Stephens' detection and evaluation of adverse drug reactions : principles and practice

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

Author Notes

John Talbot, Senior Lecturer, University of Hertfordshire, UK. Formerly, Director, Patient Safety, AstraZeneca R D
Jeffrey K. Aronson, Reader in Clinical Pharmacology, Department of Primary Health Care, University of Oxford, UK

Jeffrey K. AronsonSudeep P. Pushpakom and Munir PirmohamedD. J. Snodin and A. SuittersJohn Talbot and Marianne Keisu and Lars StåbleAlan CraigStephen J. W. Evans and Dorothea NitschJune Raine and Lesley Wise and John Talbot and Jeffrey K. AronsonKristina Leila Strutt and Barry David Charles ArnoldChristine H. BendallE. G. Brown and J. E. HarrisonNicky BrittenAndrew Erdman and James Nickas and Benton BrownE. Miller and J. StoweAnne KehelyJoanne BarnesCharlotte I. S. Barker and John Talbot and Jeffrey K. AronsonJeffrey K. Aronson

Foreword	p. xi
Preface to the Sixth Edition	p. xiii
List of Contributors	p. xv
Acknowledgements	p. xvii
1 Adverse Drug Reactions: History, Terminology, Classification, Causality, Frequency, Preventability	p. 1
1.1 Introduction	p. 1
1.2 Defining pharmacovigilance	p. 1
1.3 The modern history of pharmacovigilance	p. 3
1.4 Terminology and definitions in pharmacovigilance	p. 6
1.5 Medication errors	p. 25
1.6 Pharmacological classification of adverse drug reactions	p. 32
1.7 Drug interactions	p. 53
1.8 Reporting suspected adverse drug reactions	p. 59
1.9 Causality assessment	p. 64
1.10 Frequencies of adverse drug reactions	p. 69
1.11 Risk perception and adverse drug reactions	p. 77
1.12 Class effects of drugs	p. 78
1.13 Unlicensed indications, off-label uses, and orphan drugs	p. 80
1.14 Preventing adverse drug reactions	p. 84
1.15 Publishing accounts of adverse drug reactions	p. 95
References	p. 101
2 Pharmacogenetics of Adverse Drug Reactions	p. 121
2.1 Introduction	p. 121
2.2 Historical review	p. 121
2.3 Sources of genetic variability	p. 122
2.4 Role of pharmacogenetic factors in drug pharmacokinetics	p. 123
2.5 Role of pharmacogenetic factors in drug pharmacodynamics	p. 133
2.6 The role of pharmacogenetics in pharmaceutical companies	p. 139
2.7 The impact of pharmacogenetics on regulatory agencies	p. 141
2.8 The impact of pharmacogenetics on clinical practice	p. 143
2.9 Conclusions	p. 145
References	p. 145
3 Toxicology and Adverse Drug Reactions	p. 157
3.1 Introduction	p. 157
3.2 Toxicity testing	p. 157
3.3 Drug discovery and development	p. 168
3.4 Data interpretation and risk assessment	p. 174
3.5 Adverse drug reactions detected after marketing authorization	p. 186
3.6 Examples of toxicological investigation of ADRs	p. 199
3.7 Conclusions	p. 200
Acknowledgements	p. 201
References	p. 201
4 Clinical Trials-Collecting Safety Data and Establishing the Adverse Drug Reactions Profile	p. 215
4.1 Introduction	p. 215
4.2 Adverse events	p. 216
4.3 Clinical studies and safety	p. 236
4.4 The emerging safety profile	p. 267
4.5 Presentation of safety data	p. 271
4.6 Conclusions	p. 280
References	p. 281
5 Clinical Laboratory Safety Data	p. 291
5.1 Introduction	p. 291
5.2 Factors that influence the interpretation of clinical laboratory data	p. 294
5.3 Sample collection procedure	p. 300
5.4 Analytical variation	p. 301
5.5 Reference ranges	p. 304
5.6 Intra-individual biological variation	p. 307
5.7 Detecting adverse events during drug development	p. 309
5.8 Test selection	p. 333
5.9 Exclusion criteria and "panic levels"	p. 335
5.10 Harmonization of data from different laboratories	p. 337
5.11 Data analysis and presentation	p. 339
5.12 Conclusions	p. 344
5.13 Appendix	p. 345
References	p. 346
6 Statistics: Analysis and Presentation of Safety Data	p. 349
6.1 Introduction and background	p. 349
6.2 Problems with efficacy trials for detecting adverse drug reactions	p. 352
6.3 Analysis and presentation of data from trials	p. 355
6.4 Statistical measures of the occurrence of adverse events	p. 356
6.5 Combining data from several trials-meta-analysis	p. 364
6.6 Use of statistical methods for signal detection from spontaneous reports	p. 365
6.7 Analysis and presentation of data from observational studies	p. 373
6.8 Summary and conclusions	p. 384
Acknowledgements	p. 385
References	p. 386
7 Proactive Pharmacovigilance and Risk Management	p. 389
7.1 Introduction	p. 389
7.2 Risk management-definition and general principles	p. 390
7.3 Defining the knowledge base-the safety specification	p. 391
7.4 Extending the knowledge of safety and characterizing risk-the pharmacovigilance plan	p. 394
7.5 Minimizing risks	p. 395
7.6 Special challenges for risk management	p. 397
7.7 Experience with risk evaluation and mitigation strategies (REMS) in the USA	p. 398
7.8 A possible method for risk management when a new adverse reaction is discovered after marketing	p. 399
7.9 Future challenges for risk management	p. 405
7.10 Conclusions	p. 406
References	p. 407
8 Regulatory Aspects of Pharmacovigilance	p. 411
8.1 Introduction	p. 411
8.2 The standardization and harmonization of safety data collection and reporting: CIOMS and ICH	p. 412
8.3 The European Union	p. 447
8.4 The UK	p. 481
8.5 France	p. 483
8.6 Germany	p. 485
8.7 USA	p. 487
8.8 Japan	p. 500
Acknowledgements	p. 505
References	p. 506
Useful web sites	p. 509
9 Legal Aspects of Pharmacovigilance in the European Union	p. 511
9.1 Introduction	p. 511
9.2 Application of EU legislation in Member States	p. 511
9.3 Interpretation of EU law	p. 514
9.4 Relationship between law and guidelines	p. 515
9.5 Issues in interpreting EU pharmacovigilance legislation	p. 517
9.6 Legal responsibility for pharmacovigilance activities	p. 519
9.7 Failures to meet pharmacovigilance requirements	p. 522
9.8 Enforcement and sanctions	p. 524
9.9 European powers and procedures in the event of a product safety issue	p. 528
9.10 Civil liability	p. 534
9.11 Personal data privacy	p. 537
9.12 Safety in research products	p. 538
References	p. 541
10 Dictionaries and Coding in Pharmacovigilance	p. 545
10.1 Introduction	p. 545
10.2 Scope of this chapter	p. 546
10.3 What is a dictionary?	p. 546
10.4 Drug dictionaries	p. 547
10.5 Disease classifications	p. 554
10.6 Medical Dictionary for Regulatory Activities, MedDRA®	p. 557
10.7 Common Terminology Criteria for Adverse Events (CTCAE)	p. 567
10.8 Definition of adverse reaction terms	p. 567
10.9 Dictionaries used in electronic health records	p. 568
10.10 Use of dictionaries in standard product information	p. 570
10.11 Conclusions	p. 571
Acknowledgements	p. 571
References	p. 571
11 Adverse Drug Reactions: Societal Considerations	p. 573
11.1 Introduction	p. 573
11.2 Adverse drug reactions at the population level	p. 574
11.3 The social production of ADRs	p. 576
11.4 Trust	p. 579
11.5 Information about ADRs	p. 581
11.6 Conclusions	p. 583
References	p. 583
12 Safety of Biotherapeutics	p. 585
12.1 Introduction	p. 585
12.2 Properties of proteins	p. 586
12.3 Classification of biotherapeutics	p. 587
12.4 Monitoring for adverse events due to biotherapeutics	p. 589
12.5 Conclusions	p. 598
References	p. 598
13 Vaccine Safety Surveillance	p. 603
13.1 Introduction	p. 603
13.2 What is special about vaccine safety compared with other drugs?	p. 604
13.3 Pathogenesis of vaccine reactions	p. 605
13.4 Criteria for establishing causality after vaccine-related adverse events	p. 608
13.5 Pre-licensing evaluation of vaccine safety	p. 610
13.6 Objectives of an ideal post-licensing vaccine safety surveillance system	p. 611
13.7 Conclusions	p. 620
References	p. 620
14 Assessing the Safety of Drugs Used in Oncology	p. 625
14.1 Introduction	p. 625
14.2 Factors to consider when assessing the safety of drugs used in oncology	p. 627
14.3 Sources of adverse effect data	p. 632
14.4 Nature of the data	p. 634
14.5 Assessment of adverse effects data in oncology	p. 635
14.6 Conclusions	p. 641
References	p. 642
15 Adverse Drug Reactions and Pharmacovigilance of Herbal Medicines	p. 645
15.1 Introduction	p. 645
15.2 Herbal medicines: definitions and descriptions	p. 646
15.3 Characteristics of herbal medicines	p. 647
15.4 Regulation of herbal medicines and pharmacovigilance requirements	p. 648
15.5 Access to and use of herbal medicines	p. 655
15.6 Adverse reactions associated with herbal medicines	p. 656
15.7 Methods for pharmacovigilance of herbal medicines	p. 666
15.8 Responding to safety concerns associated with herbal medicines	p. 673
15.9 The future for pharmacovigilance of herbal medicines	p. 674
15.10 Conclusions	p. 675
References	p. 676
Appendix 1 Web Sites Relevant to Pharmacovigilance-An Analysis of Contents	p. 685
A1.1 Introduction	p. 685
A1.2 Ten national pharmacovigilance web sites	p. 685
A1.3 Twelve institutional web sites	p. 689
Acknowledgements	p. 697
References	p. 697
Appendix 2 Guidelines and a Checklist for Reporting Suspected Adverse Drug Reactions Anecdotally in Journals	p. 699
A2.1 Introduction	p. 699
A2.2 Notes on the checklist	p. 700
A2.3 Conclusions	p. 706
Note	p. 706
References	p. 706
Index	p. 709

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