Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins

Assessing the Science and Recommending a Research Agenda

Committee on Antiprogestins: Assessing the Science

Division of Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE

Molla S. Donaldson, Laneta Dorflinger, Sarah S. Brown, and Leslie Z. Benet, Editors

NATIONAL ACADEMY PRESS
Washington, D.C. 1993



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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda Committee on Antiprogestins: Assessing the Science Division of Health Promotion and Disease Prevention INSTITUTE OF MEDICINE Molla S. Donaldson, Laneta Dorflinger, Sarah S. Brown, and Leslie Z. Benet, Editors NATIONAL ACADEMY PRESS Washington, D.C. 1993

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda National Academy Press 2101 Constitution Avenue, NW Washington, DC 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 competences 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. Support for this project was provided by a grant from the Henry J. Kaiser Family Foundation, Menlo Park, California. Library of Congress Catalog Card No. 93-85360 ISBN 0-309-04949-0 Additional copies of this report are available from: National Academy Press Box 285 2101 Constitution Avenue, NW Washington, DC 20055 Call 800-624-6242 or 202-334-3313 (in the Washington Metropolitan Area) B182 Copyright 1993 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 Staatlichemuseen in Berlin.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda COMMITTEE ON ANTIPROGESTINS: ASSESSING THE SCIENCE LESLIE Z. BENET, Ph.D.,* Chair, Professor and Chair, Department of Pharmacy, University of California at San Francisco, San Francisco, California ELI Y. ADASHI, M.D., Professor of Obstetrics/Gynecology and Physiology, University of Maryland School of Medicine, Baltimore, Maryland MICHAELE CHRISTIAN, M.D., Head, Developmental Chemotherapy Section, Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland BARBARA B. HULKA, M.D., M.P.H.,* Kenan Professor and Chair, Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina ERNST KNOBIL, Ph.D. Sc.D.,** H. Wayne Hightower Professor in the Medical Sciences and Director, Laboratory for Neuroendocrinology, University of Texas Health Science Center, Houston, Texas MARY LAKE POLAN, M.D.,* Professor and Chair, Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, California JAMES TRUSSELL, Ph.D., Professor of Economics and Public Affairs, Associate Dean, Woodrow Wilson School of Public and International Affairs, and Director, Office of Population Research, Princeton University, Princeton, New Jersey Science Editor LANETA DORFLINGER, Ph.D., Director Regulatory Affairs and Quality Assurance, Family Health International, Research Triangle Park, North Carolina Study Staff MICHAEL STOTO, Ph.D., Director, Division of Health Promotion and Disease Prevention MOLLA S. DONALDSON, M.S., Study Director SARAH S. BROWN, M.P.H., Senior Program Officer HELEN ROGERS, Senior Project Assistant TERRI BARBA, Project Assistant *   Member, Institute of Medicine **   Member, National Academy of Sciences

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Preface The first clinically available antiprogestin, mifepristone (RU 486), has generated great interest in the research community since its discovery in France in the early 1980s. Seldom has a research discovery (in this case, a compound exhibiting a high affinity for progesterone receptors, but with little or no progesterone-like activity) been so rapidly applied in clinical medicine. Today it is recognized that mifepristone and other antiprogestins have a significant potential role in human health and disease, with likely applicability to a variety of pregnancy-related conditions (e.g., management of labor), contraception, endometriosis, and cancer, as well as several other diseases and conditions. Mifepristone has been most widely studied and used as a means of nonsurgical abortion in early pregnancy and has been approved for marketing for that purpose in France, the United Kingdom, and Sweden. Although great interest in mifepristone and other antiprogestins has been shown by both the medical and the lay communities in the United States, the political issues surrounding abortion have thus far prevented the introduction of the drug into the U.S. market, and research on this compound in America has been limited. However, pressure is mounting to accelerate the pace of approval and use of mifepristone. An Executive Order signed by President Clinton in January, 1993, signalled a change in climate and called for research on the benefits and risks of the antiprogestins as therapeutic agents. Such research is a necessary first step before their wider availability in the United States. In late April, 1993, it was announced that Roussel-Uclaf had agreed to grant a license for distribution of mifepristone to the non-profit organization the Population Council. The Population Coun-

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda cil has agreed to sponsor an application to the U.S. Food and Drug Administration (FDA) and manage a clinical trial in the United States. Roussel-Uclaf has also agreed to provide the FDA with its toxicologic and chemical data on mifepristone. To provide an unbiased evaluation of the science and potential clinical uses of antiprogestins for numerous diseases and conditions in addition to inducing abortion, the Institute of Medicine (IOM) of the National Academy of Sciences, with funding from the Henry J. Kaiser Family Foundation, convened an expert committee to conduct an evaluation and to develop recommendations concerning future research on the potential clinical use of antiprogestins in the United States. The seven member committee included individuals with expertise in cell biology, pharmacology, epidemiology, reproductive endocrinology, care of women with hormone-dependent clinical conditions, population demography, and oncology. The committee held a two-day invitational workshop in Washington, D.C., on April 13 and 14, 1993, to review the status of scientific and clinical investigations regarding antiprogestins. Leading researchers throughout the world with expertise in antiprogestin science accepted the IOM's invitation to prepare papers and to participate in this workshop. Their papers are included in this volume as Appendix B to the committee's report. Although these manuscripts have not been peer-reviewed, they summarize the extensive published literature of those invited to make presentations, as well as many recent and often, as yet, unpublished studies related to the science and clinical uses of the antiprogestins. Besides the invited speakers and committee members, 54 outside observers attended the workshop and provided thoughtful commentaries as well as supplementary information and discussion during the two-day workshop. The workshop agenda and a listing of the observers are included in Appendixes A and C, respectively. The committee and speakers had the opportunity to hear from Margaret Cately-Carlson, president of the Population Council, during an evening presentation. Immediately following the workshop, the committee met to review and discuss an initial set of conclusions and recommendations concerning the scientific issues presented at the workshop. Each of the committee members then prepared a draft section of the committee's report, including initial recommendations related to that section. During and after another meeting in early May, the committee reached consensus on its report and recommendations. The committee's report is a summary of what is known; it reviews the data that served as the bases for approval of mifepristone in other countries. The report includes 20 recommendations about various scientific issues that are important to the evaluation of mifepristone and other antiprogestins. The report has been subject to external review by a specially appointed expert panel according to National Research Council procedures.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda The committee's report begins with an overview of research and three cross-cutting recommendations that should lead to a better understanding of the mechanisms of action of the antiprogestins and the potential for developing additional compounds that are directed exclusively toward progesterone receptors. The next nine recommendations are ordered to follow the time sequence of potential pregnancy-related uses of antiprogestins (e.g., pre-coital contraception, post-coital contraception, missed menses, pregnancy termination, term and post-term labor induction). The final eight recommendations relate to other possible therapeutic uses of antiprogestins for the treatment of endometriosis, uterine leiomyomas, breast cancer, meningiomas, and antiglucocorticoid-dependent conditions. These 20 recommendations reveal how uneven current scientific knowledge is regarding the many actual and potential uses of antiprogestins in clinical practice. In some areas, such as treatment for endometriosis, much research is needed to understand whether and how to use antiprogestins to treat this particular condition; in other areas, such as the use of antiprogestins to induce early abortion or to serve as post-coital contraception, clinical data gathered in Europe appear complete enough for their prompt review by U.S. regulatory authorities. I am extremely grateful to my fellow committee members for the dedication and industry that they exhibited in preparing this evaluation within such a short time frame, without sacrificing scientific integrity. With the rapid acceleration of interest in the possible introduction of mifepristone and other antiprogestins into the U.S. market, this IOM report provides a timely independent review and assessment of current knowledge that should be useful to researchers and clinicians, federal officials in the Department of Health and Human Services (the National Institutes of Health and the Food and Drug Administration, especially), the U.S. Congress, the report's sponsors as well as other foundations, and the more knowledgeable public. The committee and I are extremely grateful to the IOM staff who tirelessly and with unselfish dedication helped to prepare this report in a timely manner. We are particularly appreciative of the efforts of the Study Director, Molla S. Donaldson; the Senior Program Officer, Sarah S. Brown; and the Director of the Division of Health Promotion and Disease Prevention, Michael Stoto. We are cognizant of the excellent judgment that they exhibited in assisting the committee in evaluating many of the controversial and technical issues related to this study. The committee also acknowledges and appreciates the work of Senior Project Assistant, Helen Rogers, and Project Assistant, Terri Barba, who were unflagging in their responses to committee needs. The committee had the good fortune to have the services of Laneta Dorflinger, Director of Regulatory Affairs and Quality Assurance at

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Family Health International. Dr. Dorflinger provided extensive expertise in the issues addressed by the committee, and served as an excellent and knowledgeable science editor for the committee's draft report and recommendations. She also helped to edit the papers presented at the workshop and published in Appendix B. The committee and the Institute of Medicine are particularly grateful for the support provided by the Henry J. Kaiser Family Foundation, which requested that the IOM conduct this study, and thank the Foundation's project officer, Sarah Samuels, for her assistance. LESLIE Z. BENET, Ph.D. Chair

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Contents     SUMMARY   1     Cross-Cutting Recommendations,   2     Uses of Antiprogestins: The Reproductive Cycle,   3     Other Potential Therapeutic Uses of Antiprogestins,   8     Antiglucocorticoid Effects of Antiprogestins,   13 1   INTRODUCTION   14     Background and Historical Perspectives,   14     The IOM Report,   17     Cross-Cutting Recommendations,   17 2   USES OF ANTIPROGESTINS: THE REPRODUCTIVE CYCLE (PART I)   19     Contraception,   20     Post-Coital Contraception,   22     Menses Induction,   23 3   USES OF ANTIPROGESTINS: THE REPRODUCTIVE CYCLE (PART II)   26     Pregnancy Termination During the First Trimester,   26     Pregnancy Termination During the Second Trimester,   30     Cervical Ripening,   32     Labor Induction in Late Pregnancy,   33     Summary,   34

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda 4   OTHER THERAPEUTIC USES OF ANTIPROGESTINS   36     Endometriosis,   36     Uterine Leiomyomas (Fibroids),   39     Breast Cancer,   41     Meningiomas,   48 5   ANTIGLUCOCORTICOID EFFECTS OF ANTIPROGESTINS   52     Glucocorticoid Function,   52     Therapeutic Use of Mifepristone (RU 486) as an Antiglucocorticoid,   53     Adverse Antiglucocorticoid Effects of Antiprogestins,   55 6   ANIMALS AS MODELS FOR STUDYING ANTIPROGESTINS   57     APPENDIXES     A   AGENDA FOR THE IOM WORKSHOP "ANTIPROGESTINS: ASSESSING THE SCIENCE"   65 B   BACKGROUND PAPERS AND PRESENTATIONS (IN ORDER OF PRESENTATION AT IOM WORKSHOP)   69     B1 1993: RU 486—A Decade on Today and Tomorrow Étienne-Émile Baulieu, M.D., Ph.D.   71     B2 Overview and Background: Mechanism of Action of Antiprogestins Nancy L. Weigel, Ph.D.   120     B3 The Use of Antiprogestins in the Reproductive Cycle Lynnette Kaye Nieman, M.D.   139     B4 Potential Contraceptive Effects of Antigestogens David T. Baird, M.D.   148     B5 Use of Antiprogestins Before 63 Days of Amenorrhea Marc Bygdeman, M.D.   164     B6 Uses of Antiprogestins After 63 Days of Amenorrhea André Ulmann, M.D., Ph.D., and Louise Silvestre, M.D.   174     B7 Comments on Session II David Grimes, M.D.   183     B8 Use of Antiprogestins in the Management of Endometriosis and Leiomyoma Samuel S.C. Yen, M.D., D.Sc.   189

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda     B9 Antiprogestins and the Treatment of Breast Cancer Kathryn B. Horwitz, Ph.D.   210     B10 Uses of RU 486 as an Antiglucocorticoid Lynnette Kaye Nieman, M.D.   229     B11 Primate Models for the Study of Antiprogestins in Reproductive Medicine Gary D. Hodgen, Ph.D.   243     B12 Antiprogestogens: Perspectives from a Global Research Program P.F.A. Van Look, M.D., Ph.D., and H. von Hertzen, M.D., D.D.S.   253 C   OBSERVERS AT THE WORKSHOP ON ANTIPROGESTINS   278     INDEX   281

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