Bioequivalence and Statistics in Clinical Pharmacology

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