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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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