Table of contents for Bioequivalence studies in drug development : methods and applications / Dieter Hauschke, Volker Steinijans, Iris Pigeot.

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Contents
Preface
1 Introduction
1.1 Definitions
	1.1.1 Bioavailability
	1.1.2 Bioequivalence
	1.1.3 Therapeutic equivalence
1.2 When are bioequivalence studies performed
	1.2.1 Applications for products containing new active substances
	1.2.2 Applications for products containing approved active substances
	1.2.3 Applications for modified release forms essentially similar to a marketed modified
	release form
1.3 Design and conduct of bioequivalence studies
	1.3.1 Crossover design and alternatives
	1.3.2 Single vs. multiple dose studies
	1.3.3 Pharmacokinetic characteristics
	1.3.4 Subjects
	1.3.5 Statistical models
		1.3.5.1 Average bioequivalence
		1.3.5.2 Population bioequivalence
		1.3.5.3 Individual bioequivalence
	1.3.6 Sample size
1.4 Aims and structure of the book
References
2 Metrics to characterize concentration-time profiles in single- and multiple-dose bioequivalence studies
2.1 Introduction
2.2 Pharmacokinetic characteristics (metrics) for single-dose studies
	2.2.1 Extent of bioavailability
	2.2.2 Rate of bioavailability
2.3 Pharmacokinetic rate and extent characteristics (metrics) for multiple-dose studies
2.4 Conclusions
References
3 Basic statistical considerations
3.1 Introduction
3.2 Additive and multiplicative model
	3.2.1 The normal distribution
	3.2.2 The lognormal distribution
3.3 Hypotheses testing
	3.3.1 Consumer and producer risk
	3.3.2 Types of hypotheses 
		3.3.2.1 Test for difference
		3.3.2.2 Test for superiority
		3.3.2.3 Test for noninferiority
		3.3.2.4 Test for equivalence
	3.3.3 Difference versus ratio of expected means
		3.3.3.1 The normal distribution
		3.3.3.2 The lognormal distribution
3.4 The RT/TR crossover design assuming an additive model
	3.4.1 Additive model and effects
	3.4.2 Parametric analysis based on t-tests
		3.4.2.1 Test for difference in carryover effects
		3.4.2.2 Test for difference in formulation effects
		3.4.2.3 Test for difference in period effects
	3.4.3 Nonparametric analysis based on Wilcoxon rank sum tests
		3.4.3.1 Test for difference in carryover effects
		3.4.3.2 Test for difference in formulation effects
		3.4.3.3 Test for difference in period effects
References
4 Assessment of average bioequivalence in the RT/TR design
4.1 Introduction
4.2 The RT/TR crossover design assuming a multiplicative model
	4.2.1 Multiplicative model and effects
	4.2.2 Test problem
	4.2.3 Estimation of the formulation difference
4.3 Test procedures for bioequivalence assessment
	4.3.1 Analysis of variance
		4.3.1.1 Example: Dose equivalence study
	4.3.2 Two one-sided t-tests and 100% -confidence interval
		4.3.2.1 Example: Dose equivalence study
	4.3.3 Two one-sided Wilcoxon rank sum tests and 100%-confidence interval
		4.3.3.1 Example: Dose equivalence study
		4.3.3.2 Analysis of the characteristic time to maximum concentration
	4.3.4 Bioequivalence ranges
4.4 Conclusions
References
5 Power and sample size determination for testing average bioequivalence in the RT/TR design (18 pp, final)
5.1 Introduction
5.2 Challenging the classical approach
5.3 Exact power and sample size calculation
5.4 Modified acceptance ranges
5.5 Approximate formulas for sample size calculation
5.6 Exact power and sample size calculation by nQuery?
References
Appendix
6 Presentation of bioequivalence studies
6.1 Introduction
6.2 Results from a single-dose study
6.3 Results from a multiple-dose study
6.4 Conclusions
References
7 Designs with more than two formulations
7.1 Introduction
7.2 Williams designs
7.3 Example: Dose linearity study
7.4 Multiplicity
	7.4.1 Joint decision rule
	7.4.2 Multiple decision rule
7.5 Conclusions
References
8 Analysis of pharmacokinetic interactions
8.1 Introduction
8.2 Pharmacokinetic drug-drug interaction studies
	8.2.1 Absorption
	8.2.2 Distribution
	8.2.3 Elimination
		8.2.3.1 Metabolism
			8.2.3.1.1 Metabolic induction
			8.2.3.1.2 Metabolic inhibition
			8.2.3.1.3 Change of blood flow
		8.2.3.2 Renal excretion
		8.2.3.3 Hepatic/biliary excretion
	8.2.4 Experimental design of in vivo drug-drug interaction studies
	8.2.5 Examples to illustrate drug-drug interactions and the lack thereof
	8.2.6 Pharmacokinetic characteristics for extent of absorption and clearance in drug-drug 
		interaction studies
		8.2.6.1 Theoretical background on AUC as a composite measure of absorption and 
			clearance
		8.2.6.2 Examples to illustrate the composite character of AUC
		8.2.6.3 Recommendations for subsequent analyses
8.3 Pharmacokinetic food-drug interactions
	8.3.1 Classification of food effects
	8.3.2 Experimental design of food-drug interaction studies
	8.3.3 Example: Theophylline food interaction study
8.4 Goal posts for drug interaction studies including no effect boundaries
8.5 Labeling
8.6 Conclusions
References
9 Population and individual bioequivalence
9.1 Introduction
9.2 Brief history
9.3 Study Designs and statistical models
	9.3.1 Classical two-period, two-sequence crossover design
	9.3.2 Replicate designs
	9.3.3 Additive model
	9.3.4 Basic concepts of aggregate measures
	9.3.5 Example
9.4 Population bioequivalence
	9.4.1 Moment-based criteria
		9.4.1.1 Statistical procedures
		9.4.1.1.1 The bootstrap procedure
		9.4.1.1.2 A parametric confidence interval
	9.4.2 Probability-based criteria
		9.4.2.1 Statistical procedures
		9.4.2.1.1 A distribution-free approach
		9.4.2.1.1 A parametric approach
9.5 Individual bioequivalence
	9.5.1 Moment-based criteria
		9.5.1.1 Statistical procedures
		9.5.1.1.1 The bootstrap procedure
		9.5.1.1.2 A parametric confidence interval
	9.5.2 Probability-based criteria
		9.5.2.1 Statistical procedures
		9.5.2.1.1 A distribution-free approach
		9.5.2.1.1 A parametric approach
		9.5.2.1.3 Test for individual equivalence ratio (TIER)
	9.5.3 Relationships between aggregate bioequivalence criteria
	9.5.4 Drawbacks of aggregate criteria
9.6 Disaggregate criteria
	9.6.1 Stepwise procedure on the original scale
	9.6.2 Stepwise procedure on the logarithmic scale
9.7 Other approaches
	9.7.1 Trimmed Mallows distance
	9.7.2 Kullback-Leibler divergence
	9.7.3 Structural equation model
9.8 Average bioequivalence in replicate designs
9.9 Example: The anti-hypertensive patch dataset
9.10 Conclusions
References
10 Equivalence assessment in case of clinical endpoints
10.1 Introduction
10.2 Design and testing procedure
	 10.2.1 Parallel group design
	 10.2.2 Crossover design
10.3 Power and sample size calculation
	 10.3.1 Parallel group design
	 10.3.2 Crossover design
	 10.3.3 Approximate formulas for sample size calculation
	 10.3.4 Exact power and sample size calculation by nQuery?
10.4 Conclusions
References
Appendix
Subject index

Library of Congress Subject Headings for this publication:

Drugs -- Therapeutic equivalency.
Therapeutic Equivalency.
Clinical Trials -- methods.
Drug Design.