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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 220.127.116.11 Average bioequivalence 18.104.22.168 Population bioequivalence 22.214.171.124 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 126.96.36.199 Test for difference 188.8.131.52 Test for superiority 184.108.40.206 Test for noninferiority 220.127.116.11 Test for equivalence 3.3.3 Difference versus ratio of expected means 18.104.22.168 The normal distribution 22.214.171.124 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 126.96.36.199 Test for difference in carryover effects 188.8.131.52 Test for difference in formulation effects 184.108.40.206 Test for difference in period effects 3.4.3 Nonparametric analysis based on Wilcoxon rank sum tests 220.127.116.11 Test for difference in carryover effects 18.104.22.168 Test for difference in formulation effects 22.214.171.124 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 126.96.36.199 Example: Dose equivalence study 4.3.2 Two one-sided t-tests and 100% -confidence interval 188.8.131.52 Example: Dose equivalence study 4.3.3 Two one-sided Wilcoxon rank sum tests and 100%-confidence interval 184.108.40.206 Example: Dose equivalence study 220.127.116.11 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 18.104.22.168 Metabolism 22.214.171.124.1 Metabolic induction 126.96.36.199.2 Metabolic inhibition 188.8.131.52.3 Change of blood flow 184.108.40.206 Renal excretion 220.127.116.11 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 18.104.22.168 Theoretical background on AUC as a composite measure of absorption and clearance 22.214.171.124 Examples to illustrate the composite character of AUC 126.96.36.199 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 188.8.131.52 Statistical procedures 184.108.40.206.1 The bootstrap procedure 220.127.116.11.2 A parametric confidence interval 9.4.2 Probability-based criteria 18.104.22.168 Statistical procedures 22.214.171.124.1 A distribution-free approach 126.96.36.199.1 A parametric approach 9.5 Individual bioequivalence 9.5.1 Moment-based criteria 188.8.131.52 Statistical procedures 184.108.40.206.1 The bootstrap procedure 220.127.116.11.2 A parametric confidence interval 9.5.2 Probability-based criteria 18.104.22.168 Statistical procedures 22.214.171.124.1 A distribution-free approach 126.96.36.199.1 A parametric approach 188.8.131.52.3 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.
Clinical Trials -- methods.