In clinical trial practice, controversial statistical issues inevitably occur regardless of the compliance with good statistical practice and good clinical practice. But by identifying the causes of the issues and correcting them, the study objectives of clinical trials can be better achieved. Controversial Statistical Issues in Clinical Trials covers commonly encountered controversial statistical issues in clinical trials and, whenever possible, makes recommendations to resolve these problems.
The book focuses on issues occurring at various stages of clinical research and development, including early-phase clinical development (such as bioavailability/bioequivalence), bench-to-bedside translational research, and late-phase clinical development. Numerous examples illustrate the impact of these issues on the evaluation of the safety and efficacy of the test treatment under investigation. The author also offers recommendations regarding possible resolutions of the problems.
Written by one of the preeminent experts in the field, this book provides a useful desk reference and state-of-the art examination of problematic issues in clinical trials for scientists in the pharmaceutical industry, medical/statistical reviewers in government regulatory agencies, and researchers and students in academia.
Shein-Chung Chow, Ph.D., is a professor in the Department of Biostatistics and Bioinformatics at Duke University School of Medicine. Dr. Chow is also an adjunct professor of clinical sciences at Duke-National University of Singapore Graduate Medical School and the editor-in-chief of the Journal of Biopharmaceutical Statistics. He has authored or co-authored more than 200 papers and 19 books, including the recently published Handbook of Adaptive Designs in Pharmaceutical and Clinical Development. He earned his Ph.D. in statistics from the University of Wisconsin-Madison.
Introduction Pharmaceutical Development Controversial Issues Aim and Structure of the Book Good Statistical Practices Statistical Principles Good Statistical Practices in Europe Implementation of GSP Bench-to-Bedside Translational Research Biomarker Development One-Way/Two-Way Translational Process Lost in Translation Animal Model versus Human Model Bioavailability and Bioequivalence Bioequivalence Assessment Drug Interchangeability Controversial Issues Frequently Asked Questions Hypotheses for Clinical Evaluation and Significant Digits Hypotheses for Clinical Evaluation Statistical Methods for Testing Composite Hypotheses of NS The Impact on Power and Sample Size Calculation Significant Digits Instability of Sample Size Calculation Sample Size Calculation Instability and Bootstrap-Median Approach Simulation Study An Example Integrity of Randomization/Blinding The Effect of Mixed-Up Randomization Blocking Size in Randomization Test for Integrity of Blinding Analysis under Breached Blindness An Example Clinical Strategy for Endpoint Selection Clinical Strategy for Endpoint Selection Translations among Clinical Endpoints Comparison of Different Clinical Strategies A Numerical Study Protocol Amendments Moving Target Patient Population Analysis with Covariate Adjustment Assessment of Sensitivity Index Sample Size Adjustment Seamless Adaptive Trial Designs Controversial Issues Types of Two-Stage Seamless Adaptive Designs Analysis for Seamless Design with Same Study Objectives/Endpoints Analysis for Seamless Design with Different Endpoints Analysis for Seamless Design with Different Objectives/Endpoints Multiplicity in Clinical Trials General Concept Regulatory Perspective and Controversial Issues Statistical Method for Adjustment of Multiplicity Gatekeeping Procedures Independence of Data Monitoring Committee Regulatory Requirements DMC Composition and Charter DMC's Functions and Activities Independence of DMC Two-Way ANOVA versus One-Way ANOVA with Repeated Measures One-Way ANOVA with Repeated Measures Two-Way ANOVA Statistical Evaluation Simulation Study An Example Discussion Validation of QOL Instruments QOL Assessment Performance Characteristics Responsiveness and Sensitivity Utility Analysis and Calibration Analysis of Parallel Questionnaire An Example Missing Data Imputation Last Observation Carry Forward Mean/Median Imputation Regression Imputation Marginal/Conditional Imputation for Contingency Testing for Independence Controversial Issues Recent Development Center Grouping Selection of the Number of Centers Impact of Treatment Imbalance on Power Center Grouping Procedure for Center Grouping An Example Non-Inferiority Margin Non-Inferiority Margin Statistical Test Based on Treatment Difference Statistical Tests Based on Relative Risk Mixed Non-Inferiority Margin Recent Developments QT Studies with Recording Replicates Study Designs and Models Power and Sample Size Calculation Adjustment for Covariates Optimization for Sample Size Allocation Test for QT/QTc Prolongation Recent Developments Multiregional Clinical Trials Multiregional (Multinational), Multicenter Trials Selection of the Number of Sites Sample Size Calculation and Allocation Statistical Methods for Bridging Studies Dose Escalation Trials Traditional Escalation Rule Continual Reassessment Method Design Selection and Sample Size Enrichment Process in Target Clinical Trials Identification of Differentially Expressed Genes Optimal Representation of In Vitro Diagnostic Multivariate Index Assays Validation of In Vitro Diagnostic Multivariate Index Assays Enrichment Process Study Designs of Target Clinical Trials Analysis of Target Clinical Trials Discussion Clinical Trial Simulation Process for Clinical Trial Simulation EM Algorithm Resampling Method: Bootstrapping Clinical Applications Traditional Chinese Medicine Fundamental Differences Basic Considerations Controversial Issues Recent Development The Assessment of Follow-On Biologic Products Regulatory Requirements Criteria for Biosimilarity Scientific Issues Assessing Similarity Using Genomic Data Generalizability/Reproducibility Probability The Estimated Power Approach The Confidence Bound Approach The Bayesian Approach Applications Good Review Practices Regulatory Process and Requirements Good Review Practices Obstacles and Challenges Probability of Success Go/No-Go Decision in Development Process POS Assessment References Index