Written with practitioners in mind, this new edition of Stephen s Detection of Adverse Drug Reactions: Principle and Practice continues to be one of the corner stones of the pharmaceutical medicine list.

Foreword xi Preface to the Sixth Edition xiii List of Contributors xv Acknowledgements xvii 1 Adverse Drug Reactions: History, Terminology, Classification, Causality, Frequency, Preventability 1 Jeffrey K. Aronson 1.1 Introduction 1 1.2 Defining pharmacovigilance 1 1.3 The modern history of pharmacovigilance 3 1.4 Terminology and definitions in pharmacovigilance 6 1.5 Medication errors 25 1.6 Pharmacological classification of adverse drug reactions 32 1.7 Drug interactions 53 1.8 Reporting suspected adverse drug reactions 59 1.9 Causality assessment 64 1.10 Frequencies of adverse drug reactions 69 1.11 Risk perception and adverse drug reactions 77 1.12 Class effects of drugs 78 1.13 Unlicensed indications, off-label uses, and orphan drugs 80 1.14 Preventing adverse drug reactions 84 1.15 Publishing accounts of adverse drug reactions 95 References 101 2 Pharmacogenetics of Adverse Drug Reactions 121 Sudeep P. Pushpakom and Munir Pirmohamed 2.1 Introduction 121 2.2 Historical review 121 2.3 Sources of genetic variability 122 2.4 Role of pharmacogenetic factors in drug pharmacokinetics 123 2.5 Role of pharmacogenetic factors in drug pharmacodynamics 133 2.6 The role of pharmacogenetics in pharmaceutical companies 139 2.7 The impact of pharmacogenetics on regulatory agencies 141 2.8 The impact of pharmacogenetics on clinical practice 143 2.9 Conclusions 145 References 145 3 Toxicology and Adverse Drug Reactions 157 D. J. Snodin and A. Suitters 3.1 Introduction 157 3.2 Toxicity testing 157 3.3 Drug discovery and development 168 3.4 Data interpretation and risk assessment 174 3.5 Adverse drug reactions detected after marketing authorization 186 3.6 Examples of toxicological investigation of ADRs 199 3.7 Conclusions 200 Acknowledgements 201 References 201 4 Clinical Trials—Collecting Safety Data and Establishing the Adverse Drug Reactions Profile 215 John Talbot, Marianne Keisu, and Lars St°ahle 4.1 Introduction 215 4.2 Adverse events 216 4.3 Clinical studies and safety 236 4.4 The emerging safety profile 267 4.5 Presentation of safety data 271 4.6 Conclusions 280 References 281 5 Clinical Laboratory Safety Data 291 Alan Craig 5.1 Introduction 291 5.2 Factors that influence the interpretation of clinical laboratory data 294 5.3 Sample collection procedure 300 5.4 Analytical variation 301 5.5 Reference ranges 304 5.6 Intra-individual biological variation 307 5.7 Detecting adverse events during drug development 309 5.8 Test selection 333 5.9 Exclusion criteria and “panic levels” 335 5.10 Harmonization of data from different laboratories 337 5.11 Data analysis and presentation 339 5.12 Conclusions 344 5.13 Appendix 345 References 346 6 Statistics: Analysis and Presentation of Safety Data 349 Stephen J. W. Evans and Dorothea Nitsch 6.1 Introduction and background 349 6.2 Problems with efficacy trials for detecting adverse drug reactions 352 6.3 Analysis and presentation of data from trials 355 6.4 Statistical measures of the occurrence of adverse events 356 6.5 Combining data from several trials—meta-analysis 364 6.6 Use of statistical methods for signal detection from spontaneous reports 365 6.7 Analysis and presentation of data from observational studies 373 6.8 Summary and conclusions 384 Acknowledgements 385 References 386 7 Proactive Pharmacovigilance and Risk Management 389 June Raine, Lesley Wise, John Talbot, and Jeffrey K. Aronson 7.1 Introduction 389 7.2 Risk management—definition and general principles 390 7.3 Defining the knowledge base—the safety specification 391 7.4 Extending the knowledge of safety and characterizing risk—the pharmacovigilance plan 394 7.5 Minimizing risks 395 7.6 Special challenges for risk management 397 7.7 Experience with risk evaluation and mitigation strategies (REMS) in the USA 398 7.8 A possible method for risk management when a new adverse reaction is discovered after marketing 399 7.9 Future challenges for risk management 405 7.10 Conclusions 406 References 407 8 Regulatory Aspects of Pharmacovigilance 411 Kristina Leila Strutt and Barry David Charles Arnold 8.1 Introduction 411 8.2 The standardization and harmonization of safety data collection and reporting: CIOMS and ICH 412 8.3 The European Union 447 8.4 The UK 481 8.5 France 483 8.6 Germany 485 8.7 USA 487 8.8 Japan 500 Acknowledgements 505 References 506 Useful web sites 509 9 Legal Aspects of Pharmacovigilance in the European Union 511 Christine H. Bendall 9.1 Introduction 511 9.2 Application of EU legislation in Member States 511 9.3 Interpretation of EU law 514 9.4 Relationship between law and guidelines 515 9.5 Issues in interpreting EU pharmacovigilance legislation 517 9.6 Legal responsibility for pharmacovigilance activities 519 9.7 Failures to meet pharmacovigilance requirements 522 9.8 Enforcement and sanctions 524 9.9 European powers and procedures in the event of a product safety issue 528 9.10 Civil liability 534 9.11 Personal data privacy 537 9.12 Safety in research products 538 References 541 10 Dictionaries and Coding in Pharmacovigilance 545 E. G. Brown and J. E. Harrison 10.1 Introduction 545 10.2 Scope of this chapter 546 10.3 What is a dictionary? 546 10.4 Drug dictionaries 547 10.5 Disease classifications 554 10.6 Medical Dictionary for Regulatory Activities, MedDRA R557 10.7 Common Terminology Criteria for Adverse Events (CTCAE) 567 10.8 Definition of adverse reaction terms 567 10.9 Dictionaries used in electronic health records 568 10.10 Use of dictionaries in standard product information 570 10.11 Conclusions 571 Acknowledgements 571 References 571 11 Adverse Drug Reactions: Societal Considerations 573 Nicky Britten 11.1 Introduction 573 11.2 Adverse drug reactions at the population level 574 11.3 The social production of ADRs 576 11.4 Trust 579 11.5 Information about ADRs 581 11.6 Conclusions 583 References 583 12 Safety of Biotherapeutics 585 Andrew Erdman, James Nickas, and Benton Brown 12.1 Introduction 585 12.2 Properties of proteins 586 12.3 Classification of biotherapeutics 587 12.4 Monitoring for adverse events due to biotherapeutics 589 12.5 Conclusions 598 References 598 13 Vaccine Safety Surveillance 603 E. Miller and J. Stowe 13.1 Introduction 603 13.2 What is special about vaccine safety compared with other drugs? 604 13.3 Pathogenesis of vaccine reactions 605 13.4 Criteria for establishing causality after vaccine-related adverse events 608 13.5 Pre-licensing evaluation of vaccine safety 610 13.6 Objectives of an ideal post-licensing vaccine safety surveillance system 611 13.7 Conclusions 620 References 620 14 Assessing the Safety of Drugs Used in Oncology 625 Anne Kehely 14.1 Introduction 625 14.2 Factors to consider when assessing the safety of drugs used in oncology 627 14.3 Sources of adverse effect data 632 14.4 Nature of the data 634 14.5 Assessment of adverse effects data in oncology 635 14.6 Conclusions 641 References 642 15 Adverse Drug Reactions and Pharmacovigilance of Herbal Medicines 645 Joanne Barnes 15.1 Introduction 645 15.2 Herbal medicines: definitions and descriptions 646 15.3 Characteristics of herbal medicines 647 15.4 Regulation of herbal medicines and pharmacovigilance requirements 648 15.5 Access to and use of herbal medicines 655 15.6 Adverse reactions associated with herbal medicines 656 15.7 Methods for pharmacovigilance of herbal medicines 666 15.8 Responding to safety concerns associated with herbal medicines 673 15.9 The future for pharmacovigilance of herbal medicines 674 15.10 Conclusions 675 References 676 Appendix 1 Web Sites Relevant to Pharmacovigilance—An Analysis of Contents 685 Charlotte I. S. Barker, John Talbot, and Jeffrey K. Aronson A1.1 Introduction 685 A1.2 Ten national pharmacovigilance web sites 685 A1.3 Twelve institutional web sites 689 Acknowledgements 697 References 697 Appendix 2 Guidelines and a Checklist for Reporting Suspected Adverse Drug Reactions Anecdotally in Journals 699 Jeffrey K. Aronson A2.1 Introduction 699 A2.2 Notes on the checklist 700 A2.3 Conclusions 706 Note 706 References 706 Index 709

The detection and evaluation of adverse drug reactions is crucial for understanding the safety of medicines and for preventing harm in patients. Not only is it necessary to detect new adverse drug reactions, but the principles and practice of pharmacovigilance apply to the surveillance of a wide range of medicinal products. Stephens' Detection and Evaluation of Adverse Drug Reactions provides a comprehensive review of all aspects of adverse drug reactions throughout the life cycle of a medicine, from toxicology and clinical trials through to pharmacovigilance, risk management, and legal and regulatory requirements. It also covers the safety of biotherapeutics and vaccines and includes new chapters on pharmacogenetics, proactive risk management, societal considerations, and the safety of drugs used in oncology and herbal medicines. This sixth edition of the classic text on drug safety is an authoritative reference text for all those who work in pharmacovigilance or have an interest in adverse drug reactions, whether in regulatory authorities, pharmaceutical companies, or academia. Praise for previous editions "This book presents a comprehensive and wide-ranging overview of the science of pharmacovigilance. For those entering or already experienced in the pharmaceutical sciences, this is an essential work.” - from a review in E-STREAMS "...a key text in the area of pharmacovigilance...extensively referenced and well-written...a valuable resource..." - from a review in The Pharmaceutical Journal

“A vast array of experts in the science of pharmacovigilance contribute to this book, but the editors have maintained a clarity of presentation, keeping in mind that communication is a key factor in pharmacovigilance.”  (Doody’s, 27 July 2012)