Pharmacogenomics: Social, Ethical, and Clinical Dimensions

364 Pages·2003·2.049 MB·English

by  Mark A. Rothstein

PHARMACOGENOMICS
P
HARMACOGENOMICS
S , E ,
OCIAL THICAL AND
C D
LINICAL IMENSIONS
EDITED BY
MARK A. ROTHSTEIN
Herbert F. Boehl Chair of Law and Medicine
Director, Institute for Bioethics, Health Policy and Law
University of Louisville, School of Medicine
Louisville, KY
AJOHN WILEY& SONS, INC., PUBLICATION
Copyright © 2003 by John Wiley & Sons, Inc. All rights reserved.
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Library of Congress Cataloging-in-Publication Data:
Pharmacogenomics : social, ethical, and clinical dimensions /
edited by Mark A. Rothstein.
p. ; cm.
Includes bibliographical references and index.
ISBN 0-471-22769-2 (cloth)
1. Pharmacogenomics. I. Rothstein, Mark A.
[DNLM: 1. Pharmacogenetics. 2. Drug Design. 3. Ethics,
Medical. 4. Legislation, Medical. 5. Public Policy. 6. Social
Environment. QV 38 P53197 2003]
RM301.3.G45P435 2003
615(cid:2) .7—dc21
2002012137
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
CONTENTS
FOREWORD, IX
Francis S. Collins, M.D., Ph.D.
Director, National Human Genome Research Institute
PREFACE, XI
PART I INTRODUCTION: SCIENCE AND SOCIETY
1 PUBLIC ATTITUDES ABOUT PHARMACOGENOMICS, 3
Mark A. Rothstein, J.D. and Carlton A. Hornung, Ph.D., M.P.H.
University of Louisville School of Medicine
2 PHARMACOGENOMICS: PHARMACOLOGY AND TOXICOLOGY IN THE
GENOMICS ERA, 29
Harvey W. Mohrenweiser, Ph.D.
Biology and Biotechnology Research Program, Lawrence Livermore National
Laboratory
3 THE IMPLICATIONS OF POPULATION GENETICS FOR PHARMACOGENOMICS, 51
Craig L. Hanis, Ph.D.
Human Genetics Center, University of Texas Health Science Center at Houston
PART II RESEARCH AND DEVELOPMENT CHALLENGES AND
CONSIDERATIONS
4 GENOME RESEARCH AND MINORITIES, 67
Henry T. Greely, J.D.
Stanford University
5 DRUG DEVELOPMENT STRATEGIES, 83
Penelope K. Manasco, M.D. and Teresa E. Arledge, D.V.M.
First Genetic Trust
V
VI CONTENTS
6 DRUG DEVELOPMENT, REGULATION, AND GENETICALLY
GUIDED THERAPY, 99
David W. Feigal, Jr., M.D., M.P.H. and Steven I. Gutman, M.D.
Food and Drug Administration
7 INTELLECTUAL PROPERTY AND COMMERCIAL ASPECTS OF
PHARMACOGENOMICS, 109
Allen C. Nunnally, J.D., Scott A. Brown, J.D., and Gary A. Cohen, J.D.
Hale and Dorr LLP Millennium Pharmaceuticals
PART III CLINICAL APPLICATIONS
8 INTEGRATION OF PHARMACOGENOMICS INTO MEDICAL PRACTICE, 137
Gilbert S. Omenn, M.D., Ph.D. and Arno G. Motulsky, M.D.
University of Michigan Health System
University of Washington
9 CLINICAL UTILITY OF PHARMACOGENETICS AND
PHARMACOGENOMICS, 163
Neil A. Holtzman, M.D., M.P.H.
Genetic and Public Policy Studies, The Johns Hopkins Medical Institutions
10 MEDICAL LIABILITY FOR PHARMACOGENOMICS, 187
Larry I. Palmer, LL.B.
Institute for Bioethics, Health Policy and Law University of Louisville School of
Medicine
11 THE CHALLENGES OF PHARMACOGENOMICS FOR PHARMACY EDUCATION,
PRACTICE, AND REGULATION, 207
David B. Brushwood, R.Ph., J.D.
University of Florida College of Pharmacy
PART IV THE SOCIAL DIMENSION
12 ECONOMIC IMPLICATIONS OF PHARMACOGENOMICS, 229
C.E. Reeder, Ph.D. and W. Michael Dickson, Ph.D.
College of Pharmacy, University of South Carolina
13 PHARMACOGENOMICS AND THE SOCIAL CONSTRUCTION OF IDENTITY, 251
Morris W. Foster, Ph.D.
Department of Anthropology, University of Oklahoma
14 PHARMACOGENOMICS: CONSIDERATIONS FOR COMMUNITIES
OF COLOR, 267
Laurie Nsiah-Jefferson, M.P.H.
W.K. Kellogg Fellow, Brandeis University
CONTENTS VII
15 CONSTITUTIONAL ISSUES IN THE USE OF PHARMACOGENOMIC
VARIATIONS ASSOCIATED WITH RACE, 291
John A. Robertson, J.D.
University of Texas School of Law, Austin
V
PART
EPILOGUE: POLICY PRESCRIPTIONS, 319
Mark A. Rothstein, J.D.
Institute for Bioethics, Health Policy and Law
University of Louisville School of Medicine
PHARMACOGENOMICS AND MINORITY POPULATIONS: GENERAL POPULATION
SURVEY QUESTIONNAIRE, 337
Mark A. Rothstein, J.D.
INDEX, 349
FOREWORD
FRANCIS S. COLLINS, M.D., PH.D.
A century ago, with characteristic vision and eloquence, Sir William Osler
penned these words: “Were man always, inside and outside, cast in the same
mold, instead of differing from his fellow man, we would ere have reached
some settled principles in our art.” This variability and unpredictability of
responses to medical intervention is familiar to every health care provider,
and has been a cause of puzzlement and vexation to providers and patients
throughout the entire history of medicine. Given an ideal situation where
a diagnosis has been firmly established and rigorous evidence points to a
validated pharmaceutical intervention, it is virtually never the case that
100% of the patients treated will enjoy an optimal outcome. Instead, some
proportion (the responders) will achieve benefit, while another fraction will
have no response (the non-responders), and a small proportion may suffer
a significant side effect (the adverse responders). Pharmacogenomics offers
the bright hope of being able to make prior predictions of these outcomes,
allowing more informed choices and a better outcome.
Since Osler penned his lament, a certain amount of progress has been
made in identifying the heritable basis of variable drug response, but it has
been only modest. Afew instances of dramatic adverse drug responses, such
as malignant hyperthermia, or hemolytic anemia following chloroquine
administration, have been tracked to their genetic roots by clever detective
work. With the advent of additional tools and increasingly robust databases
of genetic information, insights into more complex drug reactions (such as
the role of Factor V Leiden in the development of deep vein thrombosis after
estrogen administration) are beginning to be more discernable. But now, at
the dawn of the 21st century, the powerful tools of genomics are finally
assembled to make it possible to identify the polygenic basis of drug
responses in a much wider variety of applications. Already a few examples
are emerging, such as the recent elucidation of a significant genetic contri-
IX
X FOREWORD
bution to abacavir adverse response, recently mapped to the major histo-
compatibility complex. The full flowering of pharmacogenomics will occur
in the next decade, building upon the foundation of the sequence of the
human genome and a detailed catalogue of human variation. In that regard,
determining not only the common variants in the genome but how they are
associated with their neighbors (the so-called Haplotype Map) will provide
the kind of toolkit to carry out whole genome association studies to identify
determinants of drug response that were only a distant dream a decade ago.
Despite some uncertainties, the clinical applications of pharmacoge-
nomics are likely to be highly significant. In instances where the positive
predictive value of a genetic test is quite high, there are compelling argu-
ments to utilize such testing as soon as rigorous clinical data has been
obtained. An example where this is already become the standard of care
involves a variant in the TPMT gene. Homozygotes for this mutation will
have a severe and even fatal reaction to the thiopurine class of drugs, the
most commonly used of which is 6-mercaptopurine, a mainstay in the treat-
ment of childhood acute lymphocytic leukemia. For many pharmacoge-
nomics tests of the future, however, the positive predictive value may be
only modest. But there may be good reasons even then to utilize genetic
testing if several interventions are available and the test results may help to
skew the odds towards a favorable outcome.
Five years ago pharmacogenomics was unfamiliar to most scientists and
health care providers. Today we are witnessing an exponential increase in
research on the topic, new journals are springing up, and observers in both
the academic and private sector are predicting a substantial impact on clin-
ical medicine in only a few years. In such a rapidly-changing environment,
it is critical to stand back from the avalanche of scientific information and
consider the broader view, with special attention towards the impact on
society. In that regard, the birth of this new textbook, which considers social
and ethical issues as well as scientific and clinical underpinnings, comes at
an auspicious moment. In this remarkably broad and far-reaching work,
editor Mark Rothstein and his distinguished list of contributors have laid
out an impressive framework for the field. Beginning with a survey of public
attitudes, and progressing through scientific, clinical, governmental, legal,
economic, and societal issues, the text builds to a final provocative epilogue
on consequences for public policy. If, as many predict, we are moving
towards a “Dx; Rx” model for medicine, in which genetic testing routinely
precedes the writing of prescriptions, this text should provide a thoughtful
foundation upon which to build that future.
PREFACE
In 1998, when I began the initial research that culminated in this volume, the
terms pharmacogenetics (the role of genetic variation in differential response
to pharmaceuticals) and pharmacogenomics (the use of genomic technolo-
gies in assessing differential response to pharmaceuticals) were limited to
the vocabularies of a few experts in genetics and pharmacology. Within a
mere five years, however, several journals have been launched devoted
exclusively to these topics, pharmacogenomics articles have begun appear-
ing regularly in general scientific and medical journals, and even the popular
press has begun to feature articles on the development of genome-specific
medications.
A notable exception to the increasing focus on pharmacogenetics and
pharmacogenomics is the literature dealing with the ethical, legal, and social
implications of genetic and genomic research. Commentators on “ELSI”
issues have only occasionally turned their attention to the range of emerg-
ing issues raised by pharmaceutical research and clinical applications based
on human genetic variation. This volume attempts to reduce this scholarship
deficit by presenting a multidisciplinary analysis of the scientific, clinical,
economic, ethical, social, and legal implications of pharmacogenomics. It
also includes, in Chapter 1, the results of the first comprehensive public
opinion survey on pharmacogenomics and, in the Epilogue, a series of pro-
posals to address the policy issues raised in the book’s fifteen wide-ranging
chapters.
Research for this book was funded by a grant from the National Insti-
tute of General Medical Sciences (lead institute), the National Human
Genome Research Institute, and the National Institute for Environmental
Health Sciences of the National Institutes of Health. I want to thank, in par-
ticular, Dr. Rochelle Long, of the NIGMS, for her commitment to the explo-
ration of these issues as well as her support and substantive contributions.
The grant application was written and submitted while I was at the
Health Law and Policy Institute of the University of Houston. My former
colleague, Elaine Lisko, who left Houston in 1999, played an integral part in
XI
XII PREFACE
researching and drafting the grant application. Phyllis Griffin Epps, who
remained in Houston after my departure in December 2000, continued to
have a central role in the project, including the public opinion survey,
editorial work on this volume, and taking the lead in several articles we
coauthored on pharmacogenomics.
Telesurveys Research Associates of Houston conducted the public
opinion survey. Rosie Zamora, Dick Jaffe, and Barry Petree demonstrated
patience and good cheer through the numerous revisions of the survey
instrument. Dr. Eun-Sul Lee of the University of Texas-Houston School of
Public Health and Dr. Sharon P. Cooper, now at the Texas A&M University
School of Rural Public Health, were the statistical consultants on the survey.
At the Institute for Bioethics, Health Policy and Law at the University
of Louisville, my colleague Gabriela Alcalde helped me in conceptualizing
the key issues and also took the lead in drafting two articles we coauthored
on the topic. Dr. Mary Anderlik coauthored a paper with me on genetic
research in which pharmacogenomics was a key element. Dr. Carl Hornung
of the Department of Medicine contributed indispensable data analysis on
the survey and coauthored Chapter 1 of this volume.
Dennis Holmgren, J.D. 2002 from the Louis D. Brandeis School of Law
of the University of Louisville, provided valuable research assistance and
generated the computer graphics for the figures in Chapter 1. Rob Wright,
J.D. 2003, ably assisted with the final reference check.
Sue Rose was responsible for the manuscript preparation and format-
ting, which she did with her customary skill and equanimity through endless
revisions. My long-time associate, Cathy Rupf, contributed expert grant
administration and project planning at both the University of Houston and
the University of Louisville. Judy Oller was responsible for the flawless
financial management on the grant.
Last, but not least, I want to thank my wife Laura for leading me into
challenging new professional adventures and providing the personal
support to make them work.
Mark A. Rothstein
July 2002