473_1Page-Cover_TechReport_Amendment.ai 2/9/2009 3:28:08 PM Canadian Agency for Agence canadienne Drugs and Technologies des médicaments et des in Health technologies de la santé technology report HTA Granulocyte-Colony Stimulating Issue 115 Factor for Antiviral-Associated December 2008 Neutropenia: Systematic Review *An amendment was made in February 2009 and Economic Evaluation Supporting Informed Decisions 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 600-865 Carling Avenue Ottawa ON Canada K1S 5S8 Tel.: (613) 226-2553 Fax: (613) 226-5392 Email: [email protected] or downloaded from CADTH’s website: http://www.cadth.ca Cite as: Dryden DM, Fassbender K, Doucette K, Tandon P, Milne A, Vandermeer B, Durec T. Granulocyte-colony stimulating factor for antiviral-associated neutropenia: Systematic review and economic evaluation [Technology report number 115]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2008. 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 – 2008 National Library of Canada ISBN: 978-1-897465-78-3 (print) ISBN: 978-1-897465-79-0 (online) H0473 – December 2008 PUBLICATIONS MAIL AGREEMENT NO. 40026386 RETURN UNDELIVERABLE CANADIAN ADDRESSES TO CANADIAN AGENCY FOR DRUGS AND TECHNOLOGIES IN HEALTH 600-865 CARLING AVENUE OTTAWA ON K1S 5S8 Canadian Agency for Drugs and Technologies in Health Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Donna M. Dryden, PhD1 Konrad Fassbender, PhD2 Karen Doucette, MD, MSc, FRCPC3 Puneeta Tandon, MD, MSc, FRCPC4 Andrea Milne, BScN1 Ben Vandermeer, MSc1 Tamara Durec, BSc Pharm, MLIS1 December 2008 1 University of Alberta Evidence-based Practice Center, Edmonton, AB 2 Division of Palliative Care Medicine, Department of Oncology, University of Alberta, Edmonton, AB 3 Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, AB 4 Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB Reviewers These individuals kindly provided comments on this report: External Reviewers Tanya Horsley, PhD Peter Ghali, MD FRCPC MSc(Epid) Adjunct Faculty Assistant Professor of Medicine Epidemiology and Community Medicine McGill University Health Centre University of Ottawa Montréal, QC Ottawa, ON Kevork M Peltekian, MD David Robinson, PhD Associate Professor, Medicine Associate Professor Dalhousie University Laurentian University Halifax, NS Sudbury, ON Rick Audas, BBA MBA MA PhD Assistant Professor Memorial University St. John’s, NL CADTH Peer Review Group Reviewers Chris Skedgel, MDE Jeffrey Barkun, MD MSc FRCSC Research Health Economist Chairman, Division of General Surgery Department of Medicine McGill University Health Centre Dalhousie University Montréal, QC Halifax, NS Industry: Amgen Canada Inc. was provided with an opportunity to comment on an earlier version of this report. 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. i Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation Authorship Donna Dryden coordinated the project, selected trials, extracted data, performed quality assessment, summarized and interpreted data, and contributed to writing all sections of the report. Konrad Fassbender, the lead for the economic analysis, developed the methods for the economic analysis; selected studies; extracted, tabulated, and analyzed data; and wrote the economic sections of the report. Karen Doucette, a content expert in clinical medicine and hepatitis C, provided guidance on the development of the clinical and economic review methods, interpreted data, and contributed to writing all sections of the report. Puneeta Tandon, a content expert in clinical medicine and hepatitis C, provided guidance on the development of the clinical and economic review methods, interpreted data, and contributed to writing all sections of the report. Andrea Milne selected trials, extracted data, performed quality assessment, summarized data, and contributed to writing and formatting all sections of the report. Ben Vandermeer performed the statistical analyses, provided methodological and statistical advice, and contributed to writing the analysis and results section of the report. Tamara Durec designed and executed the literature search strategies, wrote the associated search strategy section of the report and appendix, and managed the bibliographic software. All authors contributed to the revision of the report. Acknowledgements The authors are grateful to Elizabeth Sumamo, Carol Spooner, Jennifer Seida, Kate O’Gorman, and Mohammad Karkhaneh for their assistance with the clinical review and to Lisa Tjosvold for her assistance with the literature search strategy. Conflicts of Interest Karen Doucette received funding for consulting from Hoffman-La Roche Ltd. Schering-Plough Canada, and Astellas Pharma Inc.. Puneeta Tandon received funding in-kind from Novartis Pharmaceuticals Canada Inc. for conducting research. Funding received for both authors was unrelated to this topic. All other authors declared no conflict of interest. Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: ii Systematic Review and Economic Evaluation iii Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia: Systematic Review and Economic Evaluation EXECUTIVE SUMMARY Issue In Canada, the standard therapy for hepatitis C is pegylated interferon in combination with ribavirin. The goal of antiviral therapy is to achieve a sustained virological response (SVR), which is thought to represent a clinical cure. Given the appropriate dose and duration of pegylated interferon and ribavirin therapy, 42% to 46% of genotype 1 and 72% to 80% of genotype 2 or 3 patients will achieve SVR. To obtain optimal response rates, maximal treatment adherence to pegylated interferon and ribavirin is required. Side effects have resulted in the need to reduce the dose or discontinue therapy in up to 30% of patients. In clinical trials, neutropenia, a hematological disorder characterized by an abnormally low number of neutrophils (a type of white blood cell), is the most common reason for pegylated interferon dose reduction. The standard of care for controlling neutropenia is a dose reduction of pegylated interferon. To maintain full-dose antiviral therapy, the use of granulocyte-colony stimulating factor (G-CSF) has been proposed as a means to control neutropenia. There is uncertainty about the cost- effectiveness of G-CSF in comparison with dose reduction. Objectives The aim was to evaluate the clinical efficacy, safety, and cost-effectiveness of G-CSF (filgrastim or pegfilgrastim) for the treatment of antiviral-associated neutropenia in adults with hepatitis C. To achieve these objectives, the following research questions were addressed: • What is the clinical-effectiveness of G-CSF in improving clinical markers (neutrophil count), patient outcomes (SVR, infection, survival), and health-related quality of life compared with interferon dose reduction or treatment discontinuation? • What, if any, differences in harm are there between G-CSF monotherapy and G-CSF plus epoetin (or darbepoetin) combination therapy? • What is the cost-effectiveness of G-CSF, and what is the impact on health resources of funding G-CSF compared with interferon dose reduction or treatment discontinuation? • Are there specific reimbursement criteria (for example, disease severity, hepatitis C virus genotype, type of interferon used) that would allow the optimal use of G-CSF in this population? Clinical Review Methods: A systematic review was conducted to identify controlled trials and observational studies that assessed the effect of G-CSF or dose reduction strategies to control neutropenia in treatment- naïve adults with hepatitis C being treated with combination interferon and ribavirin. The outcomes were neutrophil count, early virological response, SVR, health-related