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--> WOMEN AND HEALTH RESEARCH ETHICAL AND LEGAL ISSUES OF INCLUDING WOMEN IN CLINICAL STUDIES VOLUME I Anna C. Mastroianni, Ruth Faden, and Daniel Federman, Editors Committee on the Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies Division of Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C. 1994
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--> National Academy Press 2101 Constitution Avenue, N.W. Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competencies and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. This project was funded by the Office of Research on Women's Health of the National Institutes of Health (Contract No. NOI-OD-2-2119) with supplemental support provided by The Ford Foundation (Grant No. 935-1335). Syntex (U.S.A.), Inc. and the Institute of Medicine also provided support for this project. Library of Congress Cataloging-in-Publication Data Women and health research : ethical and legal issues of including women in clinical studies / Anna C. Mastroianni, Ruth Faden, and Daniel Federman, editors ; Committee on the Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies, Division of Health Sciences Policy, Institute of Medicine. p. cm. Includes bibliographical references and index. ISBN 0-309-04992-X 1. Women—Health and hygiene—Research—Moral and ethical aspects. 2. Human experimentation in medicine—Moral and ethical aspects. 3. Human experimentation in medicine—Law and legislation. 4. United States. National Institutes of Health Revitalization Act of 1993. I. Mastroianni, Anna C. II. Faden, Ruth R. III. Federman, Daniel D., 1928- . IV. Institute of Medicine (U.S.). Committee on the Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies. [DNLM: 1. Ethics, Medical. 2. Clinical Protocols. 3. Women's Health. 4. Research—United States—legislation. W 20.5 W872 1994] R853.H8W66 1994 174'.28—dc20 DNLM/DLC for Library of Congress 93-50549 CIP Copyright 1994 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 image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staalichemuseen in Berlin.
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--> COMMITTEE ON THE ETHICAL AND LEGAL ISSUES RELATING TO THE INCLUSION OF WOMEN IN CLINICAL STUDIES RUTH FADEN, Ph.D., M.P.H. (Co-chair), Professor and Director, Program in Law, Ethics, and Health, School of Hygiene and Public Health, The Johns Hopkins University, and Senior Research Scholar, Kennedy Institute of Ethics, Georgetown University DANIEL FEDERMAN, M.D.* (Co-chair), Professor of Medicine, Dean of Medical Education, Harvard Medical School ANITA ALLEN, J.D., Ph.D., Professor of Law, Georgetown University Law Center HORTENSIA AMARO, Ph.D., Professor of Social and Behavioral Sciences, School of Public Health, Boston University School of Medicine KAREN H. ANTMAN, M.D., Chief, Division of Medical Oncology, Columbia-Presbyterian Medical Center, New York LIONEL D. EDWARDS, M.D., Assistant Vice President and Senior Director of Therapeutic Research Operations II, Hoffmann-La Roche, Inc., Nutley, New Jersey ANN BARRY FLOOD, Ph.D., Director of Policy Studies and Associate Professor at the Center for the Evaluative Clinical Sciences, Dartmouth Medical School SHIRIKI K. KUMANYIKA, Ph.D., M.P.H., Professor of Epidemiology, Center for Biostatistics and Epidemiology, Pennsylvania State College of Medicine RUTH MACKLIN, Ph.D.*, Professor of Epidemiology and Social Medicine, Albert Einstein College of Medicine DONALD R. MATTISON, M.D., Dean, Graduate School of Public Health, University of Pittsburgh CHARLES R. McCARTHY, Ph.D., Senior Research Fellow, Kennedy Institute of Ethics, Georgetown University, and Retired Director of the Office of Protection from Research Risks, National Institutes of Health, Richmond, Virginia CURTIS MEINERT, Ph.D., Director, Center for Clinical Trials, Professor of Epidemiology and Biostatistics, School of Hygiene and Public Health, The Johns Hopkins University KAREN H. ROTHENBERG, J.D., M.P.A., Professor of Law, Director, Law and Healthcare Programs, University of Maryland School of Law * Member, Institute of Medicine
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--> ANTHONY R. SCIALLI, M.D., Director, Residency Program, Georgetown University Medical Center, and Director, Reproductive Toxicology Center, Columbia Hospital for Women Medical Center, Washington, D.C. SHELDON J. SEGAL, Ph.D.*, Distinguished Scientist, The Population Council, New York WALTER J. WADLINGTON, LL.B.*, Professor of Law and of Legal Medicine, University of Virginia Law School Study Staff ANNA C. MASTROIANNI, Study Director RUTH ELLEN BULGER, Division Director (until August 1993) VALERIE P. SETLOW, Division Director (from August 1993) ELIZABETH MEYER BOBBY, Research Associate THELMA L. COX, Project Assistant PHILOMINA MAMMEN, Administrative Assistant * Member, Institute of Medicine
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--> Preface A perception has grown in recent years that biomedical research has focused more on the health problems of men than on those of women, and that women have been denied access to advances in medical diagnosis and therapy as a result of being excluded from clinical studies. The atmosphere surrounding this perception is one of conflict and change. There has been conflict between those who hold the perception and those who do not, and between concerns about protecting women from the risks of research participation and about their access to its potential benefits. At the same time, there have been substantial changes in public opinion about the desirability of participating in research, and equally marked changes in federal research policies. The need to illuminate the conflicts and evaluate the changes led to the present study. The National Institutes of Health (NIH) Revitalization Act of June 1993 introduced new requirements for the inclusion of women and minorities in federally funded clinical studies except where specific criteria for the exclusion of these groups can be satisfied. Congress intended the Act to be responsive to the serious allegations of "underrepresentation" of women in clinical research, and to be corrective of any disparities. Most scientists The final manuscript of this report was delivered to the sponsoring federal agency, the Office of Research on Women's Health of the National Institutes of Health, on November 30. 1993. in accordance with contractual obligations.
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--> support these objectives, yet many have expressed grave concerns that the strategies outlined in the Act for attaining these objectives may be seriously flawed. The detection of significant differences in response among subgroups, many have argued, generally requires clinical studies that are large, time-consuming, and expensive—in many cases, prohibitively so. Because cost was specified as an unacceptable criterion for exclusion, the need to design studies that comply with the new legislation may ultimately result in fewer clinical studies being done on anyone. It is not surprising that the requirements specified in the NIH Revitalization Act are contentious. The inclusion of women in clinical studies raises a mélange of often conflicting ethical, legal, scientific, and social traditions and concerns. Several efforts have been made to sort out these difficult issues and to shape an appropriate policy of inclusion. In March 1991, at NIH's request, the Institute of Medicine (IOM) convened a meeting at which a panel was asked to (a) assess the adequacy of the existing knowledge base for formulating gender-specific hypotheses and (b) consider the advisability of conducting a study to explore further women's participation in clinical studies. The panel concluded that important unresolved problems and questions remained. Given changes in societal attitudes and advances in medical technology, the panel felt a reexamination of existing policies and practices would be productive. In September 1992, in response to a request from the NIH Office of Research on Women's Health, the IOM convened the Committee on the Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies. The 16 members of the committee have backgrounds in bioethics, law, epidemiology and biostatistics, public health policy, obstetrics and gynecology, clinical research, pharmaceutical development, social and behavioral sciences, and clinical evaluative sciences. The committee's charge was to (a) consider the ethical and legal implications of including women, particularly pregnant women and women of childbearing potential, in clinical studies; (b) provide practical advice for consideration by NIH, institutional review boards, and clinical investigators; and (c) examine known instances of litigation regarding injuries to research subjects and to describe existing legal liabilities and protections. Although the committee was not asked to examine scientific issues related to women's inclusion in clinical studies, the members felt strongly that a basic understanding of both gender-specific physiological differences and methods for clinical study design was essential to its deliberations and to the development of reasoned arguments to support policy recommendations in this area. We have included a summary of the history of women's participation in clinical research to enhance readers' understanding of the origins of controversy and concern on this issue.
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--> As is discussed in the first chapter of this report, the effort to assess the current status of women's participation in clinical studies was frustrated by the lack of systematic information on the gender composition of subject populations. Despite a concerted effort to locate data, firm conclusions regarding the relative participation of women and men in the whole of clinical research could not be drawn. The members agreed that policy recommendations for the inclusion of women in clinical studies need not depend on proof that women have been "underrepresented" in clinical studies in the past. The fact that existing research guidelines from the Department of Health and Human Services and the Food and Drug Administration presumed that pregnant women and women of childbearing potential should be excluded from clinical studies except in limited circumstances was adequate evidence of a need for new policies. Moreover, an articulation of ethical and legal considerations does not require proof of ethically or legally questionable practices. Our task was to examine ethical standards in the context of American law; the empirical challenge of determining the extent to which these standards are being met still remains. Recognizing that calls to rectify women's alleged "underrepresentation" in clinical studies were based on concerns about unequal distribution of the benefits of biomedical research, the committee chose to form its analysis around principles of justice. Simply stated, the committee believes that women and men should have the opportunity to participate equally in the benefits and burdens of research. Throughout the course of our deliberations, several distinct appeals to justice in the context of clinical studies took shape. These appeals, described in Chapter 3, guided the composition of each of our arguments and recommendations. The achievement of the principles of justice outlined in this report will not be without scientific, social, ethical, and legal quandaries and challenges. The committee has attempted to anticipate these difficulties and to illuminate the concerns of all who have an interest in clinical research, including potential subjects, policymakers, members of research review committees, investigators, and the general public. Recent changes in federal research policy are intended to increase women's participation in clinical studies, but we believe further action is needed to achieve true justice throughout clinical research. For pregnant women in particular, the need is great to resolve the controversy concerning their inclusion in clinical studies. It is the committee's sincere hope that those who read this report will gain new insights from our analysis that may be helpful in moving closer toward resolution of the issues surrounding the inclusion of all women in clinical studies.
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--> The committee has tried to weave ethical, legal, social, and scientific threads into a fabric of guidelines for the full inclusion of women in clinical research. We believe that an inclusive approach will help both the subjects of research and the numerous others who indirectly benefit from their participation. We have listened broadly, argued heatedly, and concluded provisionally. Although we represent many different backgrounds, we are nevertheless unanimous in pointing out the critical importance of achieving justice in clinical research and in believing that goal will be furthered by the increased participation of women as subjects, scientists, and policymakers. Ruth Faden, Co-chair Daniel Federman, Co-chair
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--> Acknowledgments The committee wishes to express its gratitude to those who prepared background papers: Chloe Bird of the New England Medical Center and Harvard University, Bonnie Ellen Blustein of the University of Wisconsin, Sandra Cassard of the Johns Hopkins University, Elizabeth Fee of the Johns Hopkins University, Vanessa Northington Gamble of the University of Wisconsin, Tracy Johnson of the Society for the Advancement of Women's Health Research, Barbara Lex of Harvard University, Janice Racine Norris of Harvard University, Carol Weisman of the Johns Hopkins University, Elena Yu of San Diego State University, and Ruth Zambrana of the University of California at Los Angeles and the Agency for Health Care Policy and Research. The committee also thanks those who gave presentations at its workshop: Leslie Benet of the University of California at San Francisco, R. Alta Charo of the University of Wisconsin, Ellen Wright Clayton of Vanderbilt University, Debra DeBruin of the University of Illinois at Chicago, Ellen Flannery and Sanford N. Greenberg of the Washington, D.C., law firm of Covington and Burling, Robert Levine of Yale University, Wendy Mariner of Boston University, Vanessa Merton of Pace University, Janet Mitchell of Harlem Hospital Center and Columbia University, Jonathan Moreno of the State University of New York Health Sciences Center (Brooklyn), John Robertson of the University of Texas, Susan Sherwin of Dalhousie University, Bonnie Steinbock of the State University of New York at Albany, and Diane Stoy of the George Washington University.
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--> Staff at the following organizations were also very helpful: ACT-UP, Center for Women's Policy Studies, Congressional Caucus for Women's Issues, Food and Drug Administration, Food and Drug Law Institute, Institute for Research on Women's Health, National Women's Health Network, Pharmaceutical Manufacturers Association, Society for the Advancement of Women's Health Research, the University of Washington, and the U.S. General Accounting Office. We also thank the products liability attorneys and directors of regulatory affairs at pharmaceutical companies who provided information as their corporate policies allowed. We also appreciate the efforts of the staff at the National Institutes of Health in providing the committee with data. We owe particular appreciation to Elizabeth Meyer, research associate, who helped organize the committee, provided necessary support throughout the study, and assisted with the research and drafting of the report. We also thank Thelma Cox, project assistant, who helped with meeting planning and logistics, distributed briefing materials, and provided general committee support. Special thanks are owed to Ruth Ellen Bulger, who continued to provide valuable advice after leaving her position as director of the Division of Health Sciences Policy. We are especially grateful to Beth Kosiak for her organizational insight and editing, and to Deven McGraw for her legal research and drafting contributions to Chapter 6. We also thank Philomina Mammen for assisting in proposal preparation, Kimberly Kasberg Maraviglia for preparing legislative and regulatory analyses, and Gail Spears for collecting agency policies and providing research assistance. Additional thanks are owed to Paul Phelps for editing and improving many sections of the report, to Mike Edington for editing and publication coordination, to Claudia Carl for coordination of the review process, and to Nancy Diener for budgeting guidance. It would be difficult to express adequately our debt to Anna Mastroianni. As a professional colleague, she made numerous substantive contributions. As study director, she organized the efforts of all those named in these acknowledgments. And throughout, but particularly as we worked to refine our views and reach conclusions, she manifested excellent judgment and inexhaustible patience. This report truly is a committee document. Members of the committee were dedicated and involved throughout the study, from early drafting through final revisions. All of our colleagues made generous contributions of time, energy, and expert knowledge; their insights and ideas were pivotal in the development of this report. Ruth Faden, Co-chair Daniel Federman, Co-chair
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--> Contents EXECUTIVE SUMMARY 1 1 INTRODUCTION 27 Mandate and Scope of Study, 28 Structure of Report, 28 Definitions, 29 The Drug Development Process, 30 2 WOMEN'S PARTICIPATION IN CLINICAL STUDIES 36 Historical Background, 37 Current Status, 47 Conclusions and Recommendations, 68 3 JUSTICE IN CLINICAL STUDIES: GUIDING PRINCIPLES 75 Conceptions of Justice, 75 Limits to the Requirements of Justice, 81 Statement of Guiding Principles, 82 4 SCIENTIFIC CONSIDERATIONS 84 Evidence of Gender Differences, 85 Methodological Implications, 95 Conclusions and Recommendations, 103
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--> 5 SOCIAL AND ETHICAL CONSIDERATIONS 108 Science and Objectivity, 109 Questions of Gender, 110 Questions of Race and Ethnicity, 114 Recruitment and Retention Issues, 119 Protection of Research Participants, 122 Conclusions and Recommendations, 123 6 LEGAL CONSIDERATIONS 128 Institutional Framework, 129 Current Federal Policies, 132 Constitutional Issues, 143 Liability, 150 Conclusions and Recommendations, 167 7 RISKS TO REPRODUCTION AND OFFSPRING 175 Scientific Issues: Risk Assessment, 176 Ethical Issues: Risk-Benefit Analysis, 191 8 IMPLEMENTATION 203 Recommendations, 206 APPENDIXES A Reports on Women's Participation in Clinical Studies, 1977-1993 215 B NIH Revitalization Act of 1993, Public Law 103-43(June 10, 1993), Excerpt 233 C DES Case Study 237 D Compensation Systems for Research Injuries 243 E Committee Biographies 253 INDEX 261
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