Design and Analysis of Bioavailability and Bioequivalence Studies: 3rd Edition (Hardback) book cover

Design and Analysis of Bioavailability and Bioequivalence Studies

3rd Edition

By Shein-Chung Chow, Jen-pei Liu

Chapman and Hall/CRC

760 pages | 55 B/W Illus.

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Preeminent Experts Update a Well-Respected Book

Taking into account the regulatory and scientific developments that have occurred since the second edition, Design and Analysis of Bioavailability and Bioequivalence Studies, Third Edition provides a complete presentation of the latest progress of activities and results in bioavailability and bioequivalence on regulatory requirements, scientific and practical issues, and statistical methodology.

New to the Third Edition

  • Four new chapters that present a thorough account of novel developments in the field
  • New and updated sections that reflect recent advances in the statistical methodology in the design and analysis of bioavailability and bioequivalence studies
  • Reorganization of the material into five parts, making it easier to access related information together
  • Over 100 new references from the literature

Like its bestselling predecessors, this edition covers all of the statistical problems that may occur in the various stages of design and data analysis. Keeping the mathematics and statistics at a fundamental level, it continues to focus on practical concepts rather than technical details.


… the improvement in the table of contents … makes it easier to navigate around the book. The new addition has added many new and extra chapters, which does a more comprehensive job of covering the subject of bioavailability and bioequivalence. … The SAS examples are better laid out in the new edition and these provide good resources in analyzing these studies. The first and second editions of this book have been invaluable for me … and I think it would be a good addition to anybody’s shelf. I would encourage anybody working in the industry to ensure there is a copy in their company. The mathematics in the book is not so complex as to make it unreadable for a nonmathematical person. It offers good insight into the workings of the regulatory guidelines and gives good practical advice in dealing with difficult situations.

—Alun Bedding, Pharmaceutical Statistics, 2010

…the book provides an encyclopedic coverage of all these issues and more. … [The first] two parts could lead to a good course on bioequivalence and its proxy, namely, bioavailability. …

International Statistical Review (2009), 77, 2

The text is well written and rich in all statistical methods … In summary, the book provides an important reference covering nearly all of the most relevant literature. Hence, it is a very valuable reference for anyone interested in the statistical aspects of bioequivalence.

Journal of Biopharmaceutical Statistics, 2009

Praise for the Second Edition

…The second edition brings with it some 170 further pages … new material includes sample size determination for higher order cross-over designs, meta-analysis for bioequivalence, and introduction to population and individual bioequivalence and some regulatory comments. The book is a thorough expose of a subject about which the authors have considerable expert knowledge. Its strengths are its encyclopedic coverage of the subject.


…a useful reference … also provides a historical perspective on the evolution of bioequivalence test methods in the context of regulatory policies and public debates on these issues. Detailed description of current statistical concepts, methodology, and underlying assumptions are provided and exemplified. The emphasis of this volume is on statistical concepts and methodology (as it should be).

Pharmaceutical Research, 2000

… The second edition of the book very substantially revises and expands the contents of the first edition … The book is well written and is quite comprehensive. It is useful particularly to statisticians involved in the design and assessment of bioequivalence studies …The concepts are presented clearly, and the many numerical illustrations helpfully assist the reader to assimilate the material … this is a valuable review of principles and procedures for the statistical assessment of bioequivalence studies. It can be recommended particularly for statisticians involved in these kinds of clinical trials. Non-statisticians interested in the quantitative aspects of these investigations could also benefit from its perusal.

ISCB News, June 2004

Table of Contents




History of Bioavailability Studies

Formulation and Routes of Administration

Pharmacokinetic Parameters

Clinically Important Differences

Assessment of Bioequivalence

Decision Rules and Regulatory Aspects

Statistical Considerations

Aims and Structure of the Book

Design of Bioavailability Studies


The Study Objectives

Basic Design Considerations

The Parallel Design

The Crossover Design

The Balanced Incomplete Block Design

The Selection of Design

Statistical Inference for Effects from a Standard 2 × 2 Crossover Design


The Carryover Effect

The Direct Drug Effect

The Period Effect

The Analysis of Variance

An Example

Average Bioequivalence

Statistical Methods for Average Bioequivalence


The Confidence Interval Approach

The Methods of Interval Hypothesis Testing

Bayesian Methods

Nonparametric Methods

Discussion and Other Alternatives

Power and Sample Size Determination


Hypotheses and Type I and Type II Errors

Power and Relative Efficiency

Sample Size Determination

Transformation and Analysis of Individual Subject Ratios


Multiplicative (or Log-transformation) Model

Bioequivalence Measures

Maximum Likelihood Estimator

Minimum Variance Unbiased Estimator

Mean of Individual Subject Ratios

Ration of Formulation Means

Comparison of MLE, MVUE, MIR, and RM

An Example


The Assessment of Inter- and Intrasubject Variabilities


Variability and Decision Making

Point and Interval Estimates

Test for Equality of Variabilities

Equivalence in Variability of Bioavailability

CV Assessment


Assumptions of Outlier Detection for Average Bioequivalence


Tests for Assumptions

The Definition of Outlying Observations

Detection of Outlying Subjects

Detection of Outlying Observations


Optimal Crossover Designs for Two Formulations for Average Bioequivalence


Balaam’s Design

The Two-Sequence Dual Design

Optimal Four-Period Designs

Transformation and Individual Subject Ratios

Sample Size for Higher-Order Crossover Designs



Assessment of Average Bioequivalence for More Than Two Formulations


Assessment of Average Bioavailability with More Than Two Formulations

Analyses for Williams Designs

Analysis for Balanced Incomplete Block Design


Population/Individual Bioequivalence

Population and Individual Bioequivalence


Limitation of Average Bioequivalence

Merits of Individual Bioequivalence and Desirable Bioequivalence Criteria

Measures of Discrepancy

Probability-Based Criteria

Moment-Based Criteria

Relations among Criteria

Bioequivalence Limits

Designs for Population and Individual Bioequivalence


Statistical Procedures for Assessment of Population and Individual   Bioequivalence


Estimation Procedures

Procedures for Moment-Based Criteria

Procedures for Probability-Based Criteria

Procedures for Evaluation of Population Bioequivalence


In Vitro and Alternative Evaluation of Bioequivalence

Assessment of Bioequivalence for Drugs with Negligible Plasma Levels


Design and Clinical Endpoints

Statistical Considerations

Weighted Least Squares Methods

Log-linear Models

Generalized Estimating Equations (GEE)

Analysis of Time to Onset of a Therapeutic Response


In Vitro Bioequivalence Testing


Regulatory Requirement

Profile Analysis

Nonprofile Analysis

An Example


In Vitro Dissolution Profiles Comparison


Criteria for Assessment Similarity between Dissolution Profiles

Estimation and Hypothesis Testing Based on f1 and f2

An Example


Other Bioequivalence Studies

Meta-analysis for Bioequivalence Review


Meta-Analysis for Average Bioequivalence

Alternative Method for Meta-Analysis

Efficiency of Meta-Analysis


Population Pharmacokinetics


Compartment model

Inter- and Intrasubject Variabilities

Nonlinear Modeling



Evaluation of Dose Proportionality, Steady State, and Food Effects


Drug Interaction Studies

Assessment of Dose Proportionality

Estimation of Steady State

Evaluation of Food Effects

Evaluation of Bioequivalence of Fixed-Combination Drug Products



Review of FDA Guidances


Guidance on Conjugated Estrogen Tablets

Guidance on General Considerations

Guidance on Statistical Procedures

Guidance on Nasal Aerosols and Nasal Spray for Local Action

Guidance on Scale-up and Postapproval Changes


Some Related Issues and Future Challenges


Assessment of Bioequivalence with Genomic Data

Bridging Bioequivalence Studies

Evaluation of Bioequivalence for Biological Products

Medical Device Equivalence

Post-approval Manufacturing Equivalence





About the Series

Chapman & Hall/CRC Biostatistics Series

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Subject Categories

BISAC Subject Codes/Headings:
MATHEMATICS / Probability & Statistics / General
MEDICAL / Pharmacology
MEDICAL / Biostatistics