Interdisciplinary Statistics

BIOEQUIVALENCE and STATISTICS in CLINICAL PHARMACOLOGY

Scott Patterson GlaxoSmithKline Pharmaceuticals Pennsylvania, USA Byron Jones Pfizer Global Research & Development Kent, UK

Chapman & Hall/CRC Taylor & Francis Croup Boca Raton London New York Contents

Preface xi

List of figures xiii

List of tables xv

1 Drug Development and Clinical Pharmacology 1 1.1 Aims of This Book 2 1.2 Drug Development 3 1.3 Clinical Pharmacology 5 1.4 Statistics in Clinical Pharmacology 11 1.5 Structure of the Book 14

2 History and Regulation of Bioequivalence 17 2.1 When and How BE Studies Are Performed 19 2.2 Why Are BE Studies Performed? 27 2.3 Deciding When Formulations Are Bioequivalent 28 2.4 Potential Issues with TOST Bioequivalence 32 2.5 Current International Regulation 36

3 Testing for Average Bioequivalence 39 3.1 Background 39 3.2 Linear Model for 2 x 2 Data 44 3.3 Applying the TOST Procedure 49 3.4 Carry-over, Sequence, and Interaction Effects 52 3.5 Checking Assumptions Made about the Linear Model 56 3.6 Power and Sample Size for ABE in the 2x2 Design 58 3.7 Example Where Test and Reference Are Not ABE (il 3.8 Nonparametric Analysis 68 3.9 Some Practical Issues 76

4 BE Studies with More Than Two Periods 79 4.1 Background 80 4.2 Three-period Designs 81 viii CONTENTS 4.3 Within-subject Variability 87 4.4 Robust Analyses for Three Period Designs 90 4.5 Four-period Designs 92 4.6 Designs with More Than Two Treatments 96 4.7 Nonparametric Analyses of Tmax 102 4.8 Technical Appendix: Efficiency 116 4.9 Tables of Data 120

5 Dealing with Unexpected BE Challenges 133 5.1 Restricted Maximum Likelihood Modelling 135 5.2 Failing BE and the DER Assessment 138 5.3 Simulation 143 5.4 Data-based Simulation 145 5.5 Carry-over 147 5.6 Optional Designs 154 5.7 Determining Trial Size 160 5.8 What Outliers Are and How to Handle Their Data 165 5.9 Bayesian BE Assessment 167 5.10 Technical Appendix 170

6 The Future and Recent Past of BE Testing 177 6.1 Brief History 178 6.2 Individual and Population BE 181 6.3 Scaled Average BE 186

7 Clinical Pharmacology Safety Studies 189 7.1 Background 191 7.2 First-time-in-humans 194 7.3 Sub-chronic Dosing Studies 208 7.4 Food-Effect Assessment and DDIs 221 7.5 Dose-Proportionality 233 7.6 Technical Appendix 240

8 QTc 243 8.1 Background 244 8.2 Modelling of QTc Data 247 8.3 Interpreting the QTc Modelling Findings 254 8.4 Design of a Thorough QTc Study in the Future 259 8.5 Technical Appendix 262

9 Clinical Pharmacology Efficacy Studies 269 9.1 Background 270 9.2 Sub-chronic Dosing 274 CONTENTS ix 9.3 Phase Ha and the Proof of Concept 282 9.4 Methodology Studies 294

10 Population Pharmacokinetics 299 10.1 Population and Pharmacokinetics 300 10.2 Absolute and Relative Bioavailability 307 10.3 Age and Gender Pharmacokinetic Studies 311 10.4 Ethnicity 316 10.5 Liver Disease 321 10.6 Kidney Disease 325

10.7 Technical Appendix 328

11 Epilogue 333

Bibliography 335

Index 371