Interface between Regulation and Statistics in Drug Development

Description

With the critical role of statistics in the design, conduct, analysis and reporting of clinical trials or observational studies intended for regulatory purposes, numerous guidelines have been issued by regulatory authorities around the world focusing on statistical issues related to drug development. However, the available literature on this important topic is sporadic, and often not readily accessible to drug developers or regulatory personnel. This book provides a systematic exposition of the interplay between the two disciplines, including emerging themes pertaining to the acceleration of the development of pharmaceutical medicines to serve patients with unmet needs. Features: Regulatory and statistical interactions throughout the drug development continuum The critical role of the statistician in relation to the changing regulatory and healthcare landscapes Statistical issues that commonly arise in the course of drug development and regulatory interactions Trending topics in drug development, with emphasis on current regulatory thinking and the associated challenges and opportunities The book is designed to be accessible to readers with an intermediate knowledge of statistics, and can be a useful resource to statisticians, medical researchers, and regulatory personnel in drug development, as well as graduate students in the health sciences. The authors’ decades of experience in the pharmaceutical industry and academia, and extensive regulatory experience, comes through in the many examples throughout the book. Cover Half Title Series Information Title Page Copyright Page Table of contents Figures Abbreviations Authors’ Disclosure Acknowledgment Preface About the Authors Chapter 1 Fundamental Principles of Clinical Trials 1.1 Introduction 1.2 General Statistical Considerations 1.2.1 Statistical Analysis Plan 1.2.2 Trial Design 1.2.3 Randomization and Blinding 1.2.4 Statistical Methodology 1.2.5 Reporting and Interpretation of Study Results 1.2.6 Data Quality and Software Validity 1.3 Evolving Roles of the Statistician in Drug Development 1.4 Potential Statistical Issues in Regulatory Review 1.4.1 Data Quality 1.4.2 Endpoint Definition 1.4.3 Design and Analysis Issues 1.4.4 Evaluation of Safety 1.4.5 Analysis Populations and Subgroups 1.4.6 Assessing Interpretation and Reliability of Results 1.5 Concluding Remarks Bibliography Chapter 2 Selected Statistical Topics of Regulatory Importance 2.1 Introduction 2.2 Multiplicity 2.2.1 Multiple Endpoints 2.2.2 Multiple Testing Over the Course of the Study 2.3 Missing Values and Estimands 2.3.1 General Considerations 2.3.2 Missingness Mechanisms 2.3.3 Approaches for Missing Data 2.3.4 Sensitivity Analyses 2.3.5 Estimands and Other Recent Regulatory Developments 2.3.6 Concluding Remarks 2.4 Non-inferiority Study 2.4.1 Efficacy Objective 2.4.2 Non-inferiority Hypothesis / Non-inferiority Margin 2.4.3 Determination of NIM 2.4.4 Example: FDA Guidance Document 2.4.5 Implications of Choice of NIM 2.4.6 Strength of a Non-inferiority Study 2.4.7 Synthesis Method for Non-inferiority 2.4.8 Summary Points 2.4.9 Non-inferiority Study with a Safety Objective 2.4.10 Summary Points 2.5 Innovative Trial Designs 2.5.1 Adaptive Designs 2.5.2 Adaptive Randomization 2.5.3 Sample Size Reestimation 2.5.4 Sequential Designs 2.5.5 Adaptive Designs for Dose and Treatment Selection 2.5.6 Adaptive Enrichment Designs 2.5.7 Master Protocols 2.5.7.1 Basket Trials 2.5.7.2 Umbrella Trials 2.5.7.3 Platform Trials 2.5.7.4 Regulatory and Operational Considerations with Novel Trials 2.6 Bayesian Analysis in a Regulatory Framework 2.6.1 Introduction 2.6.2 Potential Areas of Application 2.6.3 Regulatory Considerations 2.6.4 Challenges with Bayesian Statistics 2.6.5 Concluding Remarks 2.7 Surrogate Endpoints and Biomarkers 2.7.1 Introduction 2.7.2 Statistical Considerations 2.7.3 Regulatory Considerations 2.7.4 Concluding Remarks 2.8 Subgroup Analyses 2.8.1 Introduction 2.8.2 Subgroup Analyses in the Traditional Confirmatory Clinical-Trial Setting 2.8.3 Statistical Approaches 2.8.4 Reporting and Interpretation of Subgroup Results 2.8.5 Subgroup Analyses in the Changing Clinical-Trial and Regulatory Setting 2.8.6 Conclusion 2.9 Benefit–Risk Assessment 2.9.1 Introduction 2.9.2 Methodological Considerations in Benefit–Risk Analysis 2.9.3 Regulatory Perspectives 2.9.4 Benefit–Risk in Health-Technology Assessment 2.9.5 Concluding Remarks Bibliography Chapter 3 Statistical Engagement in Regulatory Interactions 3.1 Introduction 3.2 Internal Behaviors 3.3 Data Monitoring Committee 3.4 Regulatory Meetings and Advisory Committee Meetings 3.5 Statistical Role in Promotional Material and Medical Communication 3.6 Concluding Remarks Bibliography Chapter 4 Emerging Topics 4.1 The Use of RWE to Support Licensing and Label Enhancement 4.1.1 Introduction 4.1.2 Methodological and Operational Considerations 4.1.3 Current Regulatory Landscape 4.1.4 Concluding Remarks 4.2 Patient-Reported Outcomes in Regulatory Settings 4.2.1 Introduction 4.2.2 Development and Validation of PRO Instruments 4.2.3 Statistical Considerations 4.2.4 Regulatory Considerations 4.2.5 Concluding Remarks 4.3 Artificial Intelligence and Modern Analytics in Regulatory Settings 4.3.1 Introduction 4.3.2 AI in Drug Development 4.3.3 Regulatory Experience with Machine Learning and Artificial Intelligence 4.3.4 Concluding Remarks Bibliography Index