Contributors xvii

Preface xxi

Acknowledgements xxv

Part I Introduction to Pharmacoepidemiology 1

1 What is Pharmacoepidemiology? 3
Brian L. Strom

Introduction 3

Definition of Pharmacoepidemiology 3

Historical Background 5

The Current Drug Approval Process 13

Potential Contributions of Pharmacoepidemiology 15

Key Points 18

Further Reading 18

2 Study Designs Available for Pharmacoepidemiologic Studies 20
Brian L. Strom

Introduction 20

Overview of the Scientific Method 20

Types of Errors that one Can Make in Performing a Study 22

Criteria for the Causal Nature of an Association 23

Epidemiologic Study Designs 26

Discussion 31

Conclusion 32

Key Points 32

Further Reading 33

3 Sample Size Considerations for Pharmacoepidemiologic Studies 35
Brian L. Strom

Introduction 35

Sample Size Calculations for Cohort Studies 35

Sample Size Calculations for Case?Control Studies 40

Sample Size Calculations for Case Series 41

Discussion 43

Key Points 45

Further Reading 45

4 Basic Principles of Clinical Pharmacology Relevant to Pharmacoepidemiologic Studies 47
Jeffrey S. Barrett

Introduction 47

Clinical Pharmacology and Pharmacoepidemiology 48

Basics of Clinical Pharmacology 48

Pharmacokinetics 49

Special Populations 52

Pharmacodynamics 56

Pharmacogenomics 59

Model-Informed

Drug Development 59

Conclusion 60

Key Points 60

Further Reading 61

5 When Should One Perform Pharmacoepidemiologic Studies? 62
Brian L. Strom

Introduction 62

Reasons to Perform Pharmacoepidemiologic Studies 62

Safety Versus Risk 67

Risk Tolerance 67

Conclusion 70

Key Points 70

Further Reading 71

6 Views from Academia, Industry, Regulatory Agencies, and the Legal System 73
Joshua J. Gagne, Jerry Avorn, Nicolle M. Gatto, Jingping Mo, Gerald J. Dal Pan, June Raine, Shinobu Uzu, Aaron S. Kesselheim, and Kerstin N. Vokinger

The View from Academia 73

The View from Industry 81

The View from Regulatory Agencies 90

The View from the Legal System 98

Further Reading 107

Part II Sources of Pharmacoepidemiology Data 113

7 Postmarketing Spontaneous Pharmacovigilance Reporting Systems 115
Gerald J. Dal Pan, Marie Lindquist, and Kate Gelperin

Introduction 115

Description 116

Strengths 128

Limitations 129

Particular Applications 131

The Future 132

Key Points 132

Further Reading 134

8 Overview of Electronic Databases in Pharmacoepidemiology 136
Brian L. Strom

Introduction 136

Description 137

Strengths 138

Weaknesses 139

Particular Applications 140

The Future 140

Key Points 141

Further Reading 141

9 Encounter Databases 142
Tobias Gerhard, Yola Moride, Anton Pottegard, and Nicole Pratt

Introduction 142

Description 142

Strengths 161

Limitations 162

Particular Applications 163

The Future 166

Key Points 167

Further Reading 171

US Databases 172

European Databases 172

Canadian Databases 173

Asian Databases 173

10 Electronic Health Record Databases 174
Daniel B. Horton, Harshvinder Bhullar, Francesca Cunningham, Janet Sultana, and Gialuca Trifiro

Introduction 174

Description 174

Strengths 184

Limitations 185

The Future 186

Summary Points for Electronic Health Record Databases 187

Acknowledgment 187

Further Readings 189

11 Primary Data Collection for Pharmacoepidemiology 192
Priscilla Velentgas

Introduction 192

Methods of Primary Data Collection 195

Strengths 197

Limitations 197

Particular Applications 198

Conclusions 199

Key Points 199

Further Reading 201

12 How Should One Perform Pharmacoepidemiologic Studies? Choosing Among the Available Alternatives 203
Brian L. Strom

Introduction 203

Choosing Among the Available Approaches to Pharmacoepidemiologic Studies 203

Examples 215

Conclusion 216

Key Points 216

Further Reading 216

Part III Special Issues in Pharmacoepidemiology Methodology 219

13 Validity of Drug and Diagnosis Data in Pharmacoepidemiology 221
Mary Elizabeth Ritchey, Suzanne L. West, and George Maldonado

Introduction 221

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 221

Methodological Problems to be Solved by Pharmacoepidemiologic Research 222

Currently Available Solutions 233

The Future 242

Key Points 242

Further Reading 243

14 Assessing Causality from Case Reports 246
Bernard Begaud and Judith K. Jones

Introduction 246

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 246

The Two Paradigms of Causality Assessment 246

When is Assessing Causation from Cases Reports Useful? 247

Methodological Problems to be Addressed by Pharmacoepidemiologic Research 248

Approaches for Assessing Causation from Individual Cases 249

Calibration 253

Choosing the Appropriate Approach 253

The Future 254

Key Points 255

Further Reading 255

15 Molecular Pharmacoepidemiology 257
Christine Y. Lu and Stephen E. Kimmel

Introduction 257

Definitions and Concepts 258

The Interface of Pharmacogenetics and Pharmacogenomics with Molecular

Pharmacoepidemiology 259

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 260

The Progression and Clinical Application of Molecular Pharmacoepidemiology 264

Methodological Problems to be Addressed by Pharmacoepidemiologic Research 264

Currently Available Solutions 269

The Future 271

Key Points 273

Further Reading 274

16 Bioethical Issues in Pharmacoepidemiologic Research 276
Laura E. Bothwell, Annika Richterich, and Jeremy Greene

Introduction 276

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 276

Methodologic Problems to be Solved by Pharmacoepidemiologic Research 283

Currently Available Solutions 286

The Future 289

Acknowledgement 291

Key Points 291

Further Reading 293

17 The Use of Randomized Controlled Trials for Pharmacoepidemiology 294
Samuel M. Lesko, Allen A. Mitchell, and Robert F. Reynolds

Introduction 294

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 294

Methodological Problems to be Solved by Pharmacoepidemiologic Research 296

Currently Available Solutions 298

Large Simple Trials 298

Analysis 303

Primary Analysis 303

The Future 304

Key Points 305

Further Reading 305

18 Pharmacoeconomics: Economic Evaluation of Pharmaceuticals 307
Kevin A. Schulman

Introduction 307

Clinical Problems to be Addressed by Pharmacoeconomic Research 307

Methodological Problems to be Addressed by Pharmacoeconomic Research 312

The Future 320

Acknowledgements 320

Key Points 320

Further Reading 320

19 Patient Engagement and Patient Reported Outcomes 322
Esi M. Morgan and Adam C. Carle

Introduction 322

Patient Reported Outcomes in Clinical Trials 323

Patient Reported Outcomes in Routine Care 323

Patient Reported Outcomes as Motivation to Develop New Therapeutic Strategies 325

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 326

Methodologic Problems to be Solved by Pharmacoepidemiologic Research 328

Currently Available Solutions 328

The Future 330

Key Points 331

Further Reading 331

20 The Use of Meta-analysis in Pharmacoepidemiology 334
Brenda J. Crowe, Stephen J.W. Evans, H. Amy Xia, and Jesse A. Berlin

Introduction 334

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 335

Methodological Problems to be Solved by Pharmacoepidemiologic Research 336

Currently Available Solutions 338

The Future 350

Key Points 351

Further Reading 352

21 Studies of Medication Adherence 355
Julie Lauffenburger, Trisha Acri, and Robert Gross

Introduction 355

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 356

Methodological Problems to be Addressed by Pharmacoepidemiologic Research 357

Currently Available Solutions 357

Analysis Issues in Adherence 362

Use of Adherence Data in Clinical Trials and Comparative Effectiveness Studies 362

The Future 365

Key Points 365

Further Reading 366

22 Advanced Approaches to Controlling Confounding in Pharmacoepidemiologic Studies 368
Sebastian Schneeweiss and Samy Suissa

Introduction 368

Clinical Problems to be Addressed by Pharmacoepidemiologic Research 368

Methodological Problems to be Addressed by Pharmacoepidemiologic Research 368

Currently Available Solutions 370

Conclusion 382

Key Points 382

Further Reading 384

Part IV Special Applications and the Future of Pharmacoepidemiology 387

23 Special Applications of Pharmacoepidemiology 389
David Lee, Bjorn Wettermark, Christine Y. Lu, Stephen B. Soumerai, Robert T. Chen, Sharon-Lise T.Normand, Art Sedrakyan, Danica Marinac-Dabic, Daniel B. Horton, Sonia Hernandez-Diaz, Tamar?Lasky, Krista F. Huybrechts, Claudia Manzo, Emil Cochino, Hanna M. Seidling, David W. Bates,?Bennett Levitan, Rachael L. DiSantostefano, and Scott Evans

Studies of Drug Utilization 389

Introduction 389

Evaluating and Improving Prescribing 398

Special Methodological Issues in Pharmacoepidemiologic Studies of Vaccine Safety 403

Epidemiologic Studies of Implantable Medical Devices 408

Research on the Effects of Medications in Pregnancy and in Children 418

Risk Management 427

The Pharmacoepidemiology of Medication Errors 436

Benefit?Risk Assessments of Medical Treatments 442

Further Reading 454

24 The Future of Pharmacoepidemiology 464
Brian L. Strom, Stephen E. Kimmel, and Sean Hennessy

Introduction 464

The View from Academia 465

Scientific Developments 465

The View from Industry 471

The View from Regulatory Agencies 472

The View from the Law 473

Conclusion 473

Key Points 473

Further Reading 474

Appendix A - Sample Size Tables 475

Appendix B - Glossary 493

Index 505