Bioequivalence and Statistics in Clinical Pharmacology

Scott D. Patterson, Byron Jones

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