Stephens' Detection and Evaluation of Adverse Drug Reactions

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