Lawrence M. Friedman,
Curt D. Furberg, David L. DeMets, David M. Reboussin and
Christopher B. Granger
Fundamentals of Clinical Trials5th ed. 2015
Lawrence M. Friedman
North Bethesda, MD, USA
Curt D. Furberg
Division of Public Health Sciences,
Wake Forest School of Medicine, Winston-Salem, NC, USA
David L. DeMets
Department Biostatistics and Medical
Informatics, University of Wisconsin, Madison, WI, USA
David M. Reboussin
Department of Biostatistics, Wake
Forest School of Medicine, Winston-Salem, NC, USA
Christopher B. Granger
Department of Medicine, Duke
University, Durham, NC, USA
ISBN 978-3-319-18538-5e-ISBN 978-3-319-18539-2
DOI 10.1007/978-3-319-18539-2
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Preface
The clinical trial is “the most
definitive tool for evaluation of the applicability of clinical
research.” It represents “a key research activity with the
potential to improve the quality of health care and control costs
through careful comparison of alternative treatments” [1]. It has
been called on many occasions, “the gold standard” against which
all other clinical research is measured.
Although many clinical trials are of
high quality, a careful reader of the medical literature will
notice that a large number have deficiencies in design, conduct,
analysis, presentation, and/or interpretation of results.
Improvements have occurred over the past few decades, but too many
trials are still conducted without adequate attention to the
fundamental principles. Certainly, numerous studies could have been
improved if the authors had had a better understanding of the
fundamentals.
Since the publication of the first
edition of this book in 1981, a large number of other texts on
clinical trials have appeared, most of which are indicated here
[2–21]. Several of them, however, discuss only specific issues
involved in clinical trials. Additionally, many are no longer
current. The purpose of this fifth edition is to update areas in
which major progress has been made since the publication of the
fourth edition. We have revised most chapters considerably. Because
it was becoming unwieldy, we divided the chapter on monitoring
response variables into two chapters, one on monitoring committees
and the other on monitoring approaches. We also added a chapter on
regulatory issues.
Importantly, two new authors are now
involved. This brings fresh perspectives to a book originally
published over three decades ago.
In this book, we hope to assist
investigators in improving the quality of their clinical trials by
discussing fundamental concepts with examples from our experience
and the literature. The book is intended both for investigators
with some clinical trial experience and for those who plan to
conduct a trial for the first time. It is also intended to be used
in the teaching of clinical trial methodology and to assist members
of the scientific and medical community who wish to evaluate and
interpret published reports of trials. Although not a technically
oriented book, it may be used as a reference for graduate courses
in clinical trials. Those readers who wish to consult more
technical books and articles are provided with the relevant
literature.
Because of the considerable differences
in background and objectives of the intended readership, we have
not attempted to provide exercises at the end of each chapter. We
have, however, found two exercises to be quite useful and that
apply most of the fundamental principles of this text. First, ask
students to critique a clinical trial article from the current
literature. Second, have each student develop a protocol on a
clinically relevant research question that is of interest to the
student. These draft protocols can often be turned into protocols
that are implemented. Although there is a chapter on regulatory
issues, this book is not meant to replace going to the actual
agencies for guidance on regulations and policies. Those differ
among countries and frequently change. Rather, as the title
indicates, we hope to provide the fundamentals of clinical trials
ethics, design, conduct, analysis, and reporting.
The first chapter describes the
rationale and phases of clinical trials. Chapter 2 covers selected ethical issues.
Chapter 3 describes the questions that
clinical trials seek to answer and Chap. 4 discusses the populations from
which the study samples are derived. The strengths and weaknesses
of various kinds of study designs, including noninferiority trials,
are reviewed in Chap. 5 . The process of randomization is
covered in Chap. 6 . In Chap. 7 , we discuss the importance of and
difficulties in maintaining blinding. How the sample size is
estimated is covered in Chap. 8 . Chapter 9 describes what constitutes the
baseline measures. Chapter 10 reviews recruitment techniques and
may be of special interest to investigators not having ready access
to trial participants. Methods for collecting high-quality data and
some common problems in data collection are included in Chap.
11 . Chapters 12 and 13 focus on assessment of harm and
health-related quality of life that are important clinical trial
outcomes. Measures to enhance and monitor participant adherence are
presented in Chap. 14 . Chapter 15 reviews techniques of survival
analysis. Chapter 16 presents the functions of data
monitoring committees and Chap. 17 reviews methods of data
monitoring. Which data should be analyzed? The authors develop this
question in Chap. 18 by discussing reasons for not
withdrawing participants from analysis. Topics such as subgroup
analysis and meta-analysis are also addressed. Chapter 19 deals with phasing out clinical
trials and Chap. 20 with reporting and interpretation
of results. In Chap. 21 , we present information about
multicenter, including multinational, studies, which have features
requiring special attention. Several points covered in Chap.
21 may also be of value to
investigators conducting single center studies. Finally, selected
regulatory issues, as they apply to clinical trials are reviewed in
Chap. 22 .
This book is a collaborative effort and
is based on knowledge gained in over four decades of developing,
conducting, overseeing, and analyzing data from a number of
clinical trials. This experience is chiefly, but not exclusively,
in trials of heart and lung diseases, AIDS, and cancer. As a
consequence, many of the examples cited are based on work done in
these fields. However, the principles are applicable to clinical
trials in general. The reader will note that although the book
contains examples that are relatively recent, others are quite old.
The fundamentals of clinical trials were developed in those older
studies, and we cite them because, despite important advances, many
of the basic features remain unchanged.
In the first edition, the authors had
read or were familiar with much of the relevant literature on the
design, conduct, and analysis of clinical trials. Today, that task
would be nearly impossible as the literature over the past three
and a half decades has expanded enormously. The references used in
this text are not meant to be exhaustive but rather to include the
literature that established the fundamentals and newer publications
that support the basic concepts.
The views expressed in this book are
those of the authors and do not necessarily represent the views of
the institutions with which the authors have been or are
affiliated.
References
1. NIH Inventory of Clinical Trials:
Fiscal Year 1979. Volume 1. National Institutes of Health, Division
of Research Grants, Research Analysis and Evaluation Branch,
Bethesda, MD.
2. Bulpitt CJ.
Randomised Controlled Clinical
Trials . The Hague: Martinus Nijhoff, 1983.
3. Pocock SJ.
Clinical Trials—A Practical
Approach . New York: John Wiley and Sons, 1983.
4. Ingelfinger
JA, Mosteller F, Thibodeau LA, et al. Biostatistics in Clinical Medicine .
New York: Macmillan, 1983.
5. Iber FL Riley
WA, Murray PJ. Conducting Clinical
Trials . New York: Plenum, 1987.
6. Peace KE
(ed.). Statistical Issues in Drug
Research and Development . New York: Marcel Dekker,
1990.
7. Spilker B.
Guide to Clinical Trials .
New York: Raven Press, 1991.
8. Spriet A, Dupin-Spriet T, Simon P.
Methodology of Clinical Drug
Trials (2 nd edition). Basel: Karger, 1994.
9. Chow S-C, Shao J. Statistics in Drug Research :
Methodologies and Recent
Developments . New York: Marcel Dekker, 2002.
10. Rosenberger
WF, Lachin JM. Randomization in
Clinical Trials: Theory and Practice . New York: Wiley,
2002.
11. Geller NL
(ed.). Advances in Clinical Trial
Biostatistics . New York: Marcel Dekker, 2003.
12. Piantadosi S.
Clinical Trials: A Methodologic
Perspective (2nd edition). New York: John Wiley and Sons,
2005.
13. Matthews JNS. An Introduction to Randomised Controlled
Clinical Trials (2 nd edition). Boca Raton:
Chapman & Hall/CRC, 2006.
14. Machin D, Day S, Green S.
Textbook of Clinical Trials
(2 nd edition). West Sussex: John Wiley and Sons,
2006.
15. Keech A,
Gebski V, Pike R (eds.). Interpreting and Reporting Clinical
Trials . Sidney: Australasian Medical Publishing Company,
2007.
16. Cook TD,
DeMets DL (eds.). Introduction to
Statistical Methods for Clinical Trials . Boca Raton:
Chapman & Hall/CRC, Taylor & Francis Group, LLC,
2008.
17. Machin D, Fayers P. Randomized
Clinical Trials: Design ,
Practice and Reporting .
Chichester, West Sussex: Wiley-Blackwell, 2010.
18. Green S,
Benedetti J, Crowley J. Clinical
Trials in Oncology (3rd edition). Boca Raton: Chapman &
Hall/CRC Press, 2012.
19. Meinert CL. Clinical Trials: Design, Conduct, and
Analysis (2 nd edition). New York: Oxford
University Press, 2012.
20. Hulley SB, Cummings SR, Browner
WS, et al. Designing Clinical
Research (4 rd edition). New York: Wolters
Kluwer/Lippincott Williams & Wilkins, 2013.
21. Chow S-C, Liu J-P. Design and Analysis of Clinical Trials:
Concepts and Methodologies (3 rd edition).
Hoboken, NJ: Wiley, 2014.
Lawrence M. Friedman
Curt D. Furberg
David L. DeMets
David M. Reboussin
Christopher B. Granger
Acknowledgments
Most of the ideas and concepts
discussed in this book represent what we first learned during our
years at the National Heart, Lung, and Blood Institute and in
academia. We are indebted to many colleagues, and particularly in
the case of the original three authors, to the late Dr. Max
Halperin, with whom we had numerous hours of discussion for the
earlier editions on theoretical and operational aspects of the
design, conduct, and analysis of clinical trials.
Many have contributed to this fifth
edition of the book. We appreciate the efforts of Drs. Michelle
Naughton and Sally Shumaker in revising the chapter on
health-related quality of life and Mr. Thomas Moore for his
contributions to the chapter on assessment and reporting of harm.
Also appreciated are the constructive comments of Drs. Bengt
Furberg and Bradi Granger. We want to particularly acknowledge the
outstanding administrative support of Donna Ashford and Catherine
Dalsing. Finally, nobody deserves more credit than our families and
colleagues who have unfailingly encouraged us in this effort. This
is especially true of Gene, Birgitta, Kathy, Beth, and Bradi, who
gave up many evenings and weekends with their spouses.
Contents
Appendices 17
References
18
Definitions 298
References 315
Generalizations 335
References 340
References 368
Other
Approaches 391
References 395
References 515
Erratum E1
Index543
About the Authors
Lawrence M. Friedman
received his M.D. from the University of
Pittsburgh. After training in internal medicine, he went to the
National Heart, Lung, and Blood Institute of the National
Institutes of Health. During his many years there, Dr. Friedman was
involved in numerous clinical trials and epidemiology studies,
having major roles in their design, management, and monitoring.
While at the NIH and subsequently, he served as a consultant on
clinical trials to various NIH institutes and to other governmental
and nongovernmental organizations. Dr. Friedman has been a member
of many data monitoring and other safety committees.
Curt D. Furberg
is Professor Emeritus of the Division of Public
Health Sciences of the Wake Forest University School of Medicine.
He received his M.D. and Ph.D. at the University of Umea, Sweden,
and is a former chief, Clinical Trials Branch and Associate
Director, Clinical Applications and Prevention Program, National
Heart, Lung, and Blood Institute. Dr. Furberg established the
Department of Public Health Sciences and served as its chair from
1986 to 1999. He has played major scientific and administrative
roles in numerous multicenter clinical trials and has served in a
consultative or advisory capacity on others. Dr. Furberg’s research
activities include the areas of clinical trials methodology and
cardiovascular epidemiology. He is actively involved in the debate
about the need for better documentation of meaningful clinical
efficacy and long-term safety for drugs intended for chronic
use.
David L. DeMetsPh.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 co-authored numerous papers on statistical methods 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 diverse disciplines. He served on
the Board of Directors of the American Statistical Association, as
well as having been President of the Society for Clinical Trials
and President of the Eastern North American Region (ENAR) of the
Biometric Society. In addition he was Elected Fellow of the
International Statistics Institute, the American Statistical
Association, the Association for the Advancement of Science, the
Society for Clinical Trials and the American Medical Informatics
Association. In 2013, he was elected as a member of the Institute
of Medicine.
David M. Reboussin
is a Professor in the Department of
Biostatistical Science at the Wake Forest University School of
Medicine, where he has worked since 1992. He has a master’s degree
in Statistics from the University of Chicago and received his
doctorate in Statistics from the University of Wisconsin at
Madison. He is currently Principal Investigator for the Systolic
Blood Pressure Intervention Trial Coordinating Center and has been
a co-investigator in the coordinating centers for several NIH and
industry funded clinical trials including Action to Control
Cardiovascular Risk in Diabetes (ACCORD), Action for Health in
Diabetes (Look AHEAD), the Combined Oral and Nutritional Treatment
of Late-Onset Diabetes Trial (CONTROL DM) and the Estrogen
Replacement and Atherosclerosis (ERA) Trial. Dr. Reboussin has
served on the data and safety monitoring boards for many National
Institutes of Health trials within areas including cardiology,
diabetes, nephrology, pulmonology, liver disease, psychiatry,
pediatrics, weight loss and smoking cessation. His work in
statistical methodology has included techniques and software for
sequential monitoring of clinical trials.
Christopher B. Granger
is Professor of Medicine at Duke University,
where he is an active clinical cardiologist and a clinical trialist
at the Duke Clinical Research Institute. He received his M.D. at
University of Connecticut and his residency training at the
University of Colorado. He has had Steering Committee, academic
leadership, and operational responsibilities for many clinical
trials in cardiology. He has been on numerous data monitoring
committees. He serves on the National Heart, Lung, and Blood
Institute Board of External Experts. He works with the Clinical
Trials Transformation Initiative, a partnership between the U.S.
Food and Drug Administration and Duke aiming to increase the
quality and efficiency of clinical trials. He is a founding member
of the Sensible Guidelines for the Conduct of Clinical Trials
group, a collaboration between McMaster, Oxford, and Duke
Universities.