Adaptive Design Methods in Clinical Trials, 2nd Edition

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Editor-in-Chief

Shein-Chung Chow, Ph.D.

Professor
Department of Biostatistics and Bioinformatics
Duke University School of Medicine
Durham, North Carolina

Series Editors

Byron Jones Jen-pei Liu

Biometrical Fellow Professor
Statistical Methodology Division of Biometry
Integrated Information Sciences Department of Agronomy
National Taiwan University
Novartis Pharma AG
Taipei, Taiwan
Basel, Switzerland

Karl E. Peace Bruce W. Turnbull

Georgia Cancer Coalition Professor
Distinguished Cancer Scholar School of Operations Research
Senior Research Scientist and and Industrial Engineering
Professor of Biostatistics Cornell University
Jiann-Ping Hsu College of Public Health Ithaca, New York
Georgia Southern University
Statesboro, Georgia

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Adaptive Design Methods in Computational Methods in Biomedical

Clinical Trials, Second Edition Research
Shein-Chung Chow and Mark Chang Ravindra Khattree and Dayanand N. Naik
Adaptive Design Theory and Computational Pharmacokinetics
Implementation Using SAS and R Anders Källén
Mark Chang Controversial Statistical Issues in
Advanced Bayesian Methods for Medical Clinical Trials
Test Accuracy Shein-Chung Chow
Lyle D. Broemeling Data and Safety Monitoring Committees
Advances in Clinical Trial Biostatistics in Clinical Trials
Nancy L. Geller Jay Herson
Basic Statistics and Pharmaceutical Design and Analysis of Animal Studies in
Statistical Applications, Second Edition Pharmaceutical Development
James E. De Muth Shein-Chung Chow and Jen-pei Liu
Bayesian Adaptive Methods for Design and Analysis of Bioavailability and
Clinical Trials Bioequivalence Studies, Third Edition
Scott M. Berry, Bradley P. Carlin, Shein-Chung Chow and Jen-pei Liu
J. Jack Lee, and Peter Muller Design and Analysis of Clinical Trials with
Bayesian Analysis Made Simple: An Excel Time-to-Event Endpoints
GUI for WinBUGS Karl E. Peace
Phil Woodward Design and Analysis of Non-Inferiority
Bayesian Methods for Measures of Trials
Agreement Mark D. Rothmann, Brian L. Wiens,
Lyle D. Broemeling and Ivan S. F. Chan
Bayesian Missing Data Problems: EM, Difference Equations with Public Health
Data Augmentation and Noniterative Applications
Computation Lemuel A. Moyé and Asha Seth Kapadia
Ming T. Tan, Guo-Liang Tian, DNA Methylation Microarrays:
and Kai Wang Ng Experimental Design and Statistical
Bayesian Modeling in Bioinformatics Analysis
Dipak K. Dey, Samiran Ghosh, Sun-Chong Wang and Arturas Petronis
and Bani K. Mallick DNA Microarrays and Related Genomics
Causal Analysis in Biomedicine and Techniques: Design, Analysis, and
Epidemiology: Based on Minimal Interpretation of Experiments
Sufficient Causation David B. Allison, Grier P. Page,
Mikel Aickin T. Mark Beasley, and Jode W. Edwards
Clinical Trial Data Analysis using R Dose Finding by the Continual
Ding-Geng (Din) Chen and Karl E. Peace Reassessment Method
Clinical Trial Methodology Ying Kuen Cheung
Karl E. Peace and Ding-Geng (Din) Chen Elementary Bayesian Biostatistics
Lemuel A. Moyé

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Frailty Models in Survival Analysis Randomized Clinical Trials of

Andreas Wienke Nonpharmacologic Treatments
Generalized Linear Models: A Bayesian Isabelle Boutron, Philippe Ravaud, and
Perspective David Moher
Dipak K. Dey, Sujit K. Ghosh, Sample Size Calculations in Clinical
and Bani K. Mallick Research, Second Edition
Handbook of Regression and Modeling: Shein-Chung Chow, Jun Shao
Applications for the Clinical and and Hansheng Wang
Pharmaceutical Industries Statistical Design and Analysis of
Daryl S. Paulson Stability Studies
Measures of Interobserver Agreement Shein-Chung Chow
and Reliability, Second Edition Statistical Evaluation of Diagnostic
Mohamed M. Shoukri Performance: Topics in ROC Analysis
Medical Biostatistics, Second Edition Kelly H. Zou, Aiyi Liu, Andriy Bandos,
A. Indrayan Lucila Ohno-Machado, and Howard Rockette

Meta-Analysis in Medicine and Health Statistical Methods for Clinical Trials

Policy Mark X. Norleans
Dalene Stangl and Donald A. Berry Statistics in Drug Research:
Monte Carlo Simulation for the Methodologies and Recent
Pharmaceutical Industry: Concepts, Developments
Algorithms, and Case Studies Shein-Chung Chow and Jun Shao
Mark Chang Statistics in the Pharmaceutical Industry,
Multiple Testing Problems in Third Edition
Pharmaceutical Statistics Ralph Buncher and Jia-Yeong Tsay
Alex Dmitrienko, Ajit C. Tamhane, Translational Medicine: Strategies and
and Frank Bretz Statistical Methods
Dennis Cosmatos and Shein-Chung Chow

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i

Adaptive Design
Methods in
Clinical Trials
Second Edition

Shein-Chung Chow
Mark Chang

i
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
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Version Date: 20111028

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Contents

Preface to the First Edition xi

Preface xv

1 Introduction 1
1.1 What Is Adaptive Design . . . . . . . . . . . . . . . . . . . . . 2
1.2 Regulatory Perspectives . . . . . . . . . . . . . . . . . . . . . . 7
1.3 Target Patient Population . . . . . . . . . . . . . . . . . . . . . 9
1.4 Statistical Inference . . . . . . . . . . . . . . . . . . . . . . . . 10
1.5 Practical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.6 Aims and Scope of the Book . . . . . . . . . . . . . . . . . . . . 21

2 Protocol Amendment 23
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.2 Moving Target Patient Population . . . . . . . . . . . . . . . . 24
2.3 Analysis with Covariate Adjustment . . . . . . . . . . . . . . . 26
2.4 Assessment of Sensitivity Index . . . . . . . . . . . . . . . . . 32
2.5 Sample Size Adjustment . . . . . . . . . . . . . . . . . . . . . . 37
2.6 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 38

3 Adaptive Randomization 43
3.1 Conventional Randomization . . . . . . . . . . . . . . . . . . . 44
3.2 Treatment-Adaptive Randomization . . . . . . . . . . . . . . . 48
3.3 Covariate-Adaptive Randomization . . . . . . . . . . . . . . . . 51
3.4 Response-Adaptive Randomization . . . . . . . . . . . . . . . . 54
3.5 Issues with Adaptive Randomization . . . . . . . . . . . . . . . 65
3.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

4 Adaptive Hypotheses 69
4.1 Modifications of Hypotheses . . . . . . . . . . . . . . . . . . . . 70
4.2 Switch from Superiority to Noninferiority . . . . . . . . . . . . 71
4.3 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 81

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viii CONTENTS

5 Adaptive Dose-Escalation Trials 83

5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
5.2 CRM in Phase I Oncology Study . . . . . . . . . . . . . . . . . 85
5.3 Hybrid Frequentist-Bayesian
Adaptive Design . . . . . . . . . . . . . . . . . . . . . . . . . . 87
5.4 Design Selection and Sample Size . . . . . . . . . . . . . . . . . 98
5.5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 100

6 Adaptive Group Sequential Design 103

6.1 Sequential Methods . . . . . . . . . . . . . . . . . . . . . . . . . 104
6.2 General Approach for Group Sequential Design . . . . . . . . . 108
6.3 Early Stopping Boundaries . . . . . . . . . . . . . . . . . . . . 110
6.4 Alpha Spending Function . . . . . . . . . . . . . . . . . . . . . 118
6.5 Group Sequential Design Based on Independent P-values . . . . 119
6.6 Calculation of Stopping Boundaries . . . . . . . . . . . . . . . . 121
6.7 Group Sequential Trial Monitoring . . . . . . . . . . . . . . . . 125
6.8 Conditional Power . . . . . . . . . . . . . . . . . . . . . . . . . 128
6.9 Practical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

7 Statistical Tests for Seamless Adaptive Designs 133

7.1 Why a Seamless Design Efficient . . . . . . . . . . . . . . . . . 133
7.2 Step-wise Test and Adaptive Procedures . . . . . . . . . . . . . 134
7.3 Contrast Test and Naive P-value . . . . . . . . . . . . . . . . . 135
7.4 Comparisons of Seamless Design . . . . . . . . . . . . . . . . . 137
7.5 Drop-the-Loser Adaptive Design . . . . . . . . . . . . . . . . . 139
7.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

8 Adaptive Sample Size Adjustment 143

8.1 Sample Size Re-Estimation without Unblinding Data . . . . . . 144
8.2 Cui-Hung-Wang’s Method . . . . . . . . . . . . . . . . . . . . . 146
8.3 Proschan-Hunsberger’s Method . . . . . . . . . . . . . . . . . . 148
8.4 Müller-Schafer Method . . . . . . . . . . . . . . . . . . . . . . . 151
8.5 Bauer-Köhne Method . . . . . . . . . . . . . . . . . . . . . . . 152
8.6 Generalization of Independent P-value Approaches . . . . . . . 155
8.7 Inverse-Normal Method . . . . . . . . . . . . . . . . . . . . . . 163
8.8 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 164

9 Two-Stage Adaptive Design 167

9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
9.2 Practical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
9.3 Types of Two-Stage Adaptive Designs . . . . . . . . . . . . . . 171
9.4 Analysis for Seamless Design with Same Study
Objectives/Endpoints . . . . . . . . . . . . . . . . . . . . . . . 173
9.5 Analysis for Seamless Design with Different Endpoints . . . . . 177
9.6 Analysis for Seamless Design with Different Objectives/Endpoints183
9.7 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 188

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CONTENTS ix

10 Adaptive Treatment Switching 189

10.1 Latent Event Times . . . . . . . . . . . . . . . . . . . . . . . . 190
10.2 Proportional Hazard Model with Latent Hazard Rate . . . . . 193
10.3 Mixed Exponential Model . . . . . . . . . . . . . . . . . . . . . 197
10.4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 208

11 Bayesian Approach 209

11.1 Basic Concepts of Bayesian Approach . . . . . . . . . . . . . . 210
11.2 Multiple-Stage Design for Single-Arm Trial . . . . . . . . . . . 215
11.3 Bayesian Optimal Adaptive Designs . . . . . . . . . . . . . . . 219
11.4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 223

12 Biomarker Adaptive Trials 225

12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
12.2 Types of Biomarkers and Validation . . . . . . . . . . . . . . . 227
12.3 Design with Classifier Biomarker . . . . . . . . . . . . . . . . . 232
12.4 Adaptive Design with Prognostic Biomarker . . . . . . . . . . . 237
12.5 Adaptive Design with Predictive Marker . . . . . . . . . . . . . 238
12.6 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 239
12.7 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

13 Target Clinical Trials 243

13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
13.2 Potential Impact and Significance . . . . . . . . . . . . . . . . . 244
13.3 Evaluation of Treatment Effect . . . . . . . . . . . . . . . . . . 245
13.4 Other Study Designs and Models . . . . . . . . . . . . . . . . . 252
13.5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 256

14 Sample Size and Power Estimation 259

14.1 Framework and Model/Parameter Assumptions . . . . . . . . . 260
14.2 Method Based on the Sum of P-values . . . . . . . . . . . . . . 262
14.3 Method Based on Product of P-values . . . . . . . . . . . . . . 263
14.4 Method with Inverse-Normal P-values . . . . . . . . . . . . . . 264
14.5 Sample Size Re-estimation . . . . . . . . . . . . . . . . . . . . . 266
14.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

15 Clinical Trial Simulation 271

15.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
15.2 Software Application of ExpDesign Studio . . . . . . . . . . . 272
15.3 Early Phases Development . . . . . . . . . . . . . . . . . . . . . 281
15.4 Late Phases Development . . . . . . . . . . . . . . . . . . . . . 284
15.5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 293

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x CONTENTS

16 Regulatory Perspectives - A Review of FDA Draft Guidance 297

16.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
16.2 The FDA Draft Guidance . . . . . . . . . . . . . . . . . . . . . 298
16.3 Well-Understood Designs . . . . . . . . . . . . . . . . . . . . . 299
16.4 Less Well-Understood Designs . . . . . . . . . . . . . . . . . . . 303
16.5 Adaptive Design Implementation . . . . . . . . . . . . . . . . . 307
16.6 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . 311

17 Case Studies 313

17.1 Basic Considerations . . . . . . . . . . . . . . . . . . . . . . . . 314
17.2 Adaptive Group Sequential Design . . . . . . . . . . . . . . . . 315
17.3 Adaptive Dose-Escalation Design . . . . . . . . . . . . . . . . . 318
17.4 Two-Stage Phase II/III Adaptive Design . . . . . . . . . . . . . 321

Bibliography 329

Index 351

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Preface to the First Edition

In recent years, the use of adaptive design methods in clinical trials has at-
tracted much attention from clinical investigators and biostatisticians. Adap-
tations (i.e., modifications or changes) made to the trial and/or statistical pro-
cedures of on-going clinical trials based on accrued data have been in practice
for years in clinical research and development. In the past several decades, we
have adopted statistical procedures in the literature and applied them directly
to the design of clinical trials originally planned by ignoring the fact that adap-
tations, modifications, and/or changes have been made to the trials. As pointed
out by the U.S. Food and Drug Administration (FDA), these procedures, how-
ever, may not be motivated by best clinical trial practice. Consequently, they
may not be the best tools to handle certain situations. Adaptive design meth-
ods in clinical research and development are attractive to clinical scientists and
researchers because of the following reasons. First, it reflects medical practice
in the real world. Second, it is ethical with respect to both efficacy and safety
(toxicity) of the test treatment under investigation. Third, it is not only flexi-
ble but also efficient in clinical development, especially for early phase clinical
development. However, there are issues regarding the adjustments of treatment
estimations and p-values. In addition, it is also a concern that the use of adap-
tive design methods in a clinical trial may have led to a totally different trial
that is unable to address the scientific/medical questions the trial is intended
to answer.

In practice, there exists no universal definition of adaptive design methods

in clinical research until recently PhRMA gave a formal definition. Most liter-
ature focuses on adaptive randomization with respect to covariate, treatment,
and/or clinical response, adaptive group sequential design for interim analysis,
and sample size re-assessment. In this book, our definition is broader. Adap-
tive design methods include any adaptations, modifications, or changes of trial
and/or statistical procedures that are made during the conduct of the trials.
Although adaptive design methods are flexible and useful in clinical research,
little or no regulatory guidances/guidelines are available. The purpose of this
book is to provide a comprehensive and unified presentation of the principles
and methodologies in adaptive design and analysis with respect to adapta-
tions made to trial and/or statistical procedures based on accrued data of on-

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xii PREFACE

going clinical trials. In addition, this book is intended to give a well-balanced

summary of current regulatory perspectives and recently developed statistical
methods in this area. It is our goal to provide a complete, comprehensive and
updated reference and textbook in the area of adaptive design and analysis in
clinical research and development.

Chapter 1 provides an introduction to basic concepts regarding the use of

adaptive design methods in clinical trials and some statistical considerations of
adaptive design methods. Chapter 2 focuses on the impact on target patient
population as the result of protocol amendments. Also included in this chap-
ter is the generalization of statistical inference, which is drawn based on data
collected from the actual patient population as the result of protocol amend-
ments, to the originally planned target patient population. Several adaptive
randomization procedures that are commonly employed in clinical trials are
reviewed in Chapter 3. Chapter 4 studies the use of adaptive design meth-
ods in the case where hypotheses are modified during the conduct of clinical
trials. Chapter 5 provides an overall review of adaptive design methods for
dose selection especially in dose finding and dose response relationship studies
in early clinical development. Chapter 6 introduces the commonly used adap-
tive group sequential design methods in clinical trials. Blinded procedures for
sample size re-estimation are given in Chapter 7. Statistical tests for seam-
less phase II/III adaptive designs and statistical inference for switching from
one treatment to another adaptively and the corresponding practical issues
that one may encounter are studied in Chapter 8 and Chapter 9, respectively.
Bayesian approach for the use of adaptive design methods in clinical trials are
outlined in Chapter 10. Chapter 11 provides an introduction to the methodol-
ogy of clinical trial simulation for evaluation of the performance of the adaptive
design methods under various adaptive designs that are commonly used in clin-
ical development. Case studies regarding the implementation of adaptive group
sequential design, adaptive dose-escalation design, and seamless phase II/III
adaptive trial design in clinical trials are discussed in Chapter 12.

From Taylor & Francis, we would like to thank David Grubbs and Dr. Sunil
Nair for providing us the opportunity to work on this book. We would like
to thank colleagues from the Department of Biostatistics and Bioinformatics
and Duke Clinical Research Institute (DCRI) of Duke University School of
Medicine and Millennium Pharmaceuticals, Inc. for their support during the
preparation of this book. We wish to express our gratitude to the following
individuals for their encouragement and support: Roberts Califf, M.D. and
John Hamilton, M.D. of Duke Clinical Research Institute and Duke University
Medical Center, Nancy Simonian, M.D., Jane Porter, M.S., Andy Boral, M.D.
and Jim Gilbert, M.D. of Millennium Pharmaceuticals, Inc., Greg Campbell,
Ph.D. of the U.S. Food and Drug Administration, and many friends from the
academia, the pharmaceutical industry, and regulatory agencies.

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PREFACE xiii

Finally, the views expressed are those of the authors and not necessarily
those of Duke University School of Medicine and Millennium Pharmaceuticals,
Inc. We are solely responsible for the contents and errors of this edition. Any
comments and suggestions will be very much appreciated

Shein-Chung Chow, Ph.D.

Duke University School of Medicine, Durham, NC

Mark Chang, Ph.D.

Millennium Pharmaceuticals, Inc., Cambridge, MA

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Preface

Many statistical and/or scientific issues in the area of adaptive clinical trial
design have attracted considerable attention from clinical scientists and re-
searchers from academia, the regulatory agencies, and the pharmaceutical in-
dustry since the first edition of this book was published in 2006. Most recently,
the U.S. Food and Drug Administration (FDA) released a draft guidance for
comments, which has generated more issues/concerns when utilizing adaptive
design methods in clinical trials. These statistical and/or scientific issues in-
clude (i) the feasibility of the use of adaptive design methods in clinical trials,
(ii) the validity and integrity of the commonly considered adaptive designs such
as adaptive dose finding design and two-stage seamless adaptive designs, and
(iii) the search for appropriate statistical methods under complicated adaptive
designs (or less well-understood designs). As a result, there was a need for a sec-
ond edition of this book to provide a comprehensive and unified summary of the
vast and continuously growing literature and research activities on regulatory
requirements, scientific and practical issues, and statistical methodology.
This revision maintains the same overall objectives and level of presentation
as the first edition. Similar to the first edition, the new edition focuses on the
concepts rather than technical details. It is written from a practical viewpoint
at a basic mathematical and statistical level. Feedback from the first edition
was gratifying. We received many positive comments from clinical scientists
and researchers from academia, the regulatory agencies, including the FDA,
and the pharmaceutical industry. Accordingly, we have kept our intuitive writ-
ing style as well as the emphasis on the concepts via numerous examples and
illustrations.
We have improved the second edition in the following ways. First, several
chapters/sections such as the chapters of protocol amendment and clinical trial
simulation are updated to reflect recent developments since the first edition.
Both chapters have major revisions. Second, five new chapters are added. These
chapters include (i) Two-Stage Adaptive Design (Chapter 9), (ii) Biomarker
Adaptive Trials (Chapter 12), (iii) Target Clinical Trials (Chapter 13), (iv)
Sample Size and Power Estimation (Chapter 14), and (v) Regulatory Perspec-
tives - A Review of FDA Draft Guidance on Adaptive Clinical Trial Design
(Chapter 16).
From Taylor & Francis, we would like to thank Mr. David Grubbs for provid-

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