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NEW FRONTIERS
IN CONTRACEPTIVE
RESEARCH
A Blueprint for Action
Sharyl J. Nass and Jerome F. Strauss 111, Eclitors
Committee on New Frontiers in Contraceptive Research
Board on Health Sciences Policy
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
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THE NATIONAL ACADEMIES PRESS 500 FIFTH STREET, N.W. Washington, DC 20001
NOTICE: The project that is the subject of this report was approved by the Gov-
erning Board of the National Research Council, whose members are drawn from
the councils of the National Academy of Sciences, the National Academy of Engi-
neering, and the Institute of Medicine. The members of the committee responsible
for the report were chosen for their special competences and with regard for ap-
propriate balance.
Support for this project was provided by the Bill and Melinda Gates Foundation.
The views presented in this report are those of the Institute of Medicine Commit-
tee on New Frontiers in Contraceptive Research and are not necessarily those of
the funding agency.
Library of Congress Cataloging-in-Publication Data
New frontiers in contraceptive research: a blueprint for action / Sharyl l. Nass
and Jerome F. Strauss III, editors; Committee on New Frontiers in Contraceptive
Research, Board on Health Sciences Policy.
p. ; cm.
Includes bibliographical references.
ISBN 0-309-09107-1 (pbk.)
1. Contraception Research.
[DNLM: 1. Contraception methods. WP630 N5324 2003] I. Nass,Sharyll.
II. Strauss, Jerome F. (Jerome Frank), 1947- III. Institute of Medicine (U.S.~.
Committee on New Frontiers in Contraceptive Research.
RG136.N493 2003
613.9'4'072 dc22
2003027272
Additional copies of this report are available from the National Academies Press,
500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202)
334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu.
For more information about the Institute of Medicine, visit the IOM home page at:
www.iom.edu.
Copyright 2004 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America.
The serpent has been a symbol of long life, healing, and knowledge among almost
all cultures and religions since the beginning of recorded history. The serpent
adopted as a logotype by the Institute of Medicine is a relief carving from ancient
Greece, now held by the Staatliche Museen in Berlin.
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"I(nowin,g is not enough; we mast apply.
Willing is not enough; we must dfo. "
Goethe
...........
..... ..................................
.... .... . : . .
.............. .
............ .......
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
Shaping the Future for Health
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THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
The National Academy of Sciences is a private, nonprofit, self-perpetuating
society of distinguished scholars engaged in scientific and engineering research,
dedicated to the furtherance of science and technology and to their use for the
general welfare. Upon the authority of the charter granted to it by the Congress in
1863, the Academy has a mandate that requires it to advise the federal govern-
ment on scientific and technical matters. Dr. Bruce M. Alberts is president of the
National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter
of the National Academy of Sciences, as a parallel organization of outstanding
engineers. It is autonomous in its administration and in the selection of its
members, sharing with the National Academy of Sciences the responsibility for
advising the federal government. The National Academy of Engineering also
sponsors engineering programs aimed at meeting national needs, encourages
education and research, and recognizes the superior achievements of engineers.
Dr. Wm. A. Wulf is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of
Sciences to secure the services of eminent members of appropriate professions in
the examination of policy matters pertaining to the health of the public. The
Institute acts under the responsibility given to the National Academy of Sciences
by its congressional charter to be an adviser to the federal government and, upon
its own initiative, to identify issues of medical care, research, and education.
Dr. Harvey V. Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of
Sciences in 1916 to associate the broad community of science and technology with
the Academy's purposes of furthering knowledge and advising the federal
government. Functioning in accordance with general policies determined by the
Academy, the Council has become the principal operating agency of both the
National Academy of Sciences and the National Academy of Engineering in pro-
viding services to the government, the public, and the scientific and engineering
communities. The Council is administered jointly by both Academies and the
Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and
vice chair, respectively, of the National Research Council.
www. nationa l-academies.org
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COMMITTEE ON NEW FRONTIERS IN
CONTRACEPTIVE RESEARCH
JEROME F. STRAUSS III, M.D., Ph.D. (Chair), The Luigi Mastroianni,
fir. Professor and Director, Center for Research on Reproduction
and Women's Health, University of Pennsylvania Medical Center;
Philadelphia, PA
LISA BRANNON-PEPPAS, M.S., Ph.D., Research Professor, The
University of Texas at Austin, Austin, TX
ROBERT E. BRAWN, Ph.D., Associate Professor, University of
Washington, Seattle, WA
MARLENE L. COHEN, Ph.D., Vice President, Creative Pharmacology
Solutions, LLC, Carmel, IN
VANESSA E. COLLINS, M.D., M.P.H., M.B.A., Vice President of
Medical Affairs, Planned Parenthood Federation of America,
New York, NY
JACQUELINE E. DARROCH, Ph.D., Senior Vice President, Vice President
for Science, The Alan Guttmacher Institute, New York, NY
MAHMOUD FATHALLA, M.D., Professor of Obstetrics and
Gynecology, Assiut University, Assiut, Egypt
LINDA C. GIUDICE, M.D., Ph.D., Professor, Director, Division of
Reproductive Endocrinology and Infertility, and Director,
Women's Health at Stanford, Department of Gynecology and
Obstetrics, Stanford University Medical Center, Stanford, CA
ANNA GLASIER, M.D., Director of Family Planning Services, Lothian
Primary Care Trust, and University of Edinburgh, Edinburgh,
Scotland
MICHAEL HARPER, Ph.D., Sc.D., M.B.A., Professor, Department of
Obstetrics and Gynecology, Eastern Virginia Medical School, and
Director of CICCR and GMP, CONRAD, Arlington, VA
GREGORY S. KOPF, Ph.D., Assistant Vice President, Discovery
Women's Health Research Institute, Wyeth Research,
Collegeville, PA
MARTIN M. MATZUK, M.D., Ph.D., Stuart A. Wallace Chair and
Professor, Departments of Pathology, Molecular and Cellular
Biology, and Molecular and Human Genetics, Baylor College of
Medicine, Houston, TX
RUTH MERKATZ, R.N., Ph.D., Director of Women's Health, Pfizer Inc.
New York, NY
v
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NANCY PADIAN, M.P.H., Ph.D., Professor, Department of Obstetrics,
Gynecology and Reproductive Sciences, and Director of Women's
Global Health Imperative and of International Research, AIDS
Research Institute, University of California, San Francisco, San
Francisco, CA
REGINE L. SITRUK-WARE, M.D., Executive Director, Product
Research and Development, Center for Biomedical Research,
Population Council, New York, NY
STUDY STAFF
SHARYL I. NASS, Ph.D., Study Director
JANICE MEHLER, Visiting Staff Officer
MARY}OY BALLANTYNE, Research Associate (through August 2003)
SHIRA H. FISCHER, Research Assistant (from July 2003)
NAKIA JOHNSON, Senior Project Assistant
DIVISION STAFF
ANDREW POPE, Ph.D., Director, Board on Health Sciences Policy
TROY PRINCE, Administrative Assistant
CARLOS GABRIEL, Financial Associate
Al
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Reviewers
This report has been reviewed in draft form by individuals chosen for
their diverse perspectives and technical expertise, in accordance with
procedures approved by the NRC's Report Review Committee. The
purpose of this independent review is to provide candid and critical com-
ments that will assist the institution in making its published report as
sound as possible and to ensure that the report meets institutional stan-
dards for objectivity, evidence, and responsiveness to the study charge.
The review comments and draft manuscript remain confidential to protect
the integrity of the deliberative process. We wish to thank the following
individuals for their review of this report:
STEVEN J. BRICKNER, Pfizer, Inc
WILLARD CATES, Family Health International
MITCHELL CREININ, University of Pittsburgh, Magee-Womens
Hospital
JURRIEN DEAN, National Institutes of Health
GORDON W. DUNCAN, Consultant, Seattle, WA
ELLEN HARDY, State University of Campinas, Brazil
BARRY T. HINTON, The University of Virginia
JANE MENKEN, University of Colorado
LISA RARICK, Reproductive Health and Regulatory Affairs
Consultant, Gaithersburg, MD
HENRY W. RIECKEN, University of Pennsylvania, Retired
. .
v''
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vIll
REVIEWERS
Although the reviewers listed above have provided many construc-
tive comments and suggestions, they were not asked to endorse the con-
clusions or recommendations nor did they see the final draft of the report
before its release. The review of this report was overseen by Mary Lake
Polan, Stanford University School of Medicine, and by Mary lane Osborn,
University of Connecticut Health Center. Appointed by the National
Research Council and Institute of Medicine, they were responsible for
making certain that an independent examination of this report was carried
out in accordance with institutional procedures and that all review com-
ments were carefully considered. Responsibility for the final content of
this report rests entirely with the authoring committee and the institution.
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Preface
The Institute of Medicine (IOM) began producing reports on contra-
ceptive development in 1989 and its most recent report, Contraceptive
Research and Development: Looking to the Future, was issued in 1996. Why is
another report on contraception needed at this time?
As the committee documents in this report, unintended pregnancy
remains a major problem. Recent survey data are very consistent: more
than a quarter of pregnancies worldwide are unintended. Moreover,
between 1995 and 2000 nearly 700,000 women died and many more expe-
rienced illness, injury, and disability as a result of unplanned pregnancy.
Even in cases in which maternal health is maintained, an unintended
pregnancy can cause significant harm for families and communities-
emotional, social, and economic. Dual protection from pregnancy and
HIV/AIDS infection remains elusive, while the pandemic of HIV/AIDS
continues to devastate sub-Saharan Africa and Southeast Asia. The cost of
contraceptive products and the availability and adoption of existing
contraceptive methods still remain challenges to international family plan-
ning efforts. At the same time there is increasing recognition that a wider
range of modalities is needed to address the changing contraceptive needs
of the populations of the world across the reproductive life cycle. This
unmet need has not been a major priority of the research community and
pharmaceutical industry.
Since the release of the last IOM report, there has been a remarkable
scientific revolution. The human genome has been sequenced, and many
new technologies that can be used to study biological systems on an
unprecedented scale are now available. As a result, the opportunities to
1 ~
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x
PREFACE
identify novel targets for contraceptives are extraordinary. Advances in
materials science, drug development, and drug delivery may also facili-
tate the introduction of new and innovative contraceptive methods. Thus,
the time is right for a reevaluation of the research agenda in the field.
Unfortunately, at this time of opportunity, there is flagging interest in
contraceptive development, not only in the pharmaceutical industry but
also in the academic scientific community. There are a number of factors
which have contributed to this, including the obstacles to contraceptive
development that were identified in the past reports, particularly the 1996
report, which continue to challenge the field. However, new paradigms
for science have emerged in the past few years, including large-scale col-
laborative science and new vehicles for public-private collaboration. New
parties are also interested in the process of contraceptive development
and dissemination, and new global consortia are dealing with reproduc-
tive health.
Science, product development, and implementation are all addressed
in the recommendations developed by the committee. Although contra-
ceptive research, development, and use in the United States and abroad
are influenced by political context, the committee restricted its delibera-
tions to scientific issues and ways in which science could best address
global concerns of fertility regulation and reproductive health. It is not
possible to predict which of the specific recommendations are likely to
yield the greatest benefits. Indeed, although our recommendations are
diverse, all are interconnected and important for improving the range of
products, their efficacies, and their acceptability. It is the committee's hope
that sponsors, both public and private, will find topics of interest among
this menu of research goals.
The committee chose not to estimate the costs of implementing the
research agenda. Costs will vary depending on the scale, scope, and time
frame of a given research program, and costs will change as science and
technology progress. Certainly, completing the research agenda outlined
here will require significant financial resources, but given the unmet needs
and the unprecedented opportunities before us, the time seems right to
launch a broad and ambitious initiative. Traditionally, much of the federal
investment in biomedical research has focused on treating and curing dis-
eases, many of which primarily affect individuals at a late stage of life.
The development of novel contraceptives, in contrast, offers a cost-effec-
tive preventive approach that could improve the health, quality of life,
and longevity of millions of people worldwide, particularly young adults
and their children.
On behalf of the committee, I thank the Bill and Melinda Gates Foun-
dation for its generous support of this study and for its vision of a world
made better by the availability of more effective contraception. The com-
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PREFACE
Xl
i
mittee itself was, without exception, involved, constructive, and hard
working. We came from many different perspectives biological sciences,
medicine, product development, social sciences, and service delivery-
yet we forged a common understanding of how to achieve our shared
goal of improving the lives of families worldwide. I thank the members
for their individual contributions and for their collective accomplishments.
The committee owes a debt of gratitude to the IOM staff. Sharyl Nass,
as study director, was a full intellectual participant in the study and the
guiding spirit in writing the report. It is because of her skillful project
management and writing abilities that this project was completed success-
fully and swiftly. MaryJoy Ballantyne and, later, Shira Fischer, provided
excellent and dedicated research support, and were instrumental in main-
taining the study timetable. Nakia Johnson handled the logistics of our
meetings, international conference, and report production. Janice Mehler,
on loan to the committee from the National Academies' Report Review
Committee, not only provided insight into the review process but also
contributed invaluable assistance with the research and writing. Steven
Marcus produced a written summary of the workshop proceedings, and
Michael Hayes served as copy editor of the report.
We are also indebted to the many participants in the workshop that
we held on July 15-16, 2003. The ideas expressed by the speakers and
attendees were a fundamental contribution to this report. The workshop
agenda, speakers, and attendees are provided in Appendix B.
Finally, I wish to acknowledge other individuals who provided valu-
able input to the committee, verbally or in written form, during the course
of the study, including David Archer, Diana Blithe, Doug Colvard,
Mitchell Creinin, Carl Djerassi, Florence Haseltine, Joanne Luoto, Kate
Moore, Susan Newcomer, Paolo Rinaudo, Robert Spirtas, Michael Thomas,
Kirsten Vogelsong, Livia Wan, and lames Wootton.
In 1965, Gregory Pincus wrote that his interest in fertility regulation
was stimulated primarily by Mrs. Margaret Sanger, who visited him and
expressed the hope that a relatively simple and foolproof method of con-
traception might be developed through laboratory research. The result of
that visit was research that led to the development of the oral contracep-
tive pill. This vision of how science can serve humanity should continue
to guide us in the development of the next generation of contraceptive
products.
Jerome F. Strauss III
Chair
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Contents
EXECUTIVE SUMMARY
1 INTRODUCTION
Contraceptive Use, 19
Committee Charge, 23
Framework of the Report, 25
References, 25
2 TARGET DISCOVERY AND VALIDATION
Overview of Reproductive Biology, 29
Strategies for Target Identification, 33
Target Validation Studies, 56
Promising New Targets, 61
Recommendations, 67
References, 70
3 PRODUCT IDENTIFICATION AND DEVELOPMENT
Moving from Target Selection to Product Development, 79
Examples of Technological Advances in Drug Development, 82
Strategies to Facilitate Contraceptive Product Development, 89
Recommendations, 103
References, 105
. . .
x'''
1
17
27
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XIV
4 IMPROVING CONTRACEPTIVE USE AND
ACCEPTABILITY
Research Priorities for Women and Men, 112
Methodological Research on Contraceptive Use and
Acceptability, 115
Risk Behaviors and Perceptions of Risk, 118
Operations Research on Contraceptive Method Delivery, 119
Development of Contraceptive Products with Other Benefits, 122
Improving Existing Methods, 124
Recommendations, 126
References, 127
5 CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
Elements Required for Progress in Contraceptive
Research and Development, 134
Adequate Funding, 135
A Strategy for Wise Use of Funds, 138
Staffing and Training, 143
Increasing Collaboration, 149
Improving Dialogue with Regulatory Bodies, 156
Recommendations, 157
References, 160
Appendixes
A EXAMPLES OF PROGRESS AND IMPEDIMENTS IN
CONTRACEPTIVE RESEARCH AND DEVELOPMENT
Advances in Microbicides and Spermicides, 163
Update on Male Contraception, 185
Update on Antiprogestins as Female Hormonal
Contraceptives, 193
Update on Immunocontraception, 195
References, 198
B AGENDAS AND PARTICIPANTS IN COMMITTEE
WORKSHOPS
C COMMITTEE BIOGRAPHIES
GLOSSARY
ACRONYMS
CONTENTS
108
134
163
202
212
219
231
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NEW FRONTIERS
IN CONTRACEPTIVE
RESEARCH
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