2nd Edition

Bioequivalence and Statistics in Clinical Pharmacology

By Scott D. Patterson, Byron Jones Copyright 2017
    460 Pages
    by Chapman & Hall

    460 Pages 75 B/W Illustrations
    by Chapman & Hall

    460 Pages 75 B/W Illustrations
    by Chapman & Hall

    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


    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


    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


    Data-based Simulation


    Optimal Designs

    Determining Trial Size

    What Outliers Are and How to Handle Their Data

    Bayesian BE Assessment

    Adaptive Bioequivalence Trials


    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


    Techniccal Appendix: R code

    Scaled Average Bioequivalence Testing


    Scaled Average Bioequivalence in Europe

    Scaled Average Bioequivalence in USA

    Discussion and Cautions

    Clinical Pharmacology

    Clinical Pharmacology Safety Studies



    Sub-chronic Dosing Studies

    Food-Effect Assessment and DDIs


    Technical Appendix



    Modelling of QTc Data

    Interpreting the QTc Modelling Findings

    Design of a Thorough QTc Study in the Future

    Clinical Pharmacology Efficacy Studies


    Sub-chronic Dosing

    Phase IIa and the Proof of Concept

    Population Pharmacokinetics

    Population and Pharmacokinetics

    Absolute and Relative Bioavailabili


    Scott D. Patterson, Byron Jones