Table Of ContentPharmacogenomics and Personalized Medicine
Methods in Pharmacology and Toxicology
Y. James Kang, SERIES EDITOR
Pharmacogenomics and Personalized Medicine, edited by Nadine Cohen, 2008
Biomarker Methods in Drug Discovery and Development, edited by Feng
Wang, 2008
Cytokines in Human Health: Immunotoxicology, Pathology, and Therapeutic
Applications, edited by Robert V. House and Jacques Descotes, 2007
Drug Metabolism and Transport: Molecular Methods and Mechanisms, edited by
Lawrence Lash, 2005
Optimization in Drug Discovery: In Vitro Methods, edited by Zhengyin Yan
and Gary W. Caldwell, 2004
In Vitro Neurotoxicology: Principles and Challenges, edited by Evelyn Tiffany-
Castiglioni, 2004
Cardiac Drug Development Guide, edited by Michael K. Pugsley, 2003
Methods in Biological Oxidative Stress, edited by Kenneth Hensley and Robert A. Floyd,
2003
Apoptosis Methods in Pharmacology and Toxicology: Approaches to Measurement
and Quantification, edited by Myrtle A. Davis, 2002
Ion Channel Localization: Methods and Protocols, edited by Anatoli N. Lopatin and
Colin G. Nichols, 2001
Pharmacogenomics
and Personalized Medicine
Nadine Cohen
Johnson and Johnson Pharmaceutical Research and Development, L.L.C.,
Raritan, NJ, USA
Editor
Editor
Nadine Cohen
Johnson and Johnson Pharmaceutical Research
and Development, L.L.C.,
Raritan, NJ, USA
P reface
Some of the challenges the pharmaceutical industry faces in the current research
and development processes are: (1) a lengthy process that takes, on average,
approximately 11 years from target identification to the development of a new
medicine; (2) an ever increasing costly process; (3) an inefficient process where too
many drugs fail before they reach the market because of a lack of efficacy or unac-
ceptable toxicity, as well as postmarketing withdrawal due to rare serious adverse
events; (4) drug--drug interactions or toxicity is not uncommon; (5) the increasing
difficulty in identifying novel drug targets; and (6) the mode of action for many
compounds is often unknown. This is a depressing reality. Where are the improve-
ments in both quality and efficiency often claimed in the drug development proc-
ess? Why haven’t the advances in science and technology made a greater impact?
How can improvements in the process reduce the already high cost of drug develop-
ment generally?
T o address some of these issues, the pharmaceutical industry is actively explor-
ing the relationships between human genetics and drug responsiveness, susceptibil-
ity to disease, and disease severity. While research approaches and emphases may
vary from company to company, the overarching goal of the industry is largely
consistent: to discover and develop new medicines based on an improved under-
standing of patient response to drugs (positive or negative) and of diseases etiology.
Pharmacogenomic (PGx) methods are aimed at determining the contribution of
genetic differences in ADME, drug target, and disease genes to drug response,
thereby improving the safety and efficacy of drug therapy through use of geneti-
cally guided treatments, an approach called p ersonalized medicine. Personalized
medicine is both one of the newest disciplines of medicine currently being used and
very much an ongoing work in progress. Many drug companies have incorporated
genetic research, such as the collection of genetic samples, into their drug develop-
ment programs. And while only a few examples of true success stories have
emerged during the past few years of research, it is clear that the current landscape
is driving us toward a more widespread acceptance of personalized medicine.
Currently many questions arise regarding the appropriate implementation of this
technology: how can the industry go about delivering true business value while
recognizing that the ability to address patients’ demand for safer and more efficient
novel drugs might be met by engaging this technology more fully. There are
v
vi Preface
c oncerns within the pharmaceutical industry about generating data that might be
difficult to interpret in a regulated environment. There is also a growing apprecia-
tion for the challenges in translating this new information into clinical utility,
including scientific, commercial, ethical, and policy challenges.
P harmacogenomics and Personalized Medicine, which is part of the M ethods in
Pharmacology and Toxicology series, comprises chapters on selected aspects of
pharmacogenomics and personalized medicine. Our overall intent is to assist both
novice and experienced investigators in understanding the current scientific chal-
lenges in applying PGx to discovery and clinical development and in making appro-
priate decisions to engage in and interpret PGx research. Designed to share the
experiences of leading experts in the field, the book is a useful guide for conducting
PGx research--from discovery to the market, but we also aim to present a realistic
perspective on the challenges, practicalities, and obstacles in applying pharmacog-
enomics. Generally, the book avoids statements such as “Pharmacogenomics is
going to revolutionize the practice of medicine,” which are neither realistic nor
particularly useful to anyone.
T he book presents an industry perspective on the implementation of PGx in
research and development, in drug discovery, and in clinical trials, including recom-
mendations for a systematic approach for assessing the feasibility and added value of
PGx studies in clinical trials. It also provides guidance on the key logistical issues
required to prepare the pharmacogenomics protocol and an informed consent form
for sample collection and analysis, the strategies and resources for SNP marker selec-
tion, and genotyping in genetic association studies, and the study design and statisti-
cal methodologies for data analysis in PGx research. We have included an interesting
view of the effect of genetic variation, as well as a description of recent PGx applica-
tions in drug metabolism, adverse drug reactions, and in a few selected therapeutic
areas (epilepsy, Alzheimer’s disease, psychiatry, oncology, HIV, cardiovascular dis-
eases). Additional key topics,s such as the current regulatory environment and drug
label implications, biomarker qualification and trial design, the co-development of
drugs and diagnostics, and the translation of genomics biomarkers into clinical utility,
are also covered. Furthermore, two chapters describe the current state of knowledge
of PGx in rare and monogenic disorders and in children, which are currently less well
covered in the published literature but deserve attention.
P harmacogenomics and Personalized Medicine focuses on DNA data and asso-
ciated analytical methodologies that are currently the more mature components of
the evolving constellation of genomic sciences. However, complementary RNA-
based studies are also being considered in some chapters. It is important to also
acknowledge that remarkable progress is being made in complementary methodo-
logical areas such as p roteomics, m etabolomics, and imaging. Given the layered
complexities of biological regulation, it is likely that reliable markers will be
hybrids that will cross methodological disciplines. A program of persistent innova-
tion is being required from the industry to balance near-term profit with the need to
accommodate the increasingly competitive and changing landscape. Education and
cooperation among experts from the scientific community, industry, and g overnment
are recognized as integral to greater success in personalized medicine. It is my hope
Preface vii
that the knowledge we share here regarding DNA information may be leveraged to
create a useful foundation for further progress in personalized medicine, using
other approaches that will benefit the pharmaceutical industry overall, and most
importantly the patients.
Experts from the pharmaceutical industry, scientific community, and govern-
ment have been invited to contribute their experience to this book. I would like to
express my gratitude to all contributors for their enthusiasm to this work. Without
their time and energy, Pharmacogenomics and Personalized Medicine would not
have been possible.
Nadine Cohen, PhD
Contents
Preface ............................................................................................................. v
Contributors ................................................................................................... xiii
1 Challenges, Opportunities, and Evolving Landscapes
in Pharmacogenomics and Personalized Medicine:
An Industry Perspective ............................................................................ 1
Nadine Cohen and Theresa Frangiosa
2 Implementation of Pharmacogenomic Sample
Collection in Clinical Trials .................................................................... 27
Deborah Sokol Ricci and Monique Franc
3 Pharmacogenomics: The Regulatory Environment
and Labeling Implications ........................................................................ 55
Myong-Jin Kim, Shiew-Mei Huang, Atiqur Rahman,
Felix W. Frueh, and Lawrence J. Lesko
4 Applications of Pharmacogenomics in Drug Discovery ....................... 73
Dr. Duncan McHale
5 Applications of Pharmacogenomics in Clinical Trials ......................... 89
Monique Franc
6 Pharmacogenomics Applications in Drug Metabolism:
From Genotyping to Drug Label-Challenges? ........................................ 109
Ann K. Daly
7 The Genetics of Adverse Drug Reactions:
Promises and Problems ............................................................................ 121
Martin Armstrong
ix
x Contents
8 Strategies and Resources for Marker Selection
and Genotyping in Genetic Association Studies ................................. 149
Nicole Soranzo, Dong-Jing Fu, and Qingqin S. Li
9 Study Design and Statistical Issues
in Pharmacogenetics Research: From Candidate
Genes to Genome-Wide Screens ............................................................. 185
Nicholas J. Schork, Nathalie Malo, and Eric J. Topol
10 Holy SNP, Batman! ................................................................................ 207
Reyna Favis
11 Predictive Biomarker Classifiers in the Design
of Pivotal Clinical Trials ........................................................................ 229
Richard Simon
12 Translation of Biomarkers into Clinical Utility .................................. 239
William L. Trepicchio and George Mulligan
13 Pharmacogenomic Study Feasibility Assessment
and Pharmaceutical Business Decision-Making ................................. 253
Monique Franc and Theresa Frangiosa
14 Co-Development of Drugs and Pharmacogenomics-Based
Diagnostics in Oncology ........................................................................ 267
Jeffrey S. Ross
15 Pharmacogenomics Applications in Epilepsy ..................................... 299
Chantal Depondt
16 Pharmacogenomics in Alzheimer’s Disease ........................................ 317
Ramón Cacabelos
17 Pharmacogenomics Applications in
Psychiatric Disorders ............................................................................ 369
Todd Lencz and Anil K. Malhotra
18 Pharmacogenomics in HIV Disease ..................................................... 395
Amalio Telenti
19 Pharmacogenomics and Cardiovascular Drugs .................................. 413
Gérard Siest, Hind Berrahmoune, Jean-Brice Marteau,
and Sophie Visvikis-Siest
