Bioequivalence Studies in Drug Development focuses on the planning, conducting, analysing and reporting of bioequivalence studies, covering all aspects required by regulatory authorities.

Features:

• Includes all the necessary pharmacokinetic background information
• Presents parametric and nonparametric statistical techniques
• Describes adequate methods for power and sample size determination
• Includes appropriate presentation of results from bioequivalence studies
• Provides a practical overview of the design and analysis of bioequivalence studies
• Presents the recent developments in methodology, including population and individual bioequivalence
• Reviews the regulatory guidelines for such studies, and the existing global discrepancies
• Discusses the designs and analyses of drug-drug and food-drug interaction studies

Contents

Introduction

• Bioavailability
• Bioequivalence
• Therapeutic equivalence
• When are bioequivalence studies performed
• Applications for products containing new active substances
• Applications for products containing approved active substances
• Applications for modified release forms essentially similar to a marketed modified release form
• Design and conduct of bioequivalence studies
• Crossover design and alternatives
• Single vs. multiple dose studies
• Pharmacokinetic characteristics
• Subjects
• Statistical models
• Average bioequivalence
• Population bioequivalence
• Individual bioequivalence
• Sample size
• Aims and structure of the book

Metrics to characterize concentration-time profiles in single- and multiple-dose bioequivalence studies

• Pharmacokinetic characteristics (metrics) for single-dose studies
• Extent of bioavailability
• Rate of bioavailability
• Pharmacokinetic rate and extent characteristics (metrics) for multiple-dose studies

Basic statistical considerations

• Additive and multiplicative model
• The normal distribution
• The lognormal distribution
• Hypotheses testing
• Consumer and producer risk
• Types of hypotheses
• Test for difference
• Test for superiority
• Test for noninferiority
• Test for equivalence
• Difference versus ratio of expected means
• The normal distribution
• The lognormal distribution
• The RT/TR crossover design assuming an additive model.
• Additive model and effects
• Parametric analysis based on t-tests
• Test for difference in carryover effects
• Test for difference in formulation effects
• Test for difference in period effects
• Nonparametric analysis based on Wilcoxon rank sum tests
• Test for difference in carryover effects
• Test for difference in formulation effects
• Test for difference in period effects

Assessment of average bioequivalence in the RT/TR design

• The RT/TR crossover design assuming a multiplicative model
• Multiplicative model and effects
• Test problem
• Estimation of the formulation difference
• Test procedures for bioequivalence assessment
• Analysis of variance
• Example: Dose equivalence study
• Two one-sided t-tests and (1-2a) 100% -confidence interval
• Example: Dose equivalence study
• Two one-sided Wilcoxon rank sum tests and (1-2a) 100%-confidence interval
• Example: Dose equivalence study
• Analysis of the characteristic time to maximum concentration
• Bioequivalence ranges

Power and sample size determination for testing average bioequivalence in the RT/TR design

• Challenging the classical approach
• Exact power and sample size calculation
• Modified acceptance ranges
• Approximate formulas for sample size calculation
• Exact power and sample size calculation by nQuery

Presentation of bioequivalence studies

• Results from a single-dose study
• Results from a multiple-dose study

Designs with more than two formulations

• Williams designs
• Example: Dose linearity study
• Multiplicity
• Joint decision rule
• Multiple decision rule

Analysis of pharmacokinetic interactions

• Pharmacokinetic drug-drug interaction studies
• Absorption
• Distribution
• Elimination
• Metabolism
• Metabolic induction
• Metabolic inhibition
• Change of blood flow
• Renal excretion
• Hepatic/biliary excretion
• Experimental design of in vivo drug-drug interaction studies
• Examples to illustrate drug-drug interactions and the lack thereof
• Pharmacokinetic characteristics for extent of absorption and clearance in drug-drug interaction studies
• Theoretical background on AUC as a composite measure of absorption and clearance
• Examples to illustrate the composite character of AUC
• Recommendations for subsequent analyses
• Pharmacokinetic food-drug interactions
• Classification of food effects
• Experimental design of food-drug interaction studies
• Example: Theophylline food interaction study
• Goal posts for drug interaction studies including no effect boundaries
• Labeling

Population and individual bioequivalence

• Brief history
• Study designs and statistical models
• Classical two-period, two-sequence crossover design
• Replicate designs
• Additive model
• Basic concepts of aggregate measures
• Example
• Population bioequivalence
• Moment-based criteria
• Statistical procedures

Equivalence assessment in case of clinical endpoints

• Design and testing procedure
• Parallel group design
• Crossover design
• Power and sample size calculation
• Parallel group design
• Crossover design
• Approximate formulas for sample size calculation
• Exact power and sample size calculation by nQuery

Index

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