Adaptive Design Methods in Clinical Trials, Second Edition

Adaptive Design Methods in Clinical Trials, Second Edition

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ISBN 9781439839874
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  • Discusses the FDA draft guidance on adaptive clinical trial designs
  • Includes power analysis for sample size calculations of adaptive group sequential designs
  • Covers genomic-guided/targeted clinical trials based on adaptive-biomarker design
  • Examines the impact of protocol amendments on clinical trial designs
  • Provides a comprehensive review of two-stage adaptive designs with different study objectives and endpoints at various stages
  • Outlines a Bayesian approach for the use of adaptive design methods in clinical trials
  • Presents examples of clinical trial simulation in early and late phases of development
  • Contains case studies on adaptive group sequential design, adaptive dose-escalation design, and two-stage phase II/III adaptive design


With new statistical and scientific issues arising in adaptive clinical trial design, including the U.S. FDA’s recent draft guidance, a new edition of one of the first books on the topic is needed. Adaptive Design Methods in Clinical Trials, Second Edition reflects recent developments and regulatory positions on the use of adaptive designs in clinical trials. It unifies the vast and continuously growing literature and research activities on regulatory requirements, scientific and practical issues, and statistical methodology.

New to the Second Edition
Along with revisions throughout the text, this edition significantly updates the chapters on protocol amendment and clinical trial simulation to incorporate the latest changes. It also includes five entirely new chapters on two-stage adaptive design, biomarker adaptive trials, target clinical trials, sample size and power estimation, and regulatory perspectives.

Following in the tradition of its acclaimed predecessor, this second edition continues to offer an up-to-date resource for clinical scientists and researchers in academia, regulatory agencies, and the pharmaceutical industry. Written in an intuitive style at a basic mathematical and statistical level, the book maintains its practical approach with an emphasis on concepts via numerous examples and illustrations.

Table of Contents

What Is Adaptive Design
Regulatory Perspectives
Target Patient Population
Statistical Inference
Practical Issues
Aims and Scope of the Book

Protocol Amendment
Moving Target Patient Population
Analysis with Covariate Adjustment
Assessment of Sensitivity Index
Sample Size Adjustment
Concluding Remarks

Adaptive Randomization
Conventional Randomization
Treatment-Adaptive Randomization
Covariate-Adaptive Randomization
Response-Adaptive Randomization
Issues with Adaptive Randomization

Adaptive Hypotheses
Modifications of Hypotheses
Switch from Superiority to Noninferiority
Concluding Remarks

Adaptive Dose-Escalation Trials
CRM in Phase I Oncology Study
Hybrid Frequentist-Bayesian Adaptive Design
Design Selection and Sample Size
Concluding Remarks

Adaptive Group Sequential Design
Sequential Methods
General Approach for Group Sequential Design
Early Stopping Boundaries
Alpha Spending Function
Group Sequential Design Based on Independent P-Values
Calculation of Stopping Boundaries
Group Sequential Trial Monitoring
Conditional Power
Practical Issues

Statistical Tests for Seamless Adaptive Designs
Why a Seamless Design Is Efficient
Step-Wise Test and Adaptive Procedures
Contrast Test and Naive P-Value
Comparisons of Seamless Design
Drop-the-Loser Adaptive Design

Adaptive Sample Size Adjustment
Sample Size Re-Estimation without Unblinding Data
Cui-Hung-Wang’s Method
Proschan-Hunsberger’s Method
Müller-Schafer Method
Bauer-Köhne Method
Generalization of Independent P-Value Approaches
Inverse-Normal Method
Concluding Remarks

Two-Stage Adaptive Design
Practical Issues
Types of Two-Stage 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
Concluding Remarks

Adaptive Treatment Switching
Latent Event Times
Proportional Hazard Model with Latent Hazard Rate
Mixed Exponential Model
Concluding Remarks

Bayesian Approach
Basic Concepts of Bayesian Approach
Multiple-Stage Design for Single-Arm Trial
Bayesian Optimal Adaptive Designs
Concluding Remarks

Biomarker Adaptive Trials
Types of Biomarkers and Validation
Design with Classifier Biomarker
Adaptive Design with Prognostic Biomarker
Adaptive Design with Predictive Marker
Concluding Remarks

Target Clinical Trials
Potential Impact and Significance
Evaluation of Treatment Effect
Other Study Designs and Models
Concluding Remarks

Sample Size and Power Estimation
Framework and Model/Parameter Assumptions
Method Based on the Sum of P-Values
Method Based on Product of P-Values
Method with Inverse-Normal P-Values
Sample Size Re-Estimation

Clinical Trial Simulation
Software Application of ExpDesign Studio
Early Phases Development
Late Phases Development
Concluding Remarks

Regulatory Perspectives — A Review of FDA Draft Guidance
The FDA Draft Guidance
Well-Understood Designs
Less Well-Understood Designs
Adaptive Design Implementation
Concluding Remarks

Case Studies
Basic Considerations
Adaptive Group Sequential Design
Adaptive Dose-Escalation Design
Two-Stage Phase II/III Adaptive Design


Subject Index

Author Bio(s)

Editorial Reviews

"In this second edition, the authors update two chapters on protocol amendment and clinical trial simulation to reflect new developments after the first edition and add five new chapters. … It also provides many useful algorithms for various designs and SAS code throughout the book. … this is an excellent book with wonderful resources on adaptive design methods in clinical trials. It will be very useful to graduate students in the areas of clinical development and biostatistics looking for an advanced textbook on this topic. The book is very well written and a joy to read. I think it would be a critical addition to the bookshelf for statisticians involved in adaptive design and analysis in clinical trials."
—Hongfei Guo, Journal of the American Statistical Association, December 2013

"This second edition remains a useful reference source for anyone interested in advancing innovative trial designs and wishing to incorporate adaptations, modifications, and changes to the drug development process. Five new chapters have been added and are all worth reading; bringing the technical material covered up-to-date. For anyone working in, and studying, clinical research the book is worth purchasing and will make a valuable addition to any library. … this revision continues to provide a balanced summary of statistical methods, together with the authors’ perspective on current regulatory practice."
International Statistical Review, 80, 2012

Praise for the First Edition
The authors are to be commended for the endeavour to provide a monograph about this rapidly evolving area in- to our knowledge- the first book specifically devoted to adaptive design methods . . . we think it provides a valuable contribution to the area of adaptive design.
—Frank Miller and Stig Johan Wiklund, AstraZeneca, Statistical Medicine, 2008, Vol. 27

In summary, this is an extremely useful book for clinical trials statisticians wishing to stay abreast with the innovative approaches that are being developed amid some controversies regarding their benefits.
—Yuko Palesch, Medical University of South Carolina, Journal of the American Statistical Association, March 2008, Vol. 103, No. 481

…This book is one of the first of its kind to be released solely dealing with adaptive designs in clinical trials. … a useful reference for those who have a mathematical background and wish to understand some of the adaptive design methodologies. …With the ever-increasing need for adaptive trials, we could see this book having a large influence …
Pharmaceutical Statistics, 2008

…a useful reference source for anyone interested in advancing innovative trial designs and wishing to incorporate adaptations, modifications, and changes to the drug, device, and biological developmental processes.
—C.M. O’Brien, International Statistical Review, Vol. 75, No. 2, 2007

…uses a broad definition of adaptive design methods… .This breadth of coverage is to be commended and makes the book a useful reference and overview for anyone who is starting to explore this area … the book is worth reading.
—Angela Wade, University College London, UK

The book covers a vast area. To my knowledge this book is the first attempt to provide a concise description of various methodologies in a highly dynamic area. The authors deserve to be praised for bringing this huge range of approaches, including very recent trends, together in one book … .
—Tim Friede, University of Warwick, Biometrics, March 2008