Principles and Practice of Clinical Trial Medicine - R. Chin, B. Lee (AP, 2008) WW.pdf

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Dedication
This endeavor would not have been possible had we not met as classmates (and dormitory mates) at Harvard Medical
School. This book is dedicated to our families, whose support and encouragement made the endeavor possible. We also
would like to thank everyone at Elsevier for their hard work and invaluable help and making the process an exciting and
enjoyable one.
RYC and BYL
About the Authors
Richard Chin, MD
San Francisco, California, USA
Dr. Chin is a Harvard trained, Board Certified internist with drug development across a wide range of specialties, includ-
ing oncology, immunology, ophthalmology, neurology, endocrinology, and cardiovascular medicine, among others. He
has been responsible for over 40 Investigational New Drug (IND) Applications and 8 New Drug Applications (NDAs)/
Biologic License Applications (BLAs). Some of the drugs Dr. Chin has overseen include ranibizumab, natalizumab, ten-
ecteplase, bapineuzumab, ziconotide, and omalizumab. He has both US and international experience, and has overseen
a wide variety of functions, including Clinical Development, Regulatory, Biostatistics, Quality Assurance/Compliance,
Chemistry Manufacturing, and Control, Safety and Medical Affairs.
Dr. Chin is currently President and CEO of a NASDAQ-listed a biotechnology company. Previously, he was Senior
Vice President and Head of Global Development for Elan Corporation, and before that served as the Head of Clinical
Research for the Biotherapeutics Unit at Genentech. Dr. Chin holds a Medical Degree from Harvard Medical School. He
received the equivalent of a J.D. with honors from Oxford University, England under a Rhodes Scholarship. He graduated
with a Bachelor of Arts in Biology,
magna cum laude,
from Harvard University. He previously served on the adjunct clini-
cal faculty at Stanford Medical School.
Bruce Y. Lee, MD, MBA
University of Pittsburgh
Pittsburgh, Pennsylvania, USA
Dr. Lee is currently an Assistant Professor of Medicine and Biomedical Informatics, and Epidemiology at the University
of Pittsburgh. He is also Core Faculty in the Section for Decision Sciences and Clinical Systems Modeling, the Center for
Research in Health Care, and the RAND-University of Pittsburgh Health Institute. He is a Co-Investigator for the National
Institutes of Health (NIH) Modeling of Infectious Diseases Agent Study (MIDAS) research and informatics network, and
a Co-Investigator for a Bill & Melinda Gates Foundations Grant on the evaluation of candidate vaccine technologies using
computational models.
His previous positions include serving as Senior Manager at Quintiles Transnational, working in biotechnology
equity research at Montgomery Securities, and co-founding Integrigen, a biotechnology company. His consulting experi-
ence includes a large variety of clients, ranging from large and small pharmaceutical, biotechnology, and medical device
companies.
Dr. Lee has authored three books, as well as numerous research publications, review articles, and book chapters.
Dr. Lee received his B.A. from Harvard University, M.D. from Harvard Medical School, and M.B.A. from the Stanford
Graduate School of Business. He is board-certified in Internal Medicine, having completed his residency training at the
University of California, San Diego.
Introduction
While we may not recognize it, we all use the skills
necessary to conduct and interpret “clinical trials” every
single day. Sampling and comparing one restaurant, article
of clothing, television show, fitness club, vacation loca-
tion, date, job candidate, or client to another is effectively
conducting a clinical trial. Evidence and results from these
mini-trials guide your choices and decisions throughout
the day. Should you buy that swimsuit? Is it better than the
one in the other store? Are the Philadelphia Eagles or the
Pittsburgh Steelers a better football team? Which sushi
restaurant has the best salmon? What job will provide the
best experience? Where should you live and what house
should you buy? Is it better to hire Job Candidate #1 or Job
Candidate #2? Faulty “trial” design, data, or interpretation
leads to inaccurate assessments and perhaps poor decisions.
For example, using the wrong criteria will result in hiring
the wrong person for a job. We all have suffered from that
impulse buy, that forehead-slapping wrong decision, or that
bad choice of friend, employee, or significant other.
Formal and informal clinical trials are a large part of our
lives. If you use, produce, study, purchase, invest in, or con-
duct research in drugs, medical devices, or any type of health
care intervention, understanding the science and operations of
formal clinical trials can only help. Today, even understand-
ing many major news items requires at least some knowl-
edge of clinical trials. Whenever a drug or medical device is
recalled, a medical intervention is debunked, or a new ther-
apy hits the market, clinical trial design, conduct, or analy-
sis is at the heart of the evidence or the controversy. Health
care is such a major business that even seemingly unrelated
industries and professions can be dramatically affected by a
successful or unsuccessful clinical trial. Flaws in a clinical
trial that force a major drug or device to be pulled from the
market can alter many lives and rock the economy.
Therefore, during our planning stages for
Principles and
Practices of Clinical Trial Medicine
, confining the book’s
audience was difficult. Should this book be geared toward just
physicians? Pharmaceutical industry professionals? Statis-
ticians? Academics? Clinical research specialists? Regulatory
professionals? Ethicists? Medical students? Nursing stu-
dents? Medicine residents? Graduate students? Post-doctoral
fellows? Epidemiologists? Engineers? Pharmacologists?
Pharmacists? Biologists? Pharmaceutical or medical device
executives? The more we thought about it, the more we
realized that the audience could be quite broad. Both of our
career journeys have taken us through a variety of func-
tions and domains in industry, academics, and business. We
have seen the investment, research, technical, management,
teaching, writing, consulting, and clinical practice realms
of the health care industry. In the end, while each area may
have different jargon, cultures, personalities, and perspec-
tives, the guiding principles are the same. A good clinical
trial at an academic institution is a good one in industry and
vice-versa.
Therefore, we wrote this book with a broad audience in
mind, trying to minimize the jargon and explain any impor-
tant terminology in the process. The goal was to write a
book that could be easily understood regardless of your
background, especially since people from so many differ-
ent backgrounds are involved in clinical trials. In fact, in
many professions, understanding the jargon and terminol-
ogy is half the battle.
Moreover, regardless of your interest and function in
the clinical research world, knowing the general concepts
of all aspects of clinical trials can be very advantageous.
In many ways, the clinical research world has become far
too specialized. Many individuals stay ensconced within
their areas of knowledge and expertise. But the best clini-
cal researchers or trialists have broad knowledge bases that
span statistics, regulatory affairs, ethics, clinical medicine,
science, basic probability, data management, and trial and
personnel management. The ones that stand out, are most
marketable, and do the best work cannot afford to say, “I
do not need to know that because it is not in my area.”
xi
xii
Designing, conducting, and analyzing a clinical trial is
like designing, building, and using a house. Recognizing
a house’s design and construction helps you realize its
potential use. For example, a thin-walled house may cause
problems during the winter. Very cramped rooms may not
facilitate hosting a party. At the same time, anticipating the
house’s use aids its design and construction. Your design
of a beach house likely will differ significantly from your
design of a farm house or a city dwelling.
The “building a house” analogy helps illustrate the gen-
eral organization of our book.
The Principles and Practices
of Clinical Trial Medicine
contains five sections. Section I
introduces the field of clinical research with Chapter 1 delin-
eating some general theory and Chapter 2 covering impor-
tant legal, ethical, and regulatory issues. The materials
in this section are analogous to all of the rules and regula-
tions that govern the construction of a house: ranging from
general engineering and architectural principles to zoning
laws and building codes. Just as you can’t build any kind of
house anywhere you choose (e.g., Igloos do not belong in
Philadelphia or San Francisco), you must understand general
clinical research theory and comply with legal, ethical, and
regulatory principles when designing and conducting a trial.
Section II focuses on the general design of clinical trials. If
you imagine a clinical trial to be a house, statistics (Chapter 3)
are the tools used to build the house. The final design of the
house depends heavily on the tools that you have at your dis-
posal. Sure you can rely on others to choose and wield the
tools… but would you truly know and trust the house? To be
truly competent at clinical research, you have to know your
tools, even if you have specialists to employ them. Measures
and Variables (Chapter 4) are the construction materials for
the house. Construction materials help determine the house’s
appearance and utility. Building a house resistant to harsh ele-
ments may be difficult without good quality bricks or cinder
blocks. Similarly, studying heart disease may be challenging
without accurate echocardiograms, electrocardiograms, and
blood pressure measurements. Study Groups (Chapter 5) and
Periods, Sequences and Design (Chapter 6) are the rooms
and corridors of the house. Changing these will dramatically
change the house’s functionality and purpose. Having no
kitchen makes cooking and hosting dinner parties difficult.
An indoor garage allows you to shield your car from the ele-
ments. Similarly, comparing two medical interventions nor-
mally requires employing at least two different study groups.
Seeing the long-term effects of a drug necessitates patients
being on the drug for a long period of time.
Section III takes a closer look at an array of important ele-
ments in clinical trial design. Endpoints (Chapter 7) are special
measures and variables that serve as the outcomes of the trial.
So, continuing our building analogy, endpoints are the key
construction materials that determine the worth, strength, and
use of the house. Chapter 8 (Economics and Patient Reported
Outcomes) discusses some special types of endpoints,
Introduction
Chapter 9 (Patient Selection and Sampling) reviews consid-
erations when choosing patients for your trial, and Chapter 10
(Dosing and Intervention) analyzes how medical interventions
should be administered to patients. All of these are as impor-
tant factors and parameters to clinical trials as ceiling height,
room size, lighting, house temperature, and other features are
to house construction. Chapter 11 Epidemiology, Decision
analysis and simulation offers additional tools that may help
in the planning and analysis of trials, and is analogous to the
model building and “roughing-in” phase of house building,
where you visualize how a house might look.
Section IV covers practical logistical issues involved in
conducting a trial. This is analogous to concerns that arise
when actually building the house. For example, from where
do you procure building materials? Which forms should you
complete when ordering such materials? Which nails should
you use? Where should you place the beams? How do you
select and supervise the contractor? All of these types
of issues are discussed in Chapter 12 Study Execution.
Recruiting Patients and Choosing Trial Locations (Chapter
13) are such an important part of conducting trials that a
separate chapter is devoted to the topic.
Finally, Section V discusses how to analyze the results
of clinical trial. In our building analogy, this is similar
to using and inhabiting the house. Data is the output of a
clinical trial, just as a house is the end product of house
construction. Chapter 14, Assessing Data Quality and Trans-
forming Data, is akin to inspecting the house and making
the final adjustments and reworking anything that needs to
be reworked. If the stairs are not to code, they need to be
redone, and if the painters overpainted the moldings, they
need to be repainted. Data similarly need to the cleaned and
transformed, to ameliorate missing or unreliable data points.
Chapter 15, Analysis of Data, is akin to decorating the
house and moving the furniture into the appropriate rooms.
You manipulate the data that has been gathered and prepared.
This allows you to then interpret the data, which is the subject
of Chapter 16 Data interpretation and conclusions. This is
akin to moving into the house and living in it. This is the acid
test. No matter how well-built or well-decorated the house
is, if you don’t enjoy living in it, all has been for naught.
Similarly, the ultimate end product of a clinical trial is a con-
clusion that is actionable for the treatment of future patients.
So whether you are new to the world of clinical trials or
have been conducting clinical research for many years, we
hope that this book serves you well. The importance and
use of clinical trials will only continue to grow in the future.
Concomitantly, trial design and conduct will face increasing
scrutiny. In many cases, lives of innumerable patients and
significant amount of time and resources will be riding on
them. Will you be ready?
Richard Chin, MD
Bruce Y. Lee, MD, MBA

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