Bioequivalence Studies in Drug Development Methods and Applications
by Hauschke, Dieter; Steinijans, Volker; Pigeot, IrisEdition: 1st
Format: Hardcover
Pub. Date: 2007-02-27
Publisher(s): WILEY
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Summary
Studies in bioequivalence are the commonly accepted method to demonstrate therapeutic equivalence between two medicinal products. Savings in time and cost are substantial when using bioequivalence as an established surrogate marker of therapeutic equivalence. For this reason the design, performance and evaluation of bioequivalence studies have received major attention from academia, the pharmaceutical industry and health authorities. Bioequivalence Studies in Drug Development focuses on the planning, conducting, analysing and reporting of bioequivalence studies, covering all aspects required by regulatory authorities. This text presents the required statistical methods, and with an outstanding practical emphasis, demonstrates their applications through numerous examples using real data from drug development. 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. Bioequivalence Studies in Drug Development is written in an accessible style that makes it ideal for pharmaceutical scientists, clinical pharmacologists, and medical practitioners, as well as biometricians working in the pharmaceutical industry. It will also be of great value for professionals from regulatory bodies assessing bioequivalence studies.
Author Biography
Dieter Hauschke, ALTANA Pharma, Konstanz, Germany. Well-respected statistician working in the pharmaceutical industry, specializing in bioequivalence studies, with over 60 publications in leading journals.
Volker Steinijans, ALTANA Pharma, Konstanz, Germany. Head of the Department of Biometry and Clinical Data Management at ALTANA.
Iris Pigeot, Institute for Statistics, University of Bremen, Germany. Has over 50 published papers, and also written a number of books in German.
Table of Contents
| Preface | p. xiii |
| Introduction | p. 1 |
| Definitions | p. 1 |
| Bioavailability | p. 2 |
| Bioequivalence | p. 2 |
| Therapeutic equivalence | p. 3 |
| When are bioequivalence studies performed | p. 4 |
| Applications for products containing new active substances | p. 4 |
| Applications for products containing approved active substances | p. 4 |
| Applications for modified release forms essentially similar to a marketed modified release form | p. 4 |
| Design and conduct of bioequivalence studies | p. 5 |
| Crossover design and alternatives | p. 5 |
| Single- vs. multiple-dose studies | p. 6 |
| Pharmacokinetic characteristics | p. 6 |
| Subjects | p. 7 |
| Statistical models | p. 8 |
| Average bioequivalence | p. 8 |
| Population bioequivalence | p. 9 |
| Individual bioequivalence | p. 11 |
| Sample size | p. 12 |
| Aims and structure of the book | p. 14 |
| References | p. 15 |
| Metrics to characterize concentration-time profiles in single- and multiple-dose bioequivalence studies | p. 17 |
| Introduction | p. 17 |
| Pharmacokinetic characteristics (metrics) for single-dose studies | p. 20 |
| Extent of bioavailability | p. 20 |
| Rate of bioavailability | p. 24 |
| Pharmacokinetic rate and extent characteristics (metrics) for multiple-dose studies | p. 26 |
| Conclusions | p. 34 |
| References | p. 34 |
| Basic statistical considerations | p. 37 |
| Introduction | p. 37 |
| Additive and multiplicative model | p. 38 |
| The normal distribution | p. 38 |
| The lognormal distribution | p. 41 |
| Hypotheses testing | p. 44 |
| Consumer and producer risk | p. 44 |
| Types of hypotheses | p. 46 |
| Test for difference | p. 47 |
| Test for superiority | p. 47 |
| Test for noninferiority | p. 48 |
| Test for equivalence | p. 49 |
| Difference versus ratio of expected means | p. 51 |
| The normal distribution | p. 51 |
| The lognormal distribution | p. 53 |
| The RT/TR crossover design assuming an additive model | p. 55 |
| Additive model and effects | p. 55 |
| Parametric analysis based on t-tests | p. 56 |
| Test for difference in carryover effects | p. 59 |
| Test for difference in formulation effects | p. 60 |
| Test for difference in period effects | p. 63 |
| Nonparametric analysis based on Wilcoxon rank sum tests | p. 65 |
| Test for difference in carryover effects | p. 65 |
| Test for difference in formulation effects | p. 66 |
| Test for difference in period effects | p. 67 |
| References | p. 68 |
| Assessment of average bioequivalence in the RT/TR design | p. 69 |
| Introduction | p. 69 |
| The RT/TR crossover design assuming a multiplicative model | p. 72 |
| Multiplicative model and effects | p. 73 |
| Test problem | p. 75 |
| Estimation of the formulation difference | p. 77 |
| Test procedures for bioequivalence assessment | p. 80 |
| Analysis of variance | p. 80 |
| Example: Dose equivalence study | p. 84 |
| Two one-sided t-tests and (1 - 2[alpha]) 100% confidence interval | p. 89 |
| Example: Dose equivalence study | p. 91 |
| Two one-sided Wilcoxon rank sum tests and (1 - 2[alpha]) 100% confidence interval | p. 94 |
| Example: Dose equivalence study | p. 96 |
| Analysis of time to maximum concentration | p. 97 |
| Bioequivalence ranges | p. 101 |
| Conclusions | p. 103 |
| References | p. 103 |
| Power and sample size determination for testing average bioequivalence in the RT/TR design | p. 105 |
| Introduction | p. 105 |
| Challenging the classical approach | p. 106 |
| Exact power and sample size calculation | p. 109 |
| Modified acceptance ranges | p. 112 |
| Approximate formulas for sample size calculation | p. 114 |
| Exact power and sample size calculation by nQuery | p. 117 |
| Appendix | p. 120 |
| References | p. 121 |
| Presentation of bioequivalence studies | p. 123 |
| Introduction | p. 123 |
| Results from a single-dose study | p. 124 |
| Results from a multiple-dose study | p. 140 |
| Conclusions | p. 152 |
| References | p. 154 |
| Designs with more than two formulations | p. 157 |
| Introduction | p. 157 |
| Williams designs | p. 158 |
| Example: Dose linearity study | p. 159 |
| Multiplicity | p. 161 |
| Joint decision rule | p. 165 |
| Multiple decision rule | p. 171 |
| Conclusions | p. 172 |
| References | p. 172 |
| Analysis of pharmacokinetic interactions | p. 175 |
| Introduction | p. 175 |
| Pharmacokinetic drug-drug interaction studies | p. 178 |
| Absorption | p. 178 |
| Distribution | p. 178 |
| Elimination | p. 178 |
| Metabolism | p. 179 |
| Metabolic induction | p. 179 |
| Metabolic inhibition | p. 181 |
| Change of blood flow | p. 182 |
| Renal excretion | p. 182 |
| Hepatic/biliary excretion | p. 183 |
| Experimental design of in vivo drug-drug interaction studies | p. 183 |
| Examples to illustrate drug-drug interactions and the lack thereof | p. 184 |
| Pharmacokinetic characteristics for extent of absorption and clearance in drug-drug interaction studies | p. 187 |
| Theoretical background on AUC as a composite measure of absorption and clearance | p. 190 |
| Examples to illustrate the composite character of AUC | p. 192 |
| Recommendation for subsequent analyses | p. 193 |
| Pharmacokinetic food-drug interactions | p. 194 |
| Classification of food effects | p. 194 |
| Experimental design of food-drug interaction studies | p. 196 |
| Example: Theophylline food interaction study | p. 197 |
| Goal posts for pharmacokinetic drug interaction studies including no effect boundaries | p. 197 |
| Labeling | p. 199 |
| Conclusions | p. 200 |
| References | p. 200 |
| Population and individual bioequivalence | p. 205 |
| Introduction | p. 205 |
| Brief history | p. 208 |
| Study designs and statistical models | p. 210 |
| Classical two-period, two-sequence crossover design | p. 210 |
| Replicate designs | p. 210 |
| Additive model | p. 212 |
| Basic concepts of aggregate measures | p. 213 |
| Example: The antihypertensive patch dataset | p. 215 |
| Population bioequivalence | p. 217 |
| Moment-based criteria | p. 217 |
| Statistical procedures | p. 219 |
| The bootstrap procedure | p. 219 |
| A parametric confidence interval | p. 220 |
| Probability-based criteria | p. 225 |
| Statistical procedures | p. 225 |
| A distribution-free approach | p. 225 |
| A parametric approach | p. 228 |
| Individual bioequivalence | p. 230 |
| Moment-based criteria | p. 230 |
| Statistical procedures | p. 232 |
| The bootstrap procedure | p. 232 |
| A parametric confidence interval | p. 233 |
| Probability-based criteria | p. 236 |
| Statistical procedures | p. 236 |
| A distribution-free approach | p. 237 |
| A parametric approach | p. 239 |
| Test for individual equivalence ratio (TIER) | p. 241 |
| Relationships between aggregate bioequivalence criteria | p. 243 |
| Drawbacks of aggregate measures | p. 245 |
| Disaggregate criteria | p. 246 |
| Stepwise procedure on the original scale | p. 246 |
| Stepwise procedure on the logarithmic scale | p. 253 |
| Other approaches | p. 255 |
| Trimmed Mallows distance | p. 255 |
| Kullback-Leibler divergence | p. 256 |
| Structural equation model | p. 257 |
| Average bioequivalence in replicate designs | p. 258 |
| Example: The antihypertensive patch dataset | p. 259 |
| Conclusions | p. 278 |
| References | p. 280 |
| Equivalence assessment for clinical endpoints | p. 283 |
| Introduction | p. 283 |
| Design and testing procedure | p. 285 |
| Parallel group design | p. 285 |
| Crossover design | p. 287 |
| Power and sample size calculation | p. 289 |
| Parallel group design | p. 289 |
| Crossover design | p. 292 |
| Approximate formulas for sample size calculation | p. 297 |
| Exact power and sample size calculation by nQuery | p. 302 |
| Conclusions | p. 303 |
| Appendix | p. 304 |
| References | p. 305 |
| Index | p. 307 |
| Table of Contents provided by Ingram. All Rights Reserved. |
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