Drug safety has always been important but it has undergone increased scrutiny in recent years. This book is about quantitative evaluation of the safety of biopharmaceutical products. The book is meant to be comprehensive, cov-ering design, monitoring, analysis, and reporting issues for both clinical tri-als and observational studies. In addition, since statistical methods for drug safety assessment are still evolving and new methods are under development, the book will cover developments in state-of-the-art methods for drug safety assessment. We hope our book will bring the most advanced knowledge and statistical methodology to the statistical, clinical, and safety community; share best practices; and stimulate further research and methodology development in the drug safety area.
The book presents key challenges that impact regulatory agencies, industry, and academia. It elaborates on Bayesian methods, presents approaches to creating effective safety graphics, and includes consideration for risk-benefit evaluation. The book is mainly for professionals with a quantitative background in fields such as statistics or epidemiology working in pharmaceutical, biotechnology, and device industries; regulatory agencies that govern these industries; and academic departments involved in activities related to clinical trials or observational studies in biopharmaceutical product development. The book is mainly suitable for research and could also be used as supplementary material for teaching; for example, for courses on pharmaceutical science, biostatistics, applied statistics, statistical computing, clinical trials, causal inference, and observational studies.
The chapters discuss quantitative approaches to safety evaluation and risk management in drug development. They cover broad topics such as study design, safety monitoring, and data evaluation/analysis. First, study design includes the Bayesian meta-experimental design for evaluating cardiovascular risk, non-inferiority study design and analysis for safety endpoints, and the program safety analysis plan. Second, safety monitoring is critical, and on this topic the book includes chapters on why a DMC safety report differs from a safety report written at the end of the trial, safety surveillance and signal detection processes, and Bayesian adaptive trials for drug safety. Finally, the book covers evaluation/analysis topics such as observational safety study design, analysis, and reporting; the observational medical outcomes partnership (OMOP); a roadmap for causal inference in safety analysis; safety graphics; Bayesian network meta-analysis for safety evaluation; regulatory issues in meta-analysis of safety data; Bayesian applications for drug safety evaluation; risk-benefit assessment approaches; detecting safety signals in subgroups, and an overview of safety evaluation and quantitative approaches during preclinical and early phases of drug development.
As editors of this book, we are pleased to see that such broad and critical safety topics have been addressed by well-established and experienced authors. We trust you will enjoy reading them and find them informative and useful in your drug safety evaluation as much as we do.
We are very grateful for our family members' tremendous support and patience during the completion of the book. We also wish to express our great appreciation for the terrific support received from David Grubbs, Laurie Schlags, and the production team at Taylor & Francis Group, LLC. Qi Jiang, PhD H. Amy Xia, PhD

Preface ix

Editors xi

Contributors xiii

Section I Study Design

1 Incorporating Quantitative Safety Evaluation into Risk Management 3

2 Bayesian Meta-Experimental Design for Evaluating Cardiovascular Risk 13

3 Non-Inferiority Study Design and Analysis for Safety Endpoints 39

Section II Safety Monitoring

4 Program Safety Analysis Plan: An Implementation Guide 55

5 Why a DMC Safety Report Differs from a Safety Section Written at the End of the Trial 69

6 Safety Surveillance and Signal Detection Process 93

Section III Evaluation/Analysis

7 Bayesian Adaptive Trials for Drug Safety 109

8 Observational Safety Study Design, Analysis, and Reporting 125

9 Emerging Role of Observational Health-Care Data in Pharmacovigilance 141

10 Roadmapfor Causal Inference in Safety Analysis 173

11 Safety Graphics 195

12 Bayesian Network Meta-Analysis for Safety Evaluation 223

13 Regulatory Issues in Meta-Analysis of Safety Data 237

14 Bayesian Applications for Drug Safety Evaluation 251

15 Risk-Benefit Assessment Approaches 267

16 Detecting Safety Signals in Subgroups 289

17 Overview of Safety Evaluation and Quantitative Approaches during Preclinical and Early Phases of Drug Development 321

Index 339

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