Design and Analysis of Bioavailability and Bioequivalence Studies

About this book

Maintaining the same practical viewpoint as its bestselling predecessors, this third edition presents a comprehensive, unified summary of the vast and continually growing literature and research activities in the field. It focuses on regulatory requirements, current scientific and practical issues, and the statistical methodology of designing and analyzing bioequivalence studies. The preeminent authors cover the assessment of food effect on bioequivalence, bioequivalence for drugs with local action, the qualitative determination of pharmaceutical equivalence, bioequivalence for biological products, medical devices, the use of genomic information in assessing bioequivalence, and ethnical and gender differences in assessing bioequivalence.

Contents

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 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 A-- 2 Crossover Design Introduction The Carryover Effect The Direct Drug Effect The Period Effect The Analysis of Variance An Example Average Bioequivalence Statistical Methods for Average Bioequivalence Introduction The Confidence Interval Approach The 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-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 Discussion The 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 The 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 The 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/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 Procedures 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 (GEE) Analysis of Time to Onset of a Therapeutic Response Discussion In Vitro Bioequivalence Testing Background Regulatory Requirement Profile Analysis Nonprofile Analysis An Example Discussion In Vitro Dissolution Profiles Comparison Introduction Criteria for Assessment Similarity between Dissolution Profiles Estimation and Hypothesis Testing Based on f1 and f2 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 Compartment model Inter- and Intrasubject Variabilities Nonlinear Modeling NOMEN Discussion Evaluation of Dose Proportionality, Steady State, and Food Effects Introduction Drug Interaction Studies Assessment of Dose Proportionality Estimation of Steady State Evaluation of Food Effects Evaluation of Bioequivalence of Fixed-Combination Drug Products Discussion Review of FDA Guidances Introduction 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 Discussion Some Related Issues and Future Challenges Introduction Assessment of Bioequivalence with Genomic Data Bridging Bioequivalence Studies Evaluation of Bioequivalence for Biological Products Medical Device Equivalence Post-approval Manufacturing Equivalence Discussion References Appendices Index

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Biography

Duke University School of Medicine, Durham, North Carolina, National Taiwan University, Taipei, Taiwan