Practical Aspects of Signal Detection in Pharmacovigilance

1 Geneva 2010 CIOMS Practical Aspects of Signal Detection in Pharmacovigilance 2010 CIOMS publications may be obtained directly from CIOMS, c/o World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland or by e-mail to CIOMS and WHO publications are distributed by the World Health Organization, Marketing and Dissemination, Avenue Appia, 1211 Geneva 27, Switzerland and are available from booksellers through the network of WHO sales list of these agents may be obtained from WHO by writing to the above of SignalDetection inPharmacovigilanceReport of CIOMS Working Group 11 11:11 Practical Aspects OF Signal Detection IN PHARMACOVIGILANCER eport of CIOMS Working Group VIIIG eneva 11 11.

2 12 Copyright 2010 by the Council for InternationalOrganizations of Medical Sciences (CIOMS)ISBN 92 9036 082 11 11:123 AcknowledgementsT he Council for International Organizations of Medical Sciences (CIOMS) gratefully acknowledges the contributions of the members of the CIOMS Working Group VIII on Practical Aspects of Signal Detection in Pharmacovigilance . Moreover, CIOMS recognizes the generous support of the drug regulatory authorities, pharmaceutical companies and other organizations and institutions which provided their expertise and the resources that resulted in this publication.

3 Each member participated actively in the discussions, drafting and redrafting of texts and their review, which enabled the Work-ing Group to bring the entire project to a successful thanks especially those members who chaired the meetings of the Work-ing Group VIII for their dedication and capable leadership. Each of the meetings had a nominated rapporteur and CIOMS acknowledges their professional editorial group, comprising Drs June Raine, Philippe Close, Gerald Dal Pan, Ralph Edwards, Bill Gregory, Manfred Hauben, Atsuko Shibata, June Almenoff, Lynn Macdonald and Stephen Klincewicz, merits special mention and thanks.

4 CIOMS wishes to express special appreciation to Dr June Raine as Chief Editor of the fi nal contribution by the CIOMS/WHO Working Group on Vaccine Pharmacovigi-lance of the Points to Consider in Appendix 5 is gratefully and the Working Group are grateful for important input received on sev-eral points of the report from senior experts outside the Group who made valuable suggestions: Professor Stephen Evans, Dr Toshiharu Fujita, Dr David Madigan, Dr Niklas Nor n, Dr Hironori Sakai, Professor Saad Shakir, Dr Hugh Tilson and Dr Patrick , December 2009 Gottfried Kreutz, Juhana E.

5 Id np n-Heikkil ,Dr. med., MD, PhD, ProfessorSecretary-General, CIOMS Senior Adviser, 11 11 11 11:125 Table of Contents Preface .. 7I Introduction and scope of CIOMS VIII .. 9II Background Pharmacovigilance and key defi nitions .. 13 a. Need for Pharmacovigilance after regulatory 13 b. Defi nition of Pharmacovigilance .. 14 c. Defi nition and taxonomy of drug safety signals .. 14 d. Conclusions and recommendations.

6 16 III Overview of approaches to Signal Detection .. 19 a. Traditional approaches .. 20 b. Emergence of statistical data mining 21 c. Conceptual framework for integrating traditional and statistical data mining methods .. 22 d. Interpretation of data mining results within an integrated approach .. 23 e. Conclusions and recommendations .. 23IV Spontaneously reported drug safety-related information .. 25 a. Defi nitions of adverse event and reaction.

7 25 b. Data elements in a spontaneous reporting system .. 25 c. Mechanisms for reporting .. 27 d. Patient and consumer reporting .. 28 e. Limitations and challenges of spontaneous data .. 30 f. Reporting in special populations .. 32 g. Conclusions and recommendations .. 32V Databases that support Signal Detection .. 35 a. Spontaneous reporting databases .. 36 b. Other datasets that can be used for Signal Detection .. 37 c. Data quality.

8 39 d. Pharmacoepidemiology resources .. 39 e. Conclusions and recommendations .. 40VI Traditional methods of Signal Detection .. 43 a. Case and case series review .. 43 b. Simple analyses of larger datasets .. 45 c. Conclusions and recommendations .. 47 VII More complex quantitative Signal Detection methods .. 49 a. History .. 49 b. Disproportionality analysis general concepts and caveats.

9 49 c. Theory of disproportionality analysis .. 53 Basic methodologies and metrics .. 53 Bayesian methodologies .. 55 Frequentist versus Bayesian approaches .. 59 Evaluating data mining performance .. 59 d. Disclosure and review of potential confl ict of interest .. 62 e. Conclusions and recommendations .. 62 VIII How to develop a Signal Detection strategy .. 67 a. Stakeholder perspectives.

10 67 Expectations of consumers .. 67 Expectations of prescribers .. 68 Expectations of government regulators .. 68 Expectations for pharmaceutical companies (sponsors) .. 68 b. Regulatory considerations and international guidance .. 11 11:126 Pre-marketing Signal Detection .. 69 Post-marketing surveillance .. 70 c. Value added for integrating data mining methods into a Signal Detection program.