This edited volume is a definitive text on adaptive clinical trial designs from creation and customization to utilization. As this book covers the full spectrum of topics involved in the adaptive designs arena, it will serve as a valuable reference for researchers working in industry, government and academia. The target audience is anyone involved in the planning and execution of clinical trials, in particular, statisticians, clinicians, pharmacometricians, clinical operation specialists, drug supply managers, and infrastructure providers. In spite of the increased efficiency of adaptive trials in saving costs and time, ultimately getting drugs to patients sooner, their adoption in clinical development is still relatively low. One of the chief reasons is the higher complexity of adaptive design trials as compared to traditional trials. Barriers to the use of clinical trials with adaptive features include the concerns about the integrity of study design and conduct, the risk of regulatory non-acceptance, the need for an advanced infrastructure for complex randomization and clinical supply scenarios, change management for process and behavior modifications, extensive resource requirements for the planning and design of adaptive trials and the potential to relegate key decision makings to outside entities. There have been limited publications that address these practical considerations and recommend best practices and solutions. This book fills this publication gap, providing guidance on practical considerations for adaptive trial design and implementation. The book comprises three parts: Part I focuses on practical considerations from a design perspective, whereas Part II delineates practical considerations related to the implementation of adaptive trials. Putting it all together, Part III presents four illustrative case studies ranging from description and discussion of specific adaptive trial design considerations to the logistic and regulatory issues faced in trial implementation.
Bringing together the expertise of leading key opinion leaders from pharmaceutical industry, academia, and regulatory agencies, this book provides a balanced and comprehensive coverage of practical considerations for adaptive trial design and implementation.
Weili He is a Director and Senior Principle Scientist of Clinical Biostatistics at Merck & Co., Inc. She has a Ph.D. degree in biostatistics. She has extensive experience in drug development, and has worked in many therapeutic areas over the years. Dr. He has been active both at Merck and in industry for initiatives relating to adaptive trials, with particular focus on adaptive trial design and implementation. She is a core member of the DIA Adaptive Design Scientific Working Group (ADSWG) and co-chair of the DIA ADSWG KOL Lecture series. Her research and collaboration with colleagues in various disciplines has led to over 30 publications in statistical and medical journals.
José Pinheiro has a Ph.D. in Statistics from the University of Wisconsin - Madison, having worked at Bell Labs and Novartis Pharmaceuticals, before his current position as Head of Statistical Modeling in the Model-Based Drug Development department at Janssen Research & Development. He has been involved in methodological development in various areas of statistics and drug development, including dose-finding, adaptive designs and mixed-effects models. He is a Fellow of the American Statistical Association, former co-chair of the PhRMA working group on Adaptive Dose-Ranging Studies, former core member of the PhRMA working group on Novel Adaptive Designs and co-developer of the nlme library/package in S-PLUS and R for linear and non-linear mixed-effects models.
Olga Kuznetsova is a Senior Principal Scientist in the Late Development Statistics department of Merck & Co., Inc. She has a PhD in probability theory and mathematical statistics and more than 15 years of experience in clinical trials. In the last decade, her research interests centered around randomization techniques in clinical trials, in particular, addressing the randomization needs of adaptive design trials. Her collaboration with colleagues on randomization issues resulted in more than 20 presentations and publications.
Preface.- The Need for and the Future of Adaptive Designs in Clinical Development.- Regulatory Guidance Documents on Adaptive Designs: an Industry Perspective.- A Commentary on the U.S. FDA Adaptive Design Draft Guidance and EMA Reflection Paper from a Regulatory Perspective and Regulatory Experiences.- Considerations and optimization of adaptive trial design in clinical development programs.- Optimal Cost-effective Go-No Go Decisions in Clinical Development.- Timing and frequency of interim analyses in confirmatory trials.- Approaches for optimal dose selection for adaptive design trials.- A Review of Available Software and Capabilities for Adaptive Designs.- Randomization Challenges in Adaptive Design Studies.- Response-adaptive randomization for clinical trials.- Implementing Adaptive Designs: Operational Considerations, Putting it all together.- Implementation Issues in Adaptive Design Trials.- Implementing Adaptive Designs; Using Technology to Protect Trial Integrity, Reduce Operational Bias, and Build Regulatory Trust.- Considerations for Interim Analyses in Adaptive Trials, and Perspectives on the Use of DMCs.- Approaches for Clinical Supply Modelling and Simulation.- Approaches for Patient Recruitment Modeling and Simulation.- A case study for adaptive trial design consideration and implementation.- Design Considerations for a Phase Ib Randomized, Placebo-Controlled, 4-Period Cross-over Adaptive Dose-Finding Clinical Trial.- Continual Reassessment Method for a First-In-Human Trial: From Design to Trial Implementation.- Practical Considerations for a Two-Stage Confirmatory Adaptive Clinical Trial Design and its Implementation: ADVENT Trial.