CIOMS Current Challenges in Pharmacovigilance: Pragmatic Approches CIOMS Current CIOMS publications may be obtained directly from CIOMS, c/o World Health Organization, Avenue Appia, 1211 Geneva 27, Current Challenges Switzerland or by e-mail to [email protected] in Pharmacovigilance: Both CIOMS and WHO publications are distributed by the World Health Organization, Marketing and Dissemination, Avenue Appia, 1211 Geneva 27, Switzerland and are available Pragmatic Approaches 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 V Price: CHF 30.– GenevaGeneva 20012005 GGroup5_Pharmacovigilance-cov.inddroup5_Pharmacovigilance-cov.indd 1 99.8.2007.8.2007 110:08:520:08:52 Current Challenges in Pharmacovigilance: Pragmatic Approaches Report of CIOMS Working Group V Geneva 2001 Copyright # 2001 by the Council for International Organizations of Medical Sciences (CIOMS) ISBN 92 9036 074 7 Printed in Switzerland Acknowledgements he Council for International Organizations of Medical Sciences is T grateful to the members of CIOMS Working Group V, on Current Challenges in Pharmacovigilance: Pragmatic Approaches, and to the drug regulatory authorities, pharmaceutical companies and other organizations represented, for their patience and hard work in bringing this project to its successful conclusion. Special thanks are due to the co-chairs, Drs. Murray Lumpkin and Win Castle, for their capable leadership, to Ms. Susan Roden, the secretary of the group, and to the editorial committee comprised of Drs. Lumpkin and Castle along with Dr. Arnold J. Gordon and Dr. Hugh Tilson. We wish to express our special thanks to Dr. Gordon, who as chief editor of the interim and final full reports, collected, coordinated and edited the contributions of individual members and assured the quality of the document. The Working Group is thankful for important input received on several topics from many individuals outside the Group. Particular thanks are due to Dr. James Buchanan and Ms. Linda Hostelley for their thoughtful review of the entire manuscript and for their valuable suggestions, and to Mr. Richard Kingham for his perspective on the use of the Internet; thanks are also given to more than 40 regulatory and company colleagues who completed CIOMS questionnaires whose results helped formulate the content of some of the chapters. 3 Dedication his report is dedicated to the memory of the Working Group’s T esteemed colleague and friend, Dr. Christian Benichou, who sat on all CIOMS drug safety Working Groups from their inception as a representative from pharmaceutical companies. His experience, intelligence and commitment were indispensable to their success. His important contributions to the field of pharmacovigilance are extensive and have left an indelible mark, not only through his work with CIOMS and the ICH process, but from his many publications and participation in international meetings and educational programs. We hope that the results of CIOMS V meet the high ethical and professional standards he set for himself. He will be sorely missed by all who knew him. 4 Table of Contents Page VISION ............................................................... 9 PREFACE ............................................................. 11 I INTRODUCTION ..................................................... 15 a. Background ...................................................... 17 b. Privacy and the Protection of Personal Health Data ......... 18 c. Overview ......................................................... 19 II SOURCES OF INDIVIDUAL CASE REPORTS ..................... 27 a. Introduction ...................................................... 29 b. Spontaneous Reports from Persons Other than Healthcare Professionals ............................... 31 c. Literature ......................................................... 39 d. The Internet ...................................................... 50 e. Solicited Reports ................................................ 57 f. Aspects of Clinical Trial Reports ............................... 62 g. Epidemiology: Observational Studies and Use of Secondary Databases ........................... 67 h. Disease-Specific Registries and Regulatory ADR Databases .. 72 i. Licensor-Licensee Interactions .................................. 76 III GOOD CASE MANAGEMENT PRACTICES ........................ 81 a. Introduction: Clinical Evaluation of Cases .................... 83 b. Assessing Patient and Reporter Identifiability ................ 90 c. Criteria for Seriousness ......................................... 99 d. Criteria for Expectedness ....................................... 109 e. Case Follow-up Approaches .................................... 124 f. Role of Narratives ............................................... 133 5 IV GOOD SUMMARY REPORTING PRACTICES: PSURs RECONSIDERED ............................................ 141 a. Introduction ...................................................... 143 b. Results of a Survey on PSUR Workloads ..................... 145 c. Proposals for PSUR Content Modification ................... 148 d. Proposals Relating to Frequency and Timing of Reporting .................................................. 153 e. Miscellaneous Proposals for Managing PSURs ............... 158 V DETERMINATION AND USE OF POPULATION EXPOSURE DATA ................................................... 163 a. Introduction ...................................................... 165 b. Periodic Safety Update Reports and Exposure Data Sources ................................. 167 c. Technical Considerations ....................................... 169 d. Spontaneous Reporting and Patient Exposure ................ 175 e. Real Examples of Denominator Determination and Use ..... 179 f. Patient-Exposure and Measurements of Risk ................. 181 VI CLINICAL SAFETY REPORTING REGULATIONS: AN OVERVIEW ...................................................... 185 a. Introduction ...................................................... 187 b. Basis for Comparison of Regulations .......................... 188 c. Current State of Affairs ......................................... 190 d. Recommendations ............................................... 191 e. Conclusion ....................................................... 193 VII SUMMARY OF PROPOSALS ....................................... 195 VIII APPENDICES ........................................................ 217 1. The Erice Declaration on Communicating Drug Safety Information .................................... 219 2. Membership and Process of CIOMS Working Group V ..... 221 6 3. Available Bibliographic Databases Suitable for Identifying Reports of Adverse Drug Reactions ........... 223 4. Survey Research on Standardizing Seriousness and Expectedness ............................................. 229 5. List of Adverse Event/Reaction Terms to be Considered Always ‘Serious’ ................................ 243 6. Some Regulatory Definitions of Expectedness ................ 291 7. Lists of Data Elements that Determine whether Follow-up Information is Needed .......................... 293 8. Example of a Standard Narrative Template ................... 297 9. Examples of Acceptable and Unacceptable Company Clinical Evaluation Comments in Case Narratives ........ 299 10. Basic Requirements for PSURs ................................ 301 11. Results of a Survey of Companies on Periodic Safety Reporting ............................................. 307 12. Sample of a Simplified PSUR .................................. 323 13. Sample of a Summary Bridging Report for PSURs .......... 327 14. Sample PSUR Executive Summary ............................ 333 15. Results of a Survey on Patient Exposure (Denominator) Data ......................................... 335 16. Sources of Denominator Data .................................. 349 17. Selected Bibliography on Patient Exposure Data ............. 355 18. Information Required for Expedited Reporting in the Mid-1980’s ............................................. 359 19. Summary of Regulations for Expedited Reporting as of 2000 ..................................................... 361 A. Pre-Marketing ................................................ 362 B. Post-Marketing (Outside the EU) ........................... 364 C. Post-Marketing in the EU ................................... 367 20. Existence of PSUR Requirements as of 2000 .................. 369 IX INDEX ................................................................ 373 7 Vision Over more than a dozen years of fruitful collaboration, the CIOMS Working Groups on drug safety have evolved an exciting dynamic vision: to enhance systems that advance the public health, world-wide, through better assurance of the safety of medicinal products. From the beginning, the Groups have been dedicated to focussing on the processes for detection and management of potential problems with drugs as quickly and efficiently as possible, especially in the post-approval environment. The CIOMS V Working Group, as its predecessors, was committed to finding areas for simplification, clarification, and harmonization of practices on topics that are inadequately or never addressed by regulations or guidelines. Our vision once again is that a single set of recommended ‘‘best practices’’ will lead to enhanced public health protections in the area of drug safety by ensuring proper focus on substantive