Bioequivalence Studies in Drug Development

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.

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.

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
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Bioequivalence Studies in Drug Development Methods and Applications

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