CIOMS Management of Safety Information from Clinical Trials CIOMS Management of Safety Information from CIOMS publications may be obtained directly from CIOMS, c/o World Health Organization, Avenue Appia, 1211 Geneva 27, Management of Switzerland or by e-mail to [email protected] Both CIOMS and WHO publications are distributed by the Safety Information World Health Organization, Marketing and Dissemination, Avenue Appia, 1211 Geneva 27, Switzerland and are available from Clinical Trials from booksellers through the network of WHO sales agents. A list of these agents may be obtained from WHO by writing to the above address. Report of CIOMS Working Group VI Price: CHF 40.– Geneva 2005 GGROUP6_COVERROUP6_COVER DDEF.inddEF.indd 1 77.8.2007.8.2007 112:17:502:17:50 Management of Safety Information from Clinical Trials Report of CIOMS Working Group VI Geneva 2005 ggroup6_PH.inddroup6_PH.indd 1 77.8.2007.8.2007 112:19:132:19:13 Copyright © 2005 by the Council for International Organizations of Medical Sciences (CIOMS) ISBN 92 9036 079 8 ggroup6_PH.inddroup6_PH.indd 2 77.8.2007.8.2007 112:19:152:19:15 Acknowledgements he Council for International Organizations of Medical Sciences (CIOMS) T gratefully acknowledges the contributions of the members of CIOMS Working Group VI on the Management of Safety Information from Clinical Trials as well as the drug regulatory authorities, pharmaceutical companies and other organizations and institutions which supported the work that resulted in this publication. Hard work, drafting and redrafting of papers, their reviews and a number of debates in the Working Group required patience, motivation and active collaboration from all members. CIOMS acknowledges especially the co-chairs, Drs. Wendy Stephenson and Gottfried Kreutz, for their capable leadership, and Ms Linda Hostelley, the secretary of the group. The editorial group, comprised of Drs. Gerald Dal Pan, Arnold J. Gordon, Marianne Keisu, Siddika Mithani, and Wendy Stephenson, merits special mention and thanks. CIOMS also wishes to express special appreciation to Dr. Gordon, who as chief editor of the fi nal report assured the quality of the publication. CIOMS and the Working Group are thankful for important input received on several topics from many senior experts outside the Group who reviewed the entire manuscript and made valuable suggestions: Drs. Ric Day (University of South Wales, Australia), Frank Rockhold and Rita Patwardhan (GlaxoSmithKline, US), and Patrick Waller (Consultant, UK). Members of the US and EU pharmaceutical industry associations (PhRMA and EFPIA) also provided very helpful detailed comments and suggestions; special thanks are due to Drs. Barry Arnold (AstraZeneca, UK) and Brian Edwards (Barnett Parexel, UK) and to Cindy Engle (GlaxoSmithKline, US) for their roles in syn- thesizing these contributions. Dr. Susan Ellenberg (FDA, US) contributed her expertise to material covering Data and Safety Monitoring Boards. Dr. Susan Sacks (F. Hoffmann-La Roche Ltd.) provided key information on sources of 3 ggroup6_PH.inddroup6_PH.indd 3 77.8.2007.8.2007 112:19:152:19:15 epidemiological and related databases. Thanks are also due to a number of colleagues from pharmaceutical companies who completed the CIOMS VI questionnaire (see Appendix 3). Finally, we are grateful to Meghan McLaren (Health Canada) for her administrative assistance in preparing the draft and fi nal documents. Geneva, April 2005 Juhana E.Idänpään-Heikkilä, MD. PhD Secretary-General, CIOMS 4 ggroup6_PH.inddroup6_PH.indd 4 77.8.2007.8.2007 112:19:152:19:15 Dedication his work is dedicated to the many thousands of patients and other T volunteers who generously participate in clinical research programs so vital for the development and advancement of medicines. 5 ggroup6_PH.inddroup6_PH.indd 5 77.8.2007.8.2007 112:19:162:19:16 ggroup6_PH.inddroup6_PH.indd 6 77.8.2007.8.2007 112:19:162:19:16 Table of Contents Page VISION ................................................................................................ 13 PREFACE ............................................................................................ 15 I INTRODUCTION AND OVERVIEW .............................................. 19 a. Rationale for the CIOMS VI Project .................................................... 21 b. Results of the CIOMS VI Survey on Company Practices .................... 25 c. Areas Covered by the CIOMS VI Project ............................................. 26 • Terminology and defi nitions ...................................................... 27 • Ethical aspects of clinical trials ................................................. 27 • Overall pharmacovigilance/ risk management system ............... 27 • Collection and proper management of safety data .................... 28 • Evaluation of safety data ........................................................... 28 • Statistical analysis of safety data ............................................... 29 • Regulatory reporting and communication to others of safety information during clinical trials ................................ 29 d. Limitations of Clinical Trials for Understanding Safety ................ 30 e. Scope of the Project ........................................................................ 32 II ETHICAL CONSIDERATIONS FOR CLINICAL TRIAL SAFETY MANAGEMENT ................................................................ 35 a. Background .................................................................................... 37 b. The Stakeholders ............................................................................ 39 • Patients ...................................................................................... 39 • Regulatory Authorities and the Public Health Community ....... 40 • Investigators .............................................................................. 41 • IECs and IRBs ........................................................................... 41 • Data and Safety Monitoring Boards .......................................... 43 • Pharmaceutical Companies and Their Representatives ............. 44 7 ggroup6_PH.inddroup6_PH.indd 7 77.8.2007.8.2007 112:19:162:19:16 c. Evolving Regulatory and Societal Demands .................................. 44 • Privacy and Confi dentiality of Personal Data ............................ 45 • Informed Consent ...................................................................... 46 • Transparency in Availability of Clinical Trial Results ............... 47 • Other Issues ............................................................................... 51 III GOOD PHARMACOVIGILANCE AND RISK MANAGEMENT PRACTICES: SYSTEMATIC APPROACH TO MANAGING SAFETY DURING CLINICAL DEVELOPMENT ........................ 53 a. Introduction .................................................................................... 55 b. Principles of a Systematic Approach .............................................. 57 • Begin early ................................................................................ 57 • Establish a procedure ................................................................ 57 • Establish a Multidisciplinary Safety Management Team (SMT) .............................................................................. 58 • Establish a project management function .................................. 59 • Determine background data ...................................................... 60 • Ensure accessibility of data ....................................................... 60 • Develop a proactive approach ................................................... 60 • Establish timeframes and milestones ........................................ 61 • Decision making ........................................................................ 62 • Advisory bodies ........................................................................ 62 c. Components of a Development Risk Management Plan (DRMP) . 63 d. Role of Epidemiology ..................................................................... 67 e. Specifi c Issues that Should Always be Considered ........................ 70 • Cardiac electrophysiology ......................................................... 70 • Hepatotoxicity ........................................................................... 71 • Drug-Drug and Food-Drug interactions .................................... 71 • Immunogenicity ......................................................................... 71 • Bone marrow toxicity ................................................................ 72 • Potential for reactive metabolite formation and hypersensitivity ................................................................... 72 f. Conclusion ...................................................................................... 72 8 ggroup6_PH.inddroup6_PH.indd 8 77.8.2007.8.2007 112:19:162:19:16 IV COLLECTION AND MANAGEMENT OF SAFETY DATA DURING CLINICAL TRIALS ......................................................... 75 a. Introduction .................................................................................... 77 b. Who? .............................................................................................. 79 c. What? .............................................................................................. 81 • General Principles ..................................................................... 81 • Causality Assessment ................................................................ 84 • Diagnoses vs Signs and Symptoms ..........................................