Design and Analysis of Bioavailability and Bioequivalence Studies  book cover
3rd Edition

Design and Analysis of Bioavailability and Bioequivalence Studies

ISBN 9781584886686
Published October 15, 2008 by Chapman and Hall/CRC
760 Pages 55 B/W Illustrations

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Book Description

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.

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

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… 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