Table of Contents

Bioequivalence & Biopharmaceutical Development

Drug Development and Clinical Pharmacology

Aims of This Book

Biopharmaceutical Development

Clinical Pharmacology

Statistics in Clinical Pharmacology

Structure of the Book

History and Regulation of Bioequivalence

When and How BE Studies Are Performed

Why Are BE Studies Performed?

Deciding When Formulations Are Bioequivalent

Potential Issues with TOST Bioequivalent

Current International Regulation

Some Practical Notes

Testing for Average Bioequivalence

Background

Linear Model for 2 x 2 Data

Applying the TOST Procedure

Carry-over, Sequence, and Interaction Effects

Checking Assumptions Made about the Linear Model

Power and Sample Size for ABE in the 2 x 2 Design

Example Where Test and Reference Are Not ABE

Nonparametric Analysis

BE Studies with More Than Two Periods

Background

Three-period Designs

Within-subject Variability

Robust Analyses for Three Period Designs

Four-period Designs

Designes with More Than Two Treatments

Adjusting for Multiple Testing

Nonparametric Analyses of Tmax

Technical appendix: Efficiency

Tables of Data

Special Topics in Bioequivalence

Dealing with Special BE Challenges

Restricted Maximum Likelihood Modelling

Failing BE and the DER Assessment

Simulation

Data-based Simulation

Carry-over

Optimal Designs

Determining Trial Size

What Outliers Are and How to Handle Their Data

Bayesian BE Assessment

Adaptive Bioequivalence Trials

Background

Two-stage design for testing for ABE

TOST using the standard combination test

Example of using the standard combination test

The maximum combination test

Example of using the maximum combination test

Conditional errors and conditional power

Algorithm for sample size re-estimation

Operating characteristics

Conclusions

Techniccal Appendix: R code

Scaled Average Bioequivalence Testing

Background

Scaled Average Bioequivalence in Europe

Scaled Average Bioequivalence in USA

Discussion and Cautions

Clinical Pharmacology

Clinical Pharmacology Safety Studies

Background

First-time-in-humans

Sub-chronic Dosing Studies

Food-Effect Assessment and DDIs

Dose-Proportionality

Technical Appendix

QTc

Background

Modelling of QTc Data

Interpreting the QTc Modelling Findings

Design of a Thorough QTc Study in the Future

Clinical Pharmacology Efficacy Studies

Background

Sub-chronic Dosing

Phase IIa and the Proof of Concept

Population Pharmacokinetics

Population and Pharmacokinetics

Absolute and Relative Bioavailabili

About the Author

Scott D. Patterson, Byron Jones

Reviews

"The two authors are well-respected statisticians with numerous publications in BE and broad pharmaceutical industry experience. … The book is written in plain language and statistics is presented with minimum mathematical proof, which makes it a great introduction and reference for statisticians and clinical pharmacologists. With case studies and associated SAS and R codes included in the book and website, both statisticians and clinical pharmacologists will find this book helpful in understanding the context to use a method and implementing the ready-to-use codes. Particularly, each chapter begins with an interesting real-life story of the authors working as statisticians in the pharmaceutical industry, which makes the reading delightful. …In summary, Bioequivalence and Statistics in Clinical Pharmacology, Second Edition, provides an update on regulatory recommendations, statistical methods, and applications in clinical pharmacology and BE studies to support drug product development. With its inclusion of SAS and R codes, this book will be a valuable reference for pharmaceutical scientists, statisticians, and regulators working in these areas."
—Wangjie Sun and Wenlei Jiang, US Food and Drug Administration, in Journal of the American Statistical Association, January 2018"This book is a second edition of the authors’ take on the concepts and methods in the analysis and design of bioequivalence studies, supported by references to regulation authorities’ guidelines ... The authors are working in the pharmaceutical industry and therefore bring a view from the inside compared to the other reference work in the field by academics … Throughout the book, different examples with data and codes are provided both showing and not showing bioequivalence to facilitate the learning process. … To conclude, this book covers efficiently the statistical methods of bioequivalence testing and their many applications in clinical pharmacology. Furthermore, the dense reference list provides a helpful guide for the reader to go in deeper details on topics of interest."
—Julie Bertrand, Faculté de Médecine Bichat, IAME, in Journal of Biopharmaceutical Statistics, May 2017"The first edition of Bioequivalence and Statistics in Clinical Pharmacology was a classic text book for researchers and statisticians in the field of clinical pharmacology and pharmaceutical industry. This new second edition is a timely update with the inclusion of new areas such as adaptive bioequivalence trials, scaled average bioequivalence testing, and vaccine trials. This is one of few books in the literature with the focus on statistical issues in clinical pharmacology and bioequivalence. The topics it covers are critical for understanding the pharmacology of an investigational drug, and are becoming increasingly important in the era of precision medicine. The book is just as well structured as the first edition, in an accessible, thorough, and clear manner. Case studies and associated SAS code included in the book are extremely helpful. In summary, the book is a most welcome addition to the collection of pharmaceutic statisticians and researchers in clinical pharmacology."
—Liang Fang, Director of Biostatistics, Gilead Sciences Inc."Bioequivalence and Statistics in Clinical Pharmacology, Second Edition, provides readers with a statistical background of bioequivalence and presents several special topics in clinical pharmacology. This second edition contains updated and extended discussions of these topics and includes new chapters on adaptive bioequivalence studies, scaled average bioequivalence, and vaccine trials. The book’s presentation is comprehensive and clear, and is complimented by numerous illustrations, examples, and computer programs with data analyses. Scientists and practitioners working in industry, regulatory authorities, and academia will find this book useful, interesting, and enjoyable due to the delightful and instructive stories featured in the introductions of each chapter, the various important and relevant topics covered by these chapters, and the informative and practical technical appendices."
—Laszlo Endrenyi, Professor Emeritus, University of TorontoPraise for the First Edition:"… the book provides a good introduction to common uses of statistics in early phases of the drug development process by using a good mix of technical detail, intuitive understanding and factual knowledge. … personal accounts together with the numerous real data examples which are accompanied by SAS code for analysis and the opportunity to download the data to gain first-hand experience are the best features of the book. … the authors did a fine job in providing an introduction to statistics in the early stages of the drug development process. The availability of real example data allows the reader to engage himself easily in the topic and the long experience of the authors ensures that many different aspects of pharmacological studies are discussed."
—Thomas Jaki, Lancaster University, Journal of the Royal Statistical Society, Series A, 2010"I really enjoyed reading this book. Each chapter includes an excellent introduction based on Scott Patterson's experience working as a biometrician. This will especially be of interest to young statisticians starting their career in the pharmaceutical industry. Therefore, I strongly recommend this book to all pharmaceutical statisticians to learn more of the challenging statistical problems being generated in drug development. In addition, the presented material provides a springboard for all scientists from academia who are looking to do research in this area of medical applications."
—Dieter Haushcke, Biometrics, September, 2006"The authors formulate bioequivalence exhaustively and clearly. … Given the background of the authors, they constitute a key piece of social information in understanding the context in which clinical pharmacology research develops within the pharmaceutical industry."
—Journal of Biopharmaceutical Statistics

"The two authors are well-respected statisticians with numerous publications in BE and broad pharmaceutical industry experience. … The book is written in plain language and statistics is presented with minimum mathematical proof, which makes it a great introduction and reference for statisticians and clinical pharmacologists. With case studies and associated SAS and R codes included in the book and website, both statisticians and clinical pharmacologists will find this book helpful in understanding the context to use a method and implementing the ready-to-use codes. Particularly, each chapter begins with an interesting real-life story of the authors working as statisticians in the pharmaceutical industry, which makes the reading delightful. …In summary, Bioequivalence and Statistics in Clinical Pharmacology, Second Edition, provides an update on regulatory recommendations, statistical methods, and applications in clinical pharmacology and BE studies to support drug product development. With its inclusion of SAS and R codes, this book will be a valuable reference for pharmaceutical scientists, statisticians, and regulators working in these areas."
—Wangjie Sun and Wenlei Jiang, US Food and Drug Administration, in Journal of the American Statistical Association, January 2018"This book is a second edition of the authors’ take on the concepts and methods in the analysis and design of bioequivalence studies, supported by references to regulation authorities’ guidelines ... The authors are working in the pharmaceutical industry and therefore bring a view from the inside compared to the other reference work in the field by academics … Throughout the book, different examples with data and codes are provided both showing and not showing bioequivalence to facilitate the learning process. … To conclude, this book covers efficiently the statistical methods of bioequivalence testing and their many applications in clinical pharmacology. Furthermore, the dense reference list provides a helpful guide for the reader to go in deeper details on topics of interest."
—Julie Bertrand, Faculté de Médecine Bichat, IAME, in Journal of Biopharmaceutical Statistics, May 2017"The first edition of Bioequivalence and Statistics in Clinical Pharmacology was a classic text book for researchers and statisticians in the field of clinical pharmacology and pharmaceutical industry. This new second edition is a timely update with the inclusion of new areas such as adaptive bioequivalence trials, scaled average bioequivalence testing, and vaccine trials. This is one of few books in the literature with the focus on statistical issues in clinical pharmacology and bioequivalence. The topics it covers are critical for understanding the pharmacology of an investigational drug, and are becoming increasingly important in the era of precision medicine. The book is just as well structured as the first edition, in an accessible, thorough, and clear manner. Case studies and associated SAS code included in the book are extremely helpful. In summary, the book is a most welcome addition to the collection of pharmaceutic statisticians and researchers in clinical pharmacology."
—Liang Fang, Director of Biostatistics, Gilead Sciences Inc."Bioequivalence and Statistics in Clinical Pharmacology, Second Edition, provides readers with a statistical background of bioequivalence and presents several special topics in clinical pharmacology. This second edition contains updated and extended discussions of these topics and includes new chapters on adaptive bioequivalence studies, scaled average bioequivalence, and vaccine trials. The book’s presentation is comprehensive and clear, and is complimented by numerous illustrations, examples, and computer programs with data analyses. Scientists and practitioners working in industry, regulatory authorities, and academia will find this book useful, interesting, and enjoyable due to the delightful and instructive stories featured in the introductions of each chapter, the various important and relevant topics covered by these chapters, and the informative and practical technical appendices."
—Laszlo Endrenyi, Professor Emeritus, University of TorontoPraise for the First Edition:"… the book provides a good introduction to common uses of statistics in early phases of the drug development process by using a good mix of technical detail, intuitive understanding and factual knowledge. … personal accounts together with the numerous real data examples which are accompanied by SAS code for analysis and the opportunity to download the data to gain first-hand experience are the best features of the book. … the authors did a fine job in providing an introduction to statistics in the early stages of the drug development process. The availability of real example data allows the reader to engage himself easily in the topic and the long experience of the authors ensures that many different aspects of pharmacological studies are discussed."
—Thomas Jaki, Lancaster University, Journal of the Royal Statistical Society, Series A, 2010"I really enjoyed reading this book. Each chapter includes an excellent introduction based on Scott Patterson's experience working as a biometrician. This will especially be of interest to young statisticians starting their career in the pharmaceutical industry. Therefore, I strongly recommend this book to all pharmaceutical statisticians to learn more of the challenging statistical problems being generated in drug development. In addition, the presented material provides a springboard for all scientists from academia who are looking to do research in this area of medical applications."
—Dieter Haushcke, Biometrics, September, 2006"The authors formulate bioequivalence exhaustively and clearly. … Given the background of the authors, they constitute a key piece of social information in understanding the context in which clinical pharmacology research develops within the pharmaceutical industry."
—Journal of Biopharmaceutical Statistics