Statistics for Biology and Health

Transcription

1 Statistics for Biology and Health Series Editors: Mitchell Gail Jonathan M. Samet Anastasios Tsiatis Wing Wong For further volumes:

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3 Weili He José Pinheiro Olga M. Kuznetsova Editors Practical Considerations for Adaptive Trial Design and Implementation

4 Editors Weili He Department of Clinical Biostatistics Merck & Co., Inc. Rahway, NJ, USA José Pinheiro Johnson & Johnson Raritan, NJ, USA Olga M. Kuznetsova Department of Clinical Biostatistics Merck & Co., Inc. Rahway, NJ, USA ISSN ISSN (electronic) ISBN ISBN (ebook) DOI / Springer New York Heidelberg Dordrecht London Library of Congress Control Number: Springer Science+Business Media New York 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Preface A great deal of progress has been made in the past couple of decades with regard to research and publications focused on technical and methodological aspects of planning and analyzing adaptive design. The major impetus behind the interest in the use of adaptive designs is the increased efficiency they offer, resulting in savings of cost and time, ultimately getting drugs to patients sooner. However, the adoption of adaptive designs in clinical development has been relatively low, approximately 20 % in recent years, according to a survey conducted by Tufts Center for the Study of Drug Development. One of the chief reasons for this has been the increased complexity of adaptive trials compared to traditional trials. Barriers, some perceived and some real, to the use of clinical trials with adaptive features still persist, and these may include, but are not limited to, the concerns about the integrity of study design and conduct, the risk of regulatory 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 (such as Data Monitoring Committees). There have been limited publications on practical considerations and recommendations on adaptive trial designs and suggestions regarding best practices and solutions on implementation to address these real or perceived barriers. This book aims to fill this publication void and serves as a resource for trialists who wish to consider adaptive trials in their clinical development programs, providing them with guidance on practical considerations for adaptive trial design and implementation. The target audience is anyone involved, or with an interest, in the planning and execution of clinical trials, in particular, statisticians, clinicians, pharmacometricians, clinical operation specialists, drug supply managers, infrastructure providers working in academic or contract research organizations, government, and industry. Our goal for this book is to provide, to the extent possible, a balanced and comprehensive coverage of practical considerations for adaptive trial design and implementation. v

6 vi Preface This book is comprised of three parts: Part I focuses on practical considerations from a design perspective, Part II delineates practical considerations related to the implementation of adaptive trials, and Part III presents a rich collection of practical case studies. Part I includes a total of ten chapters. Chapter 1 discusses the need for and the future of adaptive designs in clinical development. Regulatory guidance documents on adaptive designs have been released by the European Medicines Agency (EMA) and US Food and Drug Administration (US FDA). Chapters 2 and 3 discuss key points in these two guidance documents from industry and regulatory perspectives, respectively. Improving clinical development efficiency starts at the program level. To provide trialists with the tools to strategically consider their clinical development plans, Chap. 4 describes adaptive program concepts and illustrates the efficiency of complex strategies for clinical program development through a case study, while Chap. 5 provides optimal Go/No Go decisions for clinical development. To provide guidance to practitioners on key issues associated with interim analyses, Chap. 6 presents a comprehensive and balanced discussion on optimal timing and frequency of interim analyses, including logistic and regulatory considerations. Adaptive design approaches provide greater efficiency, as compared to traditional design approaches, with regard to dose finding and optimal dose selection. The main statistical methods available for planning and analysis of adaptive designs in Phase I, II, and III are covered in Chap. 7. Chapter 8 provides a review of currently available simulation software tools, discussing detailing their specific features. Often evaluation of an adaptive design approach for a trial requires careful examination of randomization needs. Randomization challenges in adaptive design trials, and randomization techniques that help addressing these challenges, are described in Chap. 9. Chapter 10 discusses response-adaptive randomization, including regulatory concerns and recommendations for the path forward. As reported in the DIA Adaptive Design Scientific Working Group (ADSWG) 2012 survey, the key barriers for the broader adoption of adaptive trials in clinical development include the lack of experience with and knowledge in the implementation of adaptive designs, along with a lack of appropriate processes and infrastructure to support efficient trial execution. Part II of the book deals with these issues in Chaps. 11 through 16. Chapter 11 highlights operational challenges that must be taken into consideration when conducting an adaptive trial and provides strategies for efficient execution of an adaptive design trial. Similarly, Chap. 12 illustrates various operational challenges via a case study, while Chap. 13 discusses logistic and operational challenges with a focus on IT and infrastructure improvement. A particularly critical issue for adaptive clinical trials, with potentially great impact on how large a role this type of studies will play in confirmatory stages of clinical development, involves the processes by which accruing data are collected and analyzed, and adaptation decisions are made and implemented. Chapter 14 discusses who should be involved in data review for adaptation decisions, how the data flow and access to results should be controlled, and the specific role that Data Monitoring Committees might play in this process. Drug supply and patient recruitment play critical roles in the ultimate success of adaptive trial execution. Chapters 14, 15, and 16 cover,

7 Preface vii respectively, the roles that modeling and simulation may play in successfully planning and carrying out clinical supply and patient recruitment strategies. Putting it all together, Part III, featuring Chaps. 17 through 20, presents four illustrative case studies ranging from description and discussion of various specific adaptive trial design considerations to the logistic and regulatory issues faced in trial implementation. The solutions to practical challenges and recommended best practices, along with the rest of the chapters in the book, should equip clinical trialists with the much needed toolkit to embark on their journey to efficient adaptive trial design and implementation. We would like to express our sincerest gratitude to all of the contributors who made this book possible. They are the leading experts in adaptive trial design and implementation from industry, regulatory and academia. Their in-depth discussions, thought-provoking considerations, and abundant advice based on a wealth of experience make this book unique and valuable for a wide range of audiences. We hope that you will find this book helpful as well. We would also like to thank Marc Strauss of Springer Science and Business Media for giving us the idea for this book and for providing us with the opportunity for publication. Thanks also go to Jonathan Gurstelle and Hannah Bracken, both of Springer Science and Business Media, for their patience and help in guiding us through the production phase of the book. Finally, our immense thanks go out to our families for their unfailing support. Rahway, NJ, USA Raritan, NJ, USA Rahway, NJ, USA Weili He José Pinheiro Olga M. Kuznetsova

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9 Contents Part I Design Considerations 1 The Need for and the Future of Adaptive Designs in Clinical Development... 3 Christy Chuang-Stein and Frank Bretz 2 Regulatory Guidance Documents on Adaptive Designs: An Industry Perspective José Pinheiro 3 A Commentary on the U.S. FDA Adaptive Design Draft Guidance and EMA Reflection Paper from a Regulatory Perspective and Regulatory Experiences Sue-Jane Wang 4 Considerations and Optimization of Adaptive Trial Design in Clinical Development Programs Michael Krams and Vladimir Dragalin 5 Optimal Cost-Effective Go No Go Decisions in Clinical Development Cong Chen, Robert A. Beckman, and Linda Z. Sun 6 Timing and Frequency of Interim Analyses in Confirmatory Trials Keaven M. Anderson 7 Approaches for Optimal Dose Selection for Adaptive Design Trials David Lawrence and Frank Bretz 8 A Review of Available Software and Capabilities for Adaptive Designs Yevgen Tymofyeyev ix

10 x Contents 9 Randomization Challenges in Adaptive Design Studies Olga M. Kuznetsova 10 Response-Adaptive Randomization for Clinical Trials Lanju Zhang and William F. Rosenberger Part II Trial Implementation Considerations 11 Implementing Adaptive Designs: Operational Considerations, Putting It All Together Olga Marchenko and Christy Nolan 12 Implementation Issues in Adaptive Design Trials Linda Danielson, Jerome Carlier, Tomasz Burzykowski, and Marc Buyse 13 Implementing Adaptive Designs: Using Technology to Protect Trial Integrity, Reduce Operational Bias, and Build Regulatory Trust Judith Quinlan and Michael Krams 14 Considerations for Interim Analyses in Adaptive Trials, and Perspectives on the Use of DMCs Paul Gallo, David DeMets, and Lisa LaVange 15 Approaches for Clinical Supply Modelling and Simulation Nitin R. Patel, Suresh Ankolekar, and Pralay Senchaudhuri 16 Approaches for Patient Recruitment Modeling and Simulation Weili He and Xiting Cao Part III Case Studies 17 A Case Study for Adaptive Trial Design Consideration and Implementation Vladimir Dragalin and Michael Krams 18 Case Study: Design Considerations for a Phase Ib Randomized, Placebo-Controlled, 4-Period Crossover Adaptive Dose-Finding Clinical Trial James A. Bolognese and Yevgen Tymofyeyev 19 Continual Reassessment Method for a First-in-Human Trial: From Design to Trial Implementation Inna Perevozskaya, Lixin Han, and Kristen Pierce

11 Contents xi 20 Practical Considerations for a Two-Stage Confirmatory Adaptive Clinical Trial Design and Its Implementation: ADVENT Trial Pravin R. Chaturvedi, Zoran Antonijevic, and Cyrus Mehta Index

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13 Contributors Keaven M. Anderson has worked in the pharmaceutical industry for over 20 years, most recently at Merck Research Laboratories. He has worked on drug development in many therapeutic areas. Previously, Dr. Anderson worked for the National Heart, Lung and Blood Institute at the Framingham Heart Study and received his Ph.D. in statistics from Stanford University. He has published frequently in the general area of adaptive design and specifically on group sequential design. He has designed and reviewed a large number of clinical trials throughout his career and has taught group sequential design at Joint Statistical Meetings for several years. Dr. Anderson has supported the gsdesign R package since Suresh Ankolekar is Professor of e-business at Maastricht School of Management (MSM, Netherlands) and consultant at Cytel Inc. (USA). He holds a Master of Technology from Indian Institute of Technology (IIT, Mumbai), and a PhD from Indian Institute of Management (IIM, Ahmedabad). At Cytel, he is involved in modeling of clinical trials, including randomization, patient recruitment, clinical supplies, and optimization of drug development portfolio. At MsM, he is involved in the executive education in IT management and business dynamics. Zoran Antonijevic Senior Director, Strategic Consulting, Cytel, is responsible for strategic quantitative input at trial, program, or portfolio level. He also contributes to developing processes and tools for implementation of adaptive clinical trials. Research areas include: adaptive design, interim data monitoring, pharmaceutical portfolio optimization, and decision-making within clinical drug development process. Externally, Zoran is the chair of DIA Adaptive Design Scientific Working Group. Zoran s prior experience includes Quintiles Innovation, GlaxoSmithKline, and Harvard School of Public Health. Robert A. Beckman an oncology clinical researcher and molecular biophysicist, has played leadership roles in developing new oncology clinical research groups at four pharmaceutical companies. He has coinvented novel clinical strategies for proof of concept studies and for biomarker driven clinical development. Educated at Harvard College and Harvard Medical School, Dr. Beckman has served on the xiii

14 xiv Contributors University of Michigan Biophysics faculty, as a Member in the Simons Center for Systems Biology, Institute for Advanced Study, Princeton, and in the Warner- Lambert Biomolecular Structure and Drug Design group. His versatile publication record, comprising greater than 135 articles and abstracts, ranges from computational chemistry to clinical oncology, emphasizing quantitative approaches. Dr. Beckman is currently Executive Director, Clinical Research Oncology, Daiichi- Sankyo Pharmaceutical Development and external faculty in the Center for Evolution and Cancer, University of California at San Francisco. James A. Bolognese (BS math Bucknell, Masters Statistics, UF) joined Merck in 1976 and led clinical pharmacology projects, a pre-clinical statistics group, and late phase coxib projects, before forming and leading Merck s experimental medicine statistics group. He joined Cytel in 2008 to work on clinical project consulting, including adaptive trials, and software development. He has researched and published on dose-adaptive designs in early phase clinical development, and designed and served as blinded statistician on steering committees of large outcomes studies. Dr. Frank Bretz joined Novartis in 2004, where he is currently Global Head of the Statistical Methodology group. He has supported the methodological development in various areas of drug development, including dose finding, multiple testing, and adaptive designs. He has authored or coauthored more than 90 articles in peerreviewed journals and four books. He is an Adjunct Professor at the Hannover Medical School (Germany) and the Shanghai University of Finance and Economics (P.R. China). Tomasz Burzykowski is Professor of Biostatistics at Hasselt University and Vice President of Research at the International Drug Development Institute (IDDI) in Louvain-la-Neuve (Belgium). He received an M.Sc. degree in applied mathematics (1990) from Warsaw University, and M.Sc. (1991) and Ph.D. (2001) degrees in biostatistics from Hasselt University. Tomasz published methodological work on, e.g., survival analysis, meta-analysis, and validation of surrogate endpoints. He is also a coauthor of numerous papers applying statistical methods to clinical data in different disease areas. Marc Buyse holds a Sc.D. in biostatistics from the Harvard School of Public Health (Boston, MA). He worked at the EORTC in Brussels and at the Dana Farber Cancer Institute in Boston. He is the founder of the International Drug Development Institute (IDDI) and of CluePoints, Inc. He is Associate Professor of Biostatistics at Hasselt University, Belgium. Xiting Cao is Associate Director in the department of Global Health Outcomes at Merck & Co. Inc. After completing her B.Sc. in Statistics from Peking University, in Beijing, China, she earned her M.Sc. and Ph.D. in Biostatistics from University of Minnesota. Dr. Cao s research interests encompass the areas of clinical trial design, statistical methods for network meta-analysis and outcomes research. She also conducts statistical analysis in the area of pharmacoeconomics and health policy.

15 Contributors xv Jerome Carlier is Associate Director, Randomization & Drug Supply Systems at the International Drug Development Institute (IDDI) in Louvain-la-Neuve, Belgium. He has over 15 years of experience in the implementation of computerized systems in clinical trials (such as IWRS, Drug Supply, EDC and CTMS). Dr. Pravin A. Chaturvedi is the Chief Scientific Officer of Napo Pharmaceuticals and also Chief Executive and/or Board member of several enterprises. He has 25 years of experience in drug discovery and development. Prior to his senior roles at Napo, IndUS, Oceanyx and Scion, he headed Lead Evaluation at Vertex and served in the preclinical and product development groups at Alkermes and Parke-Davis/ Warner-Lambert. Dr. Chaturvedi received his doctorate from West Virginia University and his undergraduate degree from the University of Bombay. Dr. Cong Chen is Director of Oncology Biostatistics at Merck & Co., Inc. He joined Merck in 1999 shortly before he graduated from Iowa State University, Ames, USA, with a Ph.D. in statistics. At Merck, he has worked in oncology drug development and other therapeutic areas including infectious disease, diabetes, and cardiovascular disease. His publication record consists of over 50 papers on statistical design and analyses, and various clinical publications. He has coinvented new paradigms for biomarker directed clinical development, for proof-of-concept studies, and for studies using progression-free-survival as a surrogate endpoint for overall survival. He is a Board Member of International Chinese Statistical Association, a member of US-China Anti-Cancer Association, American Statistical Association, and International Society of Biopharmaceutical Statistics. He is also an Associate Editor of Statistics in Biopharmaceutical Research. Christy Chuang-Stein joined the pharmaceutical industry in Currently, she is Head of the Statistical Research and Consulting Center at Pfizer. Christy is a Fellow of the American Statistical Association (ASA). She has authored or coauthored more than 140 papers including several book chapters and 2 books. Christy is a founding coeditor of the journal Pharmaceutical Statistics and has been active in several professional societies. She received ASA s Founders Award in Linda Danielson is Chief Operating Officer at the International Drug Development Institute (IDDI) in Louvain-la-Neuve, Belgium. She obtained her M.S. degree in 1990 from the University of Wisconsin, Madison. She has over 20 years of experience in the Pharmaceutical Industry and worked at UCB prior to IDDI. She has also been President of the Biostatistical Section of the Belgian Statistical Society and the Belgian representative to the European Federation of Statisticians in the Pharmaceutical Industry (EFSPI). David DeMets, Ph.D. is currently the Max Halperin Professor of Biostatistics and former Chair of the Department of Biostatistics and Medical Informatics at the University of Wisconsin- Madison. He has coauthored numerous papers and four texts on clinical trials, two specifically on data monitoring. He has served on many NIH and industry- sponsored data monitoring committees for clinical trials in

16 xvi Contributors diverse disciplines. He also served as President of the Society for Clinical Trials in In addition, he was Elected Fellow of the Society for Clinical Trials in In 2013, he was elected as a member of the Institute of Medicine. Vladimir Dragalin, Ph.D. is a Vice President, Scientific Fellow in the Quantitative Sciences at Janssen. He is a well-known adaptive design expert with more than 25 years of experience in developing the statistical methodology of adaptive designs and with over 15 years of experience in pharmaceutical industry. His professional interests include model-based adaptive and Bayesian designs, response-adaptive dose escalations, simulation, monitoring and analysis of clinical trials, bioequivalence, multi center clinical trials, and adverse event monitoring in safety trials, with the major results published in more than 75 papers in peer-reviewed journals and books. Paul Gallo is a Biometrical Fellow and a member of the Statistical Methodology Group at Novartis Pharmaceuticals in East Hanover, NJ. He received a Ph.D. in Statistics from the University of North Carolina in A main activity has involved support of Data Monitoring Committees; he has worked with DMCs in many key Novartis trials and authored company process documents and guidelines governing interim analysis procedures. He has been active in industry initiatives relating to adaptive trials, with particular focus on interim monitoring and DMC process issues. He was lead author of the PhRMA Adaptive Designs Working Group s Executive Summary in Journal of Biopharmaceutical Statistics, and coordinated the production and publication of the group s full White Paper. He has headed teams focusing on interim analysis process issues in adaptive trials for the PhRMA and DIA-sponsored working groups. Christy Nolan, B.Sc., M.T.(A.S.C.P.) Vice President of Quintiles Innovation Business Unit. Christy Nolan has thirty years of health care industry experience to include clinical laboratory, pharmaceutical, diagnostics, and executive leadership in global clinical operations clinical research in clinical research organizations. Lixin Han, Ph.D. is Director of Biostatistics at Infinity Pharmaceuticals. His previous positions included Director of Biostatistics at Pfizer, Senior Principal Biostatistician II at Wyeth, and Senior Statistician at Abbott Laboratories. 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 cochair 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.

17 Contributors xvii Michael Krams, M.D. is the Global Head of Quantitative Sciences at Janssen Pharmaceutical. He is recognized as an expert in designing, implementing and executing adaptive designs, enabling real-time learning in Learn and Confirm studies. He has built an industry leading cross-functional team of drug developers, applying modeling and simulation techniques and integrating input from clinical, translational medicine, biostatistics, discovery and commercial. As cochair of PhRMA s working group on adaptive designs Mike has contributed to an ongoing debate with regulatory agencies, with a goal to establish a common position on Good Adaptive Practices. Olga M. Kuznetsova is a Senior Principal Scientist in the Late Development Statistics department of Merck & Co., Inc. She has a Ph.D. 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. Lisa LaVange, Ph.D. is Director of the Office of Biostatistics in the Center for Drug Evaluation and Research at FDA. She is a former faculty member in the Department of Biostatistics at the University of North Carolina at Chapel Hill. Prior to that, she spent 10 years in the pharmaceutical industry and 16 years in nonprofit research. She is Fellow of the American Statistical Association and former President of the Eastern North American Region of the International Biometric Society. David Lawrence Since completing a Ph.D. in epidemiology at the University of Edinburgh, UK, in 1999, David Lawrence has worked as a clinical trial statistician in both academia (Institute of Cancer Research and University College London) and the pharmaceutical industry. He has focused on phase II and III trials in the respiratory and oncology areas. He has been working at Novartis since Olga Marchenko is Vice President and Head of Centre for Statistics in Drug Development at Quintiles. Prior to joining Quintiles, Dr. Marchenko positions included Global Head of Data Services Therapeutic Consulting and Director of Biostatistics in Americas at i3statprobe. She also worked at Pfizer, the Ohio State University, and the Belarusian State University. Olga received her PhD in Statistics from the University of Michigan, Ann Arbor. Dr. Marchenko research interests include adaptive design methodology and implementation, and drug safety methods. Cyrus Mehta is President and cofounder of Cytel Corporation and Adjunct Professor of Biostatistics, Harvard University. Dr. Mehta consults extensively with the biopharmaceutical industry. He has led the development of the StatXact, LogXact and East software packages, widely used in the biopharmaceutical industry. He is a Fellow of the American Statistical Association and an elected member of the International Statistical Institute. He is a past cowinner of the George W. Snedecor Award for the

18 xviii Contributors best paper in biometry, was named Mosteller Statistician of the Year by the Massachusetts Chapter of the American Statistical Association, and Outstanding Zoroastrian Entrepreneur by the World Zoroastrian Chamber of Commerce. Nitin R. Patel has a Ph.D. in Operations Research from Massachusetts Institute of Technology and has been a visiting professor there for over a decade. He is currently a researcher at the MIT Center for Biomedical Innovation. He is a Fellow of the American Statistical Association and has served as vice president of the International Federation of Operations Research Societies. He has published over 70 papers in professional journals. He is a cofounder of Cytel Inc. where he is currently Chairman. Inna Perevozskaya is Senior Director, Biometrics, Statistical Research and Consulting Center at Pfizer. She has 13 years of pharmaceutical industry experience, working at Pfizer, Wyeth, and Merck supporting various projects and also serving as an internal adaptive design expert and consultant. She received her Ph.D. in Statistics from University of Maryland where she specialized in novel dose-escalation designs for oncology. More recently, as a member of SRCC at Pfizer and DIA Working Group on Adaptive Designs, she continues to pursue her research interests while building expertise in other types of adaptive designs and their application. Kristen Pierce, Ph.D. is currently an Associate Director of Biostatistics at Pfizer. Her focus while at Pfizer has been on early stage drug development for oncology clinical trials. 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 dosefinding, adaptive designs, and mixed-effects models. He is a Fellow of the American Statistical Association, former cochair of the PhRMA working group on Adaptive Dose- Ranging Studies, former core member of the PhRMA working group on Novel Adaptive Designs, and codeveloper of the nlme library/package in S-PLUS and R for linear and nonlinear mixed-effects models. Judith Quinlan Following an initial career as a biometrician in agriculture in Western Australia, Ms. Quinlan later moved to the UK where she entered the pharmaceutical industry in 1996 as a statistician with SmithKline Beecham (later GSK). During her time at GSK she took on increasing roles of responsibility that included moving to the US to become Director of Statistics for Biopharmaceutical development. Ms. Quinlan has been a strong advocate for adaptive designs, and also played an active role as a member of industry s Adaptive Design Scientific Working Group (ADSWG). After leaving GSK, Ms. Quinlan spent 3 years as VP of Adaptive Trials Services at Cytel Inc., before joining Aptiv Solutions in 2011 as SVP Innovations Center, where her role has a strong focus on adaptive trial execution.

19 Contributors xix William F. Rosenberger is Professor and Chairman of Statistics at George Mason University. He received his Ph.D. in mathematical statistics from George Washington University in 1992 and since then has spent much of his career developing statistical methodology for randomized clinical trials. He has two books on the subject, Randomization in Clinical Trials : Theory and Practice (Wiley 2002), which won the Association of American Publishers Award for the best mathematics/statistics book published that year, and The Theory of Response-Adaptive Randomization in Clinical Trials (Wiley 2006). He is a Fellow of the American Statistical Association (2005) and of the Institute of Mathematical Statistics (2011). An author of more than 75 refereed papers, Prof. Rosenberger was named the 2012 Outstanding Research Faculty by the Volgenau School of Engineering, George Mason University. Pralay Senchaudhuri has a Ph.D. in Biostatistics from Harvard University. He has published over 30 papers in professional journals and coauthored chapters of books on statistical methods. He is one of the main architects of several widely used statistical software products including East, StatXact, LogXact, and COMPASS. He has been a principal investigator on a number of SBIR grants from National Institutes of Health. Currently he is a Senior Vice President at Cytel Inc. Dr. Linda Z. Sun is with Late Development Statistics at Merck & Co., Inc., focusing on oncology area. She received her Ph.D. in statistics from Northwestern University, Evanston, IL. Currently, Dr. Sun leads a team of statisticians in the Asia Pacific group of Merck, covering oncology, neuroscience, and respiratory and immunology areas. She published statistical papers about adaptive designs, early endpoint evaluation, cost effectiveness go-no-go decision, etc. She also has medical papers published in Journals like Lancet Oncology. Yevgen Tymofyeyev is a Scientific Director in the Model-Based Drug Development department of Janssen Research & Development. He specializes in statistical modeling and simulation to support studies across multiple therapeutic areas including design and implementation of adaptive clinical trials. He has a Ph.D. in Statistics from the University of Maryland, Baltimore County. Over the last decade, he is actively involved in scientific collaborations in the field of randomization, adaptive design methodology, and software which led to an extensive list of publications. Sue-Jane Wang received her Ph.D. in Biostatistics from the University of Southern California, having worked at Demographic Research Company and Cedars-Sinai Medical Genetics Institute, prior to her current position as Associate Director for Adaptive Design and Pharmacogenomics in the Office of Biostatistics, Office of Translational Sciences, Center for Drug Development and Research, U.S. Food and Drug Administration. Dr. Wang has received several awards at FDA including an FDA Scientific Achievement Award on Excellence in Analytical Science for a sustained record of published regulatory research in statistical design and methodology advancing complex and emerging clinical trial designs and analysis that support regulatory guidance, policies, and review. Dr. Wang is a Fellow of the American

20 xx Contributors Statistical Association, a DIA recipient of Thomas Teal Award for Excellence in Statistics Publishing. She has served Editor-in-Chief of Pharmaceutical Statistics, Guest (co)editor-in-chiefs for special issues: multi-regional clinical trials in Pharmaceutical Statistics, multiple comparison procedures in Biometrical Journal, subgroup analysis in Journal of Biopharmaceutical Statistics. She is an elected member of International Statistical Institute and is currently Guest Editor-in-Chief for the special issue on personalized medicine in Statistics in BioSciences. Lanju Zhang is the Head of Nonclinical Statistics at Abbvie Inc. His research interests cover all areas of drug development process, including chemistry, manufacturing, and control (CMC). He has authored/coauthored more 30 publications in professional journals and books. He has performed editorial services for most major statistical journals.