Methods and Applications of Sample Size Calculation and Recalculation in Clinical Trials (Springer Series in Pharmaceutical Statistics)

This book provides an extensive overview of the principles and methods of sample size calculation and recalculation in clinical trials. Appropriate calculation of the required sample size is crucial for the success of clinical trials. At the same time, a sample size that is too small or too large is problematic due to ethical, scientific, and economic reasons. Therefore, state-of-the art methods are required when planning clinical trials. Part I describes a general framework for deriving sample size calculation procedures. This enables an understanding of the common principles underlying the numerous methods presented in the following chapters. Part II addresses the fixed sample size design, where the required sample size is determined in the planning stage and is not changed afterwards. It covers sample size calculation methods for superiority, non-inferiority, and equivalence trials, as well as comparisons between two and more than two groups. A wide range of further topics is discussed, including sample size calculation for multiple comparisons, safety assessment, and multi-regional trials. There is often some uncertainty about the assumptions to be made when calculating the sample size upfront. Part III presents methods that allow to modify the initially specified sample size based on new information that becomes available during the ongoing trial. Blinded sample size recalculation procedures for internal pilot study designs are considered, as well as methods for sample size reassessment in adaptive designs that use unblinded data from interim analyses. The application is illustrated using numerous clinical trial examples, and software code implementing the methods is provided. The book offers theoretical background and practical advice for biostatisticians and clinicians from the pharmaceutical industry and academia who are involved in clinical trials. Covering basic as well as more advanced and recently developed methods, it is suitable for beginners, experienced applied statisticians, and practitioners. To gain maximum benefit, readers should be familiar with introductory statistics. The content of this book has been successfully used for courses on the topic. Front Matter ....Pages i-xiv Front Matter ....Pages 1-1 Introduction (Meinhard Kieser)....Pages 3-10 Statistical Test and Sample Size Calculation (Meinhard Kieser)....Pages 11-16 Front Matter ....Pages 17-17 Comparison of Two Groups for Normally Distributed Outcomes and Test for Difference or Superiority (Meinhard Kieser)....Pages 19-36 Comparison of Two Groups for Continuous and Ordered Categorical Outcomes and Test for Difference or Superiority (Meinhard Kieser)....Pages 37-45 Comparison of Two Groups for Binary Outcomes and Test for Difference or Superiority (Meinhard Kieser)....Pages 47-63 Comparison of Two Groups for Time-to-Event Outcomes and Test for Difference or Superiority (Meinhard Kieser)....Pages 65-77 Comparison of More Than Two Groups and Test for Difference (Meinhard Kieser)....Pages 79-89 Comparison of Two Groups and Test for Non-Inferiority (Meinhard Kieser)....Pages 91-112 Comparison of Three Groups in the Gold Standard Non-Inferiority Design (Meinhard Kieser)....Pages 113-124 Comparison of Two Groups for Normally Distributed Outcomes and Test for Equivalence (Meinhard Kieser)....Pages 125-132 Multiple Comparisons (Meinhard Kieser)....Pages 133-156 Assessment of Safety (Meinhard Kieser)....Pages 157-166 Cluster-Randomized Trials (Meinhard Kieser)....Pages 167-173 Multi-Regional Trials (Meinhard Kieser)....Pages 175-184 Integrated Planning of Phase II/III Drug Development Programs (Meinhard Kieser)....Pages 185-192 Simulation-Based Sample Size Calculation (Meinhard Kieser)....Pages 193-195 Front Matter ....Pages 197-197 Basic Concepts of Sample Size Recalculation (Meinhard Kieser)....Pages 199-200 Front Matter ....Pages 201-201 Internal Pilot Study Designs (Meinhard Kieser)....Pages 203-205 A General Approach for Controlling the Type I Error Rate for Blinded Sample Size Recalculation (Meinhard Kieser)....Pages 207-207 Comparison of Two Groups for Normally Distributed Outcomes and Test for Difference or Superiority (Meinhard Kieser)....Pages 209-224 Comparison of Two Groups for Binary Outcomes and Test for Difference or Superiority (Meinhard Kieser)....Pages 225-237 Comparison of Two Groups for Normally Distributed Outcomes and Test for Non-Inferiority (Meinhard Kieser)....Pages 239-246 Comparison of Two Groups for Binary Outcomes and Test for Non-Inferiority (Meinhard Kieser)....Pages 247-254 Comparison of Two Groups for Normally Distributed Outcomes and Test for Equivalence (Meinhard Kieser)....Pages 255-256 Regulatory and Operational Aspects (Meinhard Kieser)....Pages 257-258 Concluding Remarks (Meinhard Kieser)....Pages 259-260 Front Matter ....Pages 261-261 Group Sequential and Adaptive Designs (Meinhard Kieser)....Pages 263-269 Sample Size Recalculation Based on Conditional Power (Meinhard Kieser)....Pages 271-277 Sample Size Recalculation Based on Optimization (Meinhard Kieser)....Pages 279-287 Regulatory and Operational Aspects (Meinhard Kieser)....Pages 289-291 Concluding Remarks (Meinhard Kieser)....Pages 293-293 Back Matter ....Pages 295-396