Preface
Preliminaries
Introduction
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
Introduction
Study Objective
Basic Design Considerations
Parallel Design
The Crossover Design
Balanced Incomplete Block Design
Selection of Design
Statistical Inference for Effects from a Standard 2 x 2 Crossover Design
Introduction
Carryover Effects
Direct Drug Effect
Period Effect
Analysis of Variance
An Example
Average Bioequivalence
Statistical Methods for Average Bioequivalence
Introduction
Confidence Interval Approach
Methods of Interval Hypothesis Testing
Bayesian Methods
Nonparametric Methods
Discussion and Other Alternatives
Power and Sample Size Determination
Introduction
Hypotheses and Type I and Type II Errors
Power and Relative Efficiency
Sample Size Determination
Transformation and Analysis of Individual Subject Ratios
Introduction
Multiplicative (or Log-Transformed) Model
Bioequivalence Measures
Maximum Likelihood Estimator
Minimum Variance Unbiased Estimator
Mean of Individual Subject Ratios
Ratio of Formulation Means
Comparison of MLE, MVUE, MIR, and RM
An Example
Discussion
Assessment of Inter- and Intrasubject Variabilities
Introduction
Variability and Decision Making
Point and Interval Estimates
Test for Equality of Variabilities
Equivalence in Variability of Bioavailability
CV Assessment
Discussion
Assumptions of Outlier Detection for Average Bioequivalence
Introduction
Tests for Assumptions
Definition of Outlying Observations
Detection of Outlying Subjects
Detection of Outlying Observations
Discussion
Optimal Crossover Designs for Two Formulations for Average Bioequivalence
Introduction
Balaam's Design
Two-Sequence Dual Design
Optimal Four-Period Designs
Transformation and Individual Subject Ratios
Sample Size for Higher-Order Crossover Designs
Discussion
Assessment of Average Bioequivalence for More Than Two Formulations
Introduction
Assessment of Average Bioavailability with More Than Two Formulations
Analyses for Williams Designs
Analysis for Balanced Incomplete Block Design
Discussion
Population and Individual Bioequivalence
Population and Individual Bioequivalence
Introduction
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
Discussion
Statistical Procedures for Assessment of Population and Individual Bioequivalence
Introduction
Estimation Procedures
Procedures for Moment-Based Criteria
Procedures for Probability-Based Criteria
Generalized p-Values for Evaluation of Population Bioequivalence
Discussion
In Vitro and Alternative Evaluation of Bioequivalence
Assessment of Bioequivalence for Drugs with Negligible Plasma Levels
Introduction
Design and Clinical Endpoints
Statistical Considerations
Weighted Least Squares Methods
Log-Linear Models
Generalized Estimating Equations
Analysis of Time to Onset of a Therapeutic Response
Discussion
In Vitro Bioequivalence Testing
Introduction
Study Design and Data Collection
Bioequivalence Limit
Statistical Methods
An Example
Sample Size Determination
Discussion
In Vitro Dissolution Profiles Comparison
Introduction
Criterion for Assessment of Similarity between Dissolution Profiles
Inference for Similarity Factors
Approaches Based on Multivariate Confidence Regions
An Example
Discussion
Other Bioequivalence Studies
Meta-Analysis for Bioequivalence Review
Introduction
Meta-Analysis for Average Bioequivalence
Alternative Method for Meta-Analysis
Efficiency of Meta-Analysis
Discussion
Population Pharmacokinetics
Introduction
Regulatory Requirements
Population PK Modeling
Design of Population PK
An Example
Discussion
Other Pharmacokinetic Studies
Introduction
Drug Interaction Studies
Dose Proportionality Study
Steady-State Analysis
Evaluation of Food Effects
Discussion
Review of Regulatory Guidances on Bioequivalence
Introduction
Guidances on Statistical Procedures
Guidances on General Considerations for Bioequivalence
Guidances on Bioequivalence for Special Drug Products
Critical Path Opportunities for Generic Drugs
Discussion
Frequently Asked Questions and Future Challenges
Introduction
Assessment of Bioequivalence Using Genomic Information
Bridging Bioequivalence Studies
Bioequivalence for Biological Products
Frequently Asked Questions in Bioequivalence
Discussion
References
Appendix A: Statistical Tables
Appendix B: SAS Programs
Index
