Stephens Detection of New Adverse Drug Reactions, Fifth Edition.

Size: px

Start display at page:

Download "Stephens Detection of New Adverse Drug Reactions, Fifth Edition."

Caroline Fields
6 years ago
Views:

1 Stephens Detection of New Adverse Drug Reactions Fifth Edition Stephens Detection of New Adverse Drug Reactions, Fifth Edition. Edited by John Talbot and Patrick Waller Copyright 2004 John Wiley & Sons, Ltd. ISBN: X

2 Stephens Detection of New Adverse Drug Reactions Fifth Edition Edited by John Talbot Director, Global Drug Safety, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, UK Patrick Waller Consultant in Pharmacovigilance and Pharmacoepidemiology, Southampton, UK

3 Copyright # 2004 John Wiley & Sons Ltd, The Atrium, Sourthern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) (for orders and customer service enquiries): cs-books@wiley.co.uk Visit our Home Page on or All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1T 4LP, UK, without the permission in writing of the Publisher. Requests to the Publisher should be addressed to the Permissions Department, John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England, or ed to permreq@wiley.co.uk or faxed to (+44) This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the Publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Other Wiley Editorial Offices John Wiley and Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA , USA Wiley-VCH Verlag GmbH, Boschstr. 12, D Weinhein, Germany John WIley & Sons Australia Ltd, 33 Park Road, Milton, Queensland 4064, Australia John WIley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02-01, Jin Xing Distripark, Singapore John Wiley & Sons Canada Ltd, 22 Worcester Road, Etobicoke, Ontario, Canada M9W 1LI Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN X hardback Typeset in 10/12 Times by Keytec Typesetting Ltd, Bridport, Dorset, England Printed and bound in Great Britain by TJ International Ltd., Padstow This book is printed in acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.

4 Contents Foreword Preface List of Contributors xi xiii xv 1 Introduction 1 M. D. B. Stephens Mercury 1 Introduction to pharmacovigilance 1 The history of pharmacovigilance 3 Under-reporting of adverse drug reactions 10 Incidence of adverse drug reactions 17 The financial cost of adverse drug reactions 30 Preventability of adverse drug reactions 35 Risk benefit ratio 35 The changing risks with new drugs 44 Expression of risk 47 The risks we are prepared to take 52 Definitions 57 Classification of adverse drug reactions 58 Adverse reaction profile 60 Adverse events in a patient s life 61 Symptoms in healthy persons 62 Adverse reactions to placebo 63 Infectiousness of adverse drug reactions 67 Herbal medicines 69 Some final food for thought 70 References 71 Further reading 88 2 Adverse Drug Reactions and Interactions: Mechanisms, Risk Factors, Detection, Management and Prevention 92 P. Routledge Introduction 92 Classification of adverse drug reactions 92 Risk factors for type A adverse reactions 93 Risk factors for type B adverse reactions 101 Detection of adverse drug reactions 106 Stephens Detection of New Adverse Drug Reactions Fifth Edition edited by John Talbot and Patrick Waller # 2004 John Wiley & Sons, Ltd ISBN: X

5 vi CONTENTS Management of adverse drug reactions 108 Prevention of adverse drug reactions 109 Drug interactions 111 Conclusions 122 References Toxicology and Adverse Drug Reactions 128 D. J. Snodin Introduction 128 Toxicity testing 128 Drug development 137 Data interpretation and risk assessment 144 Adverse drug reactions detected after authorization 150 Examples of toxicological investigation of adverse drug reactions 157 Conclusions 159 Acknowledgements 159 References Clinical Trials: Collection of Safety Data and Establishing the Adverse Drug Reaction Profile 167 J.C.C. Talbot, M. D. B. Stephens Introduction 167 Adverse events 168 Final analysis of data 229 Inadequate reporting of safety data from clinical trials 231 Conclusions 232 Future aspirations 233 Acknowledgements 233 References Clinical Laboratory Safety Data in Drug Studies 244 A. Craig Introduction 244 Factors that influence interpretation of clinical laboratory data 245 Sample collection procedure 252 Analytical variation 255 Reference ranges 256 Intra-individual biological variation 259 Safety testing in drug development 261 Test selection 289 Exclusion criteria and panic levels 290 Harmonization of data from different laboratories 292 Data analysis and presentation 294 Conclusion 298 References 298

6 CONTENTS vii 6 Statistics: Analysis and Presentation of Safety Data 301 S. J. W. Evans Introduction and background 301 Analysis and presentation of data from trials 305 Measures that take time into account 308 Statistical tests utilizing time since start of treatment 310 Combining data from several trials: meta-analysis 312 Analysis and presentation of data from observational studies 312 Use of statistical methods for signal detection with spontaneous reports 316 Summary and conclusions 325 Acknowledgements 326 References Causality and Correlation in Pharmacovigilance 329 S. A. W. Shakir Introduction and historical background 329 The notions of necessary and sufficient causes 330 Factors to be considered in causality assessment 330 Methods for causality assessment 333 When to assess causality 336 Assessing causality from multiple information sources: the Bradford-Hill criteria 337 Conclusion 342 References Managing Drug Safety Issues with Marketed Products 345 P. C. Waller, H. H. Tilson Introduction 345 Identification of drug safety issues 346 Investigation 356 Evaluation 359 Action 361 Communicating about drug safety 364 Beyond communication: risk management 369 Managing the process 371 Conclusion: some thoughts on the future 372 References Regulatory Aspects of Pharmacovigilance 375 B. D. C. Arnold Introduction 375 Council for International Organizations of Medical Sciences 375 The International Conference on Harmonization 379 The European Union 399 The United Kingdom 419 France 424 Germany 428 United States of America 432

7 viii CONTENTS Japan 443 Acknowledgements 448 References 449 Bibliography Legal Aspects of Pharmacovigilance 453 C. Bendall Introduction 453 Legal responsibility for pharmacovigilance 454 Interpreting legal provisions 458 The relationship between European Community pharmacovigilance legislation and guidelines 460 National implementation 461 Uncertainties in European Community provisions 463 The potential impact of the 2001 review of pharmaceutical legislation 468 European powers and procedures in the event of a product safety issue 469 Referral to the Committee for Proprietary Medicinal Products 471 Failures to meet adverse drug reaction reporting requirements 478 Consequences of failure to meet requirements 481 Safety in research products 487 Personal data privacy 490 Reference Operational Aspects of the Drug Safety Function within a Pharmaceutical Company 493 J. Steiner Introduction 493 Overview of the case-handling process 493 Specifics of the case-handling process 494 Periodic safety updates 499 Staffing models for the case-handling process 504 Technology and the case-handling process 508 Quality control and the case-handling process 513 Training and the case-handling process 520 External partners and the case-handling process 525 Case distribution to external parties other than regulatory authorities 527 Conclusion: vision for the future 531 Acknowledgement 531 References 531 Further reading Dictionaries and Coding in Pharmacovigilance 533 E. Brown Introduction 533 Scope of this chapter 534 Drug dictionaries 534 Adverse drug reaction dictionaries 537

8 CONTENTS ix Disease classifications 538 Combination terminology 545 Definition of adverse reaction terms 555 Conclusion 556 Acknowledgements 556 References Safety of Biotechnology Products 559 B. Brown, M. Westland Introduction 559 Properties of proteins 560 Categories of protein therapeutic agent 560 Safety monitoring for protein therapeutic agents 562 Off-label use 566 Conclusion 568 References Vaccine Safety Surveillance 571 E. Miller What is special about vaccine safety compared with other drugs? 571 Pathogenesis of vaccine reactions 572 Criteria for establishing causality for vaccine adverse events 575 Pre-licensure evaluation of vaccine safety 577 Objectives of an ideal post-licensure vaccine safety surveillance system 579 Passive post-licensure surveillance systems 579 Active surveillance of adverse vaccine events 581 Controlled epidemiological studies of vaccine safety 582 Ecological studies of vaccine safety 585 Conclusions 587 References Ethical Issues in Drug Safety 591 M. D. B. Stephens Introduction 591 Ethics in clinical trials 591 Ethics and the pharmaceutical industry 608 Conclusions 636 References 637 Further reading A Model for the Future Conduct of Pharmacovigilance 649 P. C. Waller, S. J. W. Evans Introduction 649 Proposed model 649 Description of model components 650 Conclusions 665

9 x CONTENTS Acknowledgements 666 References 666 Appendix I 667 Appendix II 705 Bibliography 709 Index 721

10 Foreword When does a book become a classic? The fact that Stephens Detection of New Adverse Drug Reactions is now in its fifth edition speaks volumes for its value to a multiplicity of readers. The science of pharmacovigilance has grown in breadth and depth over the eighteen years of the book s existence and the present edition shows not only how the scope of the field has increased, with chapters on the safety of biotechnology products and vaccine safety surveillance, but also how the operating techniques of statistical analysis, legal aspects and ethical issues now form important areas for debate in the field of drug safety. The history of drug safety is a roll call of the practice of medicine and of the science of pharmacology and toxicology which underpin it. Even the nomenclature of adverse drug reactions has evolved as we understand more of the underlying scientific basis. Nowhere is this better illustrated than in the area of drug interactions. Two examples serve to illustrate this. The broad division into pharmacokinetic and pharmacodynamic interactions has been further complicated by new understanding of how cellular transporter mechanisms are utilised to transfer drugs across tissue boundaries in the gut, liver, kidney and brain, and how this now forms the basis of a new set of ways in which one drug can alter the disposition and response to another. Secondly, as our knowledge of the human genome has evolved, the science of pharamacogenomics has increased our ability to select patients who will respond to specific drugs, and this response may be beneficial or adverse. Again, such information must be factored into our appreciation of the basis of drug interactions. As well as considering how we have reached our present position in considering adverse drug reactions, this book looks to the future. The chapter by Patrick Waller and Stephen Evans is particularly important in this respect, showing how the prediction of drug safety will form the future of pharmacovigilance, whereas in the past this depended more on the demonstration of harm. Medicinal chemists who design drug molecules appreciate the toxicity potential of various chemical groupings in a molecule, and are increasingly able to design out the offending entity without impairing efficacy. The clinical pharmacologist and the drug regulator, always aiming to reconcile possible risk with benefit, appreciate how critical is appropriate dose selection in achieving this balance. The clinician will always play an important role by his careful documentation and reporting of patient harm on systems such as the Yellow Card. Such spontaneous reporting systems will always serve the public health by creating signals of drug safety which can be augmented and further analysed in other more sophisticated ways. The concept of balancing risk with benefit, a theme to which the book correctly repeatedly returns, remains the bedrock of drug therapy. It is not an idea which either the public or the Stephens Detection of New Adverse Drug Reactions Fifth Edition edited by John Talbot and Patrick Waller # 2004 John Wiley & Sons, Ltd ISBN: X

11 xii FOREWORD media wish to embrace, preferring to regard medicines as magic bullets. The achievement of this latest edition of Stephens Detection of New Adverse Drug Reactions is to demonstrate very clearly that as science moves forward, so must our appreciation of this balance. We can safely predict, I think, that this Fifth Edition will not be the last. Alasdair Breckenridge

12 Preface to the fifth edition This is the fifth edition of a book first published in The aims of the book have changed little over the nearly 20 years since the preface to the first edition was written, but the scope of the book, the accumulated knowledge, international regulations and number of people working in the field of pharmacovigilance have grown enormously. This book is intended for all those working in pharmacovigilance and pharmaceutical medicine, whether they be in drug regulatory authorities, the pharmaceutical industry or academia, and in all continents. This is the first edition where Dr Myles Stephens has not been the principal author and editor. The editors of this edition gratefully accepted the task from him, but Myles has still made a significant contribution to this fifth edition in the form of two large chapters and the co-authoring of another chapter. In fitting recognition of his immense contribution to previous editions and the discipline of pharmacovigilance over many years, the book has been re-titled Stephens Detection of New Adverse Drug Reactions. We were very pleased at Wiley s positive response to our proposal for this change and with their enthusiasm and support for the new edition generally. The book covers the issues and problems involved in the detection of new adverse drug reactions throughout the life cycle of a medicine from animal studies through to clinical trials, its introduction to the market, followed by wide clinical use and eventual decline in use or withdrawal. This theme is supported by topics that reach across the life cycle, such as causality assessment, regulations, legal aspects, dictionaries and coding and ethical issues. Chapters from the fourth edition have either been extensively revised or replaced. We are grateful to those authors who updated their work and welcome several new authors. Some topics have new authors and there are some completely new chapters, for instance those looking at particular types of medicine that present special safety problems such as vaccines and biotechnology products. As before, chapters are extensively referenced and there is a bibliography and list of websites to direct readers to a wealth of other resources. John Talbot Patrick Waller Stephens Detection of New Adverse Drug Reactions Fifth Edition edited by John Talbot and Patrick Waller # 2004 John Wiley & Sons, Ltd ISBN: X

13 List of Contributors Dr BDC Arnold, Vice President, Global Drug Safety, AstraZeneca, 11F133, Alderley Park, Macclesfield, SK10 4TG, UK Christine Bendall, Arnold & Porter, 25 Old Broad Street, London EC2N 1HQ, UK Professor Alasdair M. Breckenridge, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, L69 3BX, UK Dr Benton Brown, 4641 Calle San Juan, Newbury Park, CA 91320, USA Dr Elliot Brown, Managing Director, Elliot Brown Consulting Ltd, Rowan House, 7 Woodfall Avenue, Barnet, Herts EN5 2EZ, UK eb@ebconsulting.co.uk Dr Alan Craig (general correspondence), 13 Court Close, Princes Risborough, Bucks HP27 9BG, UK alan+craig@lineone.net Dr Alan Craig (publication details), Consultant Clinical Scientist, Pivotal Laboratories Ltd, Pivotal House, Aviator Court, Clifton Moorgate, York YO30 4UT, UK a.craig@pivotal-labs.com Professor Stephen Evans, Professor of Pharmacoepidemiology, Medical Statistics Unit, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1 7HT, UK Stephen.Evans@lshtm.ac.uk Dr Elizabeth Miller, Head of Immunisation Division, PHLS Communicable Disease Surveillance Centre, 61 Colindale Avenue, London NW9 5EQ, UK liz.miller@phls.org.uk Professor Phil Routledge, Department of Pharmacology, Therapeutics & Toxicology, University of Wales College of Medicine, Health Park, Cardiff CF14 4XN, UK proutledg@compuserve.com Professor Saad Shakir, Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton SO31 1AA, UK saad.shakir@dsru.org Dr David Snodin, Principal Consultant, PAREXEL International, River Court, 50 Oxford Road, Denham, Uxbridge, Middlesex UB9 4DN, UK david.snodin@parexel.com Stephens Detection of New Adverse Drug Reactions Fifth Edition edited by John Talbot and Patrick Waller # 2004 John Wiley & Sons, Ltd ISBN: X

14 xvi LIST OF CONTRIBUTORS Professor Janet Steiner, Director, Safety Strategy, US Drug Safety, AstraZeneca LP, FOC-2W, 1800 Concord Pike, PO Box 15437, Wilmington DE , USA Dr Myles Stephens, 49 Kings Court, Bishop s Stortford, Hertfordshire CM23 2AB, UK stephmdb@onetel.net.uk Dr John Talbot, Director, Global Drug Safety, AstraZeneca R & D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK John.Talbot@astrazeneca.com Dr Hugh H. Tilson, Senior Advisor to the Dean, Public Health Leadership Programme, Rosenau Hall Room 260, University of North Carolina, School of Public Health, Chapel Hill, NC , USA hugh_tilson@unc.edu Dr Patrick Waller, Patrick Waller Limited, Consultancy in Pharmacovigilance and Pharmacoepidemiology, 15 Tamella Road, Botley, Southhampton SO30 2NY, UK patrick.waller@btinternet.com Dr Margaret M. Westland, Fellow of American College of Preventative Medicine (ACPM) Recently retired from a career in Pharmacovigilance riofish@aol.com

Waste Treatment and Disposal

Waste Treatment and Disposal Waste Treatment and Disposal, Second Edition Paul T. Williams 2005 John Wiley & Sons, Ltd ISBNs: 0-470-84912-6 (HB); 0-470-84913-4 (PB) Waste Treatment and Disposal Second