Bioequivalence and Statistics in Clinical Pharmacology (2^nd Ed.) Chapman & Hall/CRC Biostatistics Series

Maintaining a practical perspective, Bioequivalence and Statistics in Clinical Pharmacology, Second Edition explores statistics used in day-to-day clinical pharmacology work. The book is a starting point for those involved in such research and covers the methods needed to design, analyze, and interpret bioequivalence trials; explores when, how, and why these studies are performed as part of drug development; and demonstrates the methods using real world examples.

Drawing on knowledge gained directly from working in the pharmaceutical industry, the authors set the stage by describing the general role of statistics. Once the foundation of clinical pharmacology drug development, regulatory applications, and the design and analysis of bioequivalence trials are established, including recent regulatory changes in design and analysis and in particular sample-size adaptation, they move on to related topics in clinical pharmacology involving the use of cross-over designs. These include, but are not limited to, safety studies in Phase I, dose-response trials, drug interaction trials, food-effect and combination trials, QTc and other pharmacodynamic equivalence trials, proof-of-concept trials, dose-proportionality trials, and vaccines trials.

This second edition addresses several recent developments in the field, including new chapters on adaptive bioequivalence studies, scaled average bioequivalence testing, and vaccine trials.

Purposefully designed to be instantly applicable, Bioequivalence and Statistics in Clinical Pharmacology, Second Edition provides examples of SAS and R code so that the analyses described can be immediately implemented. The authors have made extensive use of the proc mixed procedures available in SAS.

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 Bioavailability

Age and Gender Pharmacokinetic Studies

Ethnicity

Liver Disease

Kidney Disease

Technical Appendix

Vaccines & Epilogue

Vaccine Trials

Brief Introduction to Vaccine Research and Development

Phase I Vaccine Studies

Proof of Concept and Phase II

Lot Consistency

Concomitant Vaccination

Cross-over Trials in Vaccines

Epilogue

Bibliography

Index

Scott D. Patterson, Byron Jones