Design and Analysis of Bioavailability and Bioequivalence Studies, Third Edition BABE-Solution bundle version

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

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 × 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