare with each other, in terms of clinical- and cost-effectiveness for adult patients with refractory CD, including the luminal and fistulizing forms? How do anti-tnf-α drugs (including adalimumab, etanercept, and infliximab) compare with conventional therapy for patients with refractory CD in terms of clinical- and costeffectiveness? What are the benefits and harms that are associated with dose escalation with anti-tnf-α drugs? What potential exists that patients who have been treated with an anti-tnf-α drug could benefit or be harmed by switching to another anti-tnf-α drug? What is the optimal timing of anti-tnf-α treatment (early versus later in the course of the disease), and is there a group of patients who will benefit most from early aggressive treatment? Is there a group of patients who have CD that that respond to maintenance immunosuppressive therapy alone (after anti-tnf-α drug induction)? What is the harm associated with the formation of neutralizing antibodies to these agents? What is the effect of neutralizing antibody formation on dosing requirements? Are there interventions that can prevent the formation of neutralizing antibodies? What is the effect of anti-tnf-α drugs on clinical response, hospitalizations, surgery, clinical remission, and death? 3.2 Ulcerative Colitis How do anti-tnf-α drugs (adalimumab, etanercept, and infliximab) compare with each other, in terms of clinical- and cost-effectiveness for adult patients with refractory UC, including the luminal and fistulizing forms? How do anti-tnf-α drugs (including adalimumab, etanercept, and infliximab) compare with conventional therapy for patients with refractory UC in terms of clinical- and costeffectiveness? What are the benefits and harms associated with dose escalation with anti-tnf-α drugs? What potential exists that patients who have been treated with an anti-tnf-α drug could benefit or be harmed by switching to another anti-tnf-α drug? What is the optimal timing of anti-tnf-α treatment (early versus later in the course of the disease), and is there a group of patients who will benefit most from early aggressive treatment? Is there a group of patients who have UC that that respond to maintenance immunosuppressive therapy alone (after anti-tnf-α drug induction)? What is the harm associated with the formation of neutralizing antibodies to these agents? What is the effect of neutralizing antibody formation on dosing requirements? Are there interventions that can prevent the formation of neutralizing antibodies? 4 Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses

19 What is the effect of anti-tnf-α drugs on clinical response, hospitalization, surgery, clinical remission, and death? 4 CLINICAL REVIEW 4.1 Methods Literature searches A systematic search was undertaken to locate relevant clinical trials, cohort studies, and registries that focus on the assessment of infliximab (Remicade), adalimumab (Humira), or etanercept (Enbrel) for CD or UC. The search strategy was developed by an information specialist with input from the project team. The search underwent peer review by an information specialist from the Canadian Agency for Drugs and Technologies in Health (CADTH). All search results were imported into a Reference Manager Version 11 database for removal of duplicates, and title and abstract screening. The following bibliographic databases were searched through the Ovid interface: MEDLINE (1950 to present; In-Process & Other Non-Indexed Citations) and EMBASE (1988 to present). Parallel searches were run in PubMed (for non-medline records only), Wiley s Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register and HTA Database), and Thomson s BIOSIS Previews. A search strategy with controlled vocabulary and keywords was used to focus on Inflammatory Bowel Disease, Crohn s Disease or Ulcerative Colitis, and infliximab/remicade, adalimumab/humira, etanercept/enbrel, or anti-tumor necrosis factor alpha drugs. A methodological filter was applied to limit retrieval to clinical trials, cohort studies, registries, meta-analyses, systematic reviews, and HTAs. Retrieval was limited to the human population (clinical trials, cohort studies, or registries only) and to 1995 to the present because the anti- TNF-α drugs of interest were approved or being studied as treatment options for the conditions of interest from the late 1990s onwards. No language restrictions were used. Appendix 1 shows the detailed search strategy. Grey literature (literature that is not commercially published) was identified by searching the websites of HTA and related agencies and their associated databases, pharmaceutical manufacturers, and clinical trial registers. The websites of professional associations such as the Canadian Association of Gastroenterology, the American College of Gastroenterology, and the American Gastroenterological Association were searched for relevant evidence (including conference abstracts from 2006 to the present, if available). Google and AlltheWeb search engines were used to search for additional materials and information. These searches were supplemented by reviewing the bibliographies and abstracts of key papers and conference proceedings. Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses 5

20 OVID and PubMed AutoAlerts were set up to send monthly updates with any new literature, with the last automatic updates received on September 1, Quarterly updated searches were performed on The Cochrane Library, with the last updated search performed on November 1, 2008 (Issue 4, 2008) Selection criteria a) Inclusion criteria Studies that were suitable for inclusion were selected from those identified as potentially relevant during the search strategy, using selection criteria. Study design Randomized and non-randomized clinical trials of any duration and observational studies primarily designed to evaluate clinical efficacy, effectiveness, and adverse effects of infliximab, adalimumab, or etanercept; before-after trials and single-arm cohort studies if they evaluated immunogenicity of an anti-tnf-α drug, if they reported benefits and harms from switching from one anti-tnf-α drug to another, or if they evaluated benefits and harms of dose escalation. Population Adults who are aged 18 years and older with luminal or fistulizing CD who are not responding to conventional treatment Adults who are aged 18 years and older with luminal or fistulizing UC who are not responding to conventional treatment. Interventions Infliximab Adalimumab Etanercept. Comparators Intra-class comparison of placebo, infliximab, adalimumab, and etanercept Inter-class comparison of conventional therapy (including 5-ASA derivatives [5-ASA, olsalazine, sulfasalazine], immunosuppressant drugs [azathioprine, cyclosporine, mercaptopurine, methotrexate] and corticosteroids) Surgical interventions, particularly colectomy for UC. Outcomes Clinical response in CD: A decrease in Crohn s Disease Activity Index (CDAI) 35,36 of 70 points, or a decrease in CDAI of 70 to 100 points and a 25% improvement from the baseline (Appendix 11) Clinical response in UC: A decrease in Disease Activity Index (or Mayo score) 37,38 of three points or more from the baseline, which should be at least 30% of the baseline score; and a decrease in the subscore for rectal bleeding of one point or more, or an absolute subscore for rectal bleeding of 0 or 1 (Appendix 12) Data on clinical response that were collected using other instruments and definitions (such as the Harvey-Bradshaw activity index) 6 Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses

21 Clinical remission in CD: CDAI = 150 points or CDAI is less than 150 points and it is decreased by 50 to 100 points Clinical remission in UC: Mayo score is 2 or less with no individual subscore greater than 1 Data on clinical remission that were collected using other instruments and definitions (such as Truelove-Witts score, Ulcerative Colitis Symptoms Score, and Seo index) Hospitalization Need for dose escalation Surgery Adverse events (AEs) (including reaction to injection) Serious adverse events (including lymphoma or other cancers) Death. b) Exclusion criteria Recruiting for study has not finished Study published only the baseline characteristics Selection method Two reviewers (NA, KC) independently screened the titles and abstracts for relevance using a predefined checklist (Appendix 2). Kappa statistics for inter-rater agreement was 95%. The discrepancies between reviewers were discussed until consensus was reached. The full texts that were associated with any relevant titles and abstracts were retrieved and assessed for inclusion. Two reviewers (NA, KC), using predetermined criteria (Appendix 3), made inclusion and exclusion decisions independently. Any discrepancies between reviewers were discussed until consensus was reached Data extraction strategy Data from all included studies were extracted. The predefined data extraction forms appear in Appendix 4. Relevant data were directly abstracted from the article. In some cases, data were abstracted from the graphs. The data extraction was performed by one reviewer (NA). A second reviewer (KC) verified all the extracted data. Any discrepancies were discussed until consensus was reached Strategy for validity assessment The methodological quality of all included clinical trials and observational studies was assessed using the Jadad 39 and Newcastle-Ottawa 40 scales respectively (Appendices 5 and 6). One reviewer (NA) assessed all the included studies for methodological quality. A second reviewer (KC) checked for accuracy. The quality score was used to summarize and rank the studies. No sensitivity or subgroup analyses were performed based on the quality of the included studies Data analysis methods For each study question, evidence tables containing all the information that was abstracted from eligible studies were created. When two or more comparable studies were identified, a pooled estimate of effect was obtained in a meta-analysis. Comparability of the studies was assessed Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses 7

22 after reviewing the population, interventions, and outcome measures. Review Manager 5 was used to synthesize the data. A fixed-effects model was used for pooled estimates and confidence intervals, because the number of the studies that were included in each meta-analysis was too low to evaluate between-trial heterogeneity. The relative risk (RR) was used to summarize effect sizes for all dichotomous outcome measures. For the studies that were not comparable in terms of population, interventions, or outcome measures, a narrative synthesis is provided. The levels of significance for the comparisons of anti-tnf-α drugs with placebo were computed when they were not reported. 4.2 Results Quantity of research available A total of 2,542 citations were identified in the systematic search. Fifteen articles were identified from other sources. Based on their irrelevance to the questions of interest, 2,103 citations were excluded during the title and abstract review. The full text of the remaining 454 articles that fulfilled the inclusion criteria was retrieved. Of these articles, 407 did not meet the eligibility criteria and were excluded during full text screening. This led to the inclusion of 20 RCTs and 17 observational studies or single-arm trials that met all the inclusion criteria. Appendix 7 shows the QUOROM flowchart of the process that was used to select studies. The list of the excluded studies and the reasons for exclusion appears in Appendix Study characteristics A total of 47 citations reporting 20 RCTs 17-20,37,41-66 and 17 observational and uncontrolled studies 22,53,67-81 were included. All the RCTs had a parallel group design. Four studies were openlabel, single-arm trials. 74,75,77,79 Of the remaining 13 cohort studies, seven studies used a prospective design, 22,53,68,69,72,78,80 and the remaining six studies used a retrospective design. 67,70,71,73,76,81 Five cohort studies 69,70,78,80,81 and one RCT 52 were published as abstracts only. The remaining studies had at least one full peer-reviewed publication. Infliximab was used as the treatment for patients with CD in eight RCTs 18,41-43,45,49,51,52 (total number of participants 1,091; range 36 to 335) and 10 observational and uncontrolled studies 22,53,67-73,81 (total number of participants 1,402; range 12 to 614), and for patients with UC in six RCTs 37,37,59,63,64,66 (total number of participants 847; range 11 to 384) and one cohort study 80 (90 participants). Adalimumab was the study treatment in patients with CD in four RCTs 17,19,20,54 (total number of participants 1,477; range 299 to 499) and five observational and uncontrolled studies (total number of participants 157; range 15 to 36). One cohort study 79 (10 participants) reported the use of adalimumab in UC. One RCT 58 (43 participants) evaluated the effects of etanercept in patients with CD. Patient inclusion and exclusion criteria in individual studies varied. In general, participants were adult patients with active CD or UC that was poorly controlled or for whom previous conventional treatment had failed (Appendix 9). In most of the full articles, predefined exclusion criteria were reported. Most of the trials excluded patients with safety risks. 8 Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses

23 4.2.3 Data analyses and synthesis a) Crohn s disease Clinical-effectiveness of anti-tnf-α drugs No head-to head trials comparing the effectiveness of infliximab with adalimumab or with etanercept in CD were identified, nor were there any studies directly comparing the anti-tnf-α drugs with conventional therapy in refractory CD. A combined immune-suppression therapy (including infliximab) was compared with conventional therapy among newly diagnosed patients in one RCT. 41 In this open-label trial, patients were assigned to receive infliximab 5 mg/kg at weeks 0, 2, and 6 with azathioprine or conventional treatment with corticosteroids, followed by azathioprine and then by infliximab. Infliximab: Of six included placebo-controlled trials assessing the effectiveness of infliximab in the treatment of CD, three studies used short-term regimens of infliximab to induce disease remission, 42,43,45 and three RCTs evaluated the effectiveness of long-term infliximab in maintenance of remission. 18,49,51 Induction therapy: In Targan et al. s study, 42 patients with refractory CD used single-dose infliximab in a 12-week trial. The patients were randomly assigned to receive infliximab 5 mg/kg (27 participants), 10 mg/kg (28 participants), 20 mg/kg (28 participants), or placebo (25 participants). The primary study outcome was a 70-point response (reduction of 70 points or more in the CDAI score). At week 4, 65% of the patients who were treated with infliximab and 17% of patients on placebo achieved a response (P < 0.001). Infliximab-treated patients had a significantly higher remission rate (33%) compared with those on placebo (4%, P = 0.005). No doseresponse relationship was seen. At the end of week 12, the overall response rates were 41% and 12% in the infliximab and placebo groups respectively (P = 0.008). Overall, 24% of the patients in the infliximab group achieved clinical remission, compared with 8% of the patients in the placebo group at the end of the study (Table 2). This difference was not statistically significant (P = 0.31). Lemann et al. 43 conducted a 52-week multi-centre trial in France to compare the effectiveness of infliximab and placebo in steroid-dependent patients with CD. Participants were assigned to receive infliximab at a dose of 5 mg/kg (57 participants) or placebo (58 participants), on weeks 0, 2, and 6. All patients were treated with azathioprine or 6-mercaptopurine (6-MP). The primary outcome was remission with discontinuation of steroids. Infliximab was found to be superior to placebo in terms of steroid-free remission at week 24 (57% versus 29%, P = 0.003) and at week 52 (40% versus 22%, P = 0.04) (Table 2). This study also showed a lower steroid-resistance rate among infliximab users. In Present et al. s study, CD patients with one or more draining perianal or abdominal fistulas were randomized to receive infliximab 5 mg/kg (31 participants), infliximab 10 mg/kg (32 participants), or placebo (31 participants). Patients received their assigned treatments on weeks 0, 2, and 6 (duration of follow-up was 18 to 34 weeks).the primary end point was fistula response rate. Overall, 68% and 56% of the patients who were assigned to receive infliximab 5 mg/kg and 10 mg/kg respectively, and 26% in the placebo group achieved the primary outcome of the study (Table 3). Compared with the placebo group, the rates of fistula response were significantly greater in the infliximab 5 mg/kg (P = 0.002) and infliximab 10 mg/kg (P = 0.02) groups. There was no statistically significant difference between the two infliximab arms (P = 0.35). A complete closure Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses 9

24 of the draining fistulas was seen in significantly higher proportions of the patients on infliximab 5 mg/kg (55%) and infliximab 10 mg/kg (38%) than the placebo group (13%, P = and P = 0.04 respectively) (Table 4). The median time to response was shorter among the infliximab users (two weeks) compared with the patients who were receiving placebo (six weeks). Maintenance therapy: Hanauer et al. s study, 18 which is known as ACCENT I, evaluated the effectiveness of infliximab maintenance therapy in patients who had responded to one dose of infliximab. The response to induction therapy was measured two weeks after infusion. The responders were then randomly assigned to receive infliximab 5 mg/kg at weeks 2 and 6, and every eight weeks thereafter (113 participants); infliximab 5 mg/kg at weeks 2 and 6, and 10 mg/kg every eight weeks (112 participants); or placebo at weeks 2, 6, and every eight weeks (110 participants). Patients were followed until week 46. Infliximab regimens were found to be significantly superior to placebo in maintenance of remission and response at weeks 30 and 54 (Tables 1 and 2). Sands et al. 49 examined the effects of infliximab maintenance therapy in the treatment of adult patients with one or more draining fistulas in the ACCENT II trial. After three doses of induction therapy with infliximab 5 mg/kg on weeks 0, 2, and 6, the response to treatment was assessed, and the responders were randomized to receive infliximab 5 mg/kg (96 participants) or placebo (99 participants) every eight weeks, until week 54. At the end of the study, 42% of the infliximab users showed a response to treatment, compared with 23% of the placebo group (P = 0.001). Complete absence of draining fistulas was seen in a higher proportion of patients in the infliximab group than those in the placebo group (P = 0.009) (Tables 3 and 4). When the data from the two studies 18,49 were pooled, the patients on infliximab 5 mg/kg had a 2.75-times higher clinical response than the patients in the placebo group (pooled RR: 2.75, 95% CI 1.72 to 4.40; P < ) (Appendix 10 Graph 1). In Rutgeerts et al. s study, 51 the effectiveness of infliximab was compared with that of placebo in the maintenance of remission in CD. The patients with an initial response to open-label treatment with infliximab 10 mg/kg were given infliximab at a dose of 10 mg/kg (37 participants) or placebo (36 participants) every eight weeks (four infusions). At the last infusion (week 36), a significantly higher proportion of the patients in the infliximab group had maintained the response to treatment (72%) compared with the patients in the placebo group (44%, P = 0.018). There was no statistically significant difference in response rates between the two treatment groups eight weeks after the last infusion (62% and 37% in infliximab and placebo groups respectively; P = 0.16). This study showed an increasing pattern for the clinical remission rates in the infliximab group throughout the maintenance therapy, as opposed to the decreasing pattern for the remission rates in the placebo group (Table 2). At week 44, 52.9% patients in the infliximab group and 20% of the patients in the placebo group were in remission (P = 0.02). The pooled analysis of the data from ACCENT I 18 and Rutgeerts et al. s study 51 showed that the response and remission rates were significantly higher in the infliximab 10 mg/kg maintenance therapy group than in the placebo group (pooled RR for response rate: 2.59, 95% CI 1.85 to 3.62; P < and pooled RR for remission rate: 2.80, 95% CI 1.83 to 4.30; P < ). There was no statistically significant heterogeneity between the studies (Appendix 10 Graphs 2 and 3). 10 Anti-TNF-α Drugs for Refractory Inflammatory Bowel Disease: Clinical- and Cost-Effectiveness Analyses