An Assessment of the NIH Women's Health Initiative

Committee to Review the NIH Women's Health Initiative

Food and Nutrition Board

and

Board on Health Sciences Policy

INSTITUTE OF MEDICINE

Susan Thaul and Dana Hotra, Editors

NATIONAL ACADEMY PRESS
Washington, D.C.
1993



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An Assessment of the NIH Women's Health Initiative An Assessment of the NIH Women's Health Initiative Committee to Review the NIH Women's Health Initiative Food and Nutrition Board and Board on Health Sciences Policy INSTITUTE OF MEDICINE Susan Thaul and Dana Hotra, Editors NATIONAL ACADEMY PRESS Washington, D.C. 1993

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An Assessment of the NIH Women's Health Initiative NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W.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 the president of the Institute of Medicine. This study was supported by project no. NO1-WH-3-2114 from the National Institutes of Health. Library of Congress Catalog Card No. 93-86833 International Standard Book Number 0-309-04989-X Additional copies of this report are available for sale from: National Academy Press 2101 Constitution Avenue, NWBox 285Washington, DC20418 Call 800-624-6242 or 202-334-3313 (in the Washington Metropolitan Area). B248 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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An Assessment of the NIH Women's Health Initiative COMMITTEE TO REVIEW THE NATIONAL INSTITUTES OF HEALTH WOMEN'S HEALTH INITIATIVE MARION J. FINKEL (Chair), Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey LUCILE L. ADAMS-CAMPBELL, Howard University Cancer Center ABDELMONEM A. AFIFI, University of California, Los Angeles KELLY D. BROWNELL, Yale University GARY R. CUTTER, Pythagoras, Inc., Birmingham, Alabama JOHN W. FARQUHAR, * Stanford University School of Medicine M.R.C. GREENWOOD, * University of California, Davis (Resigned July 7, 1993) Stanford University School of Medicine PENNY M. KRIS-ETHERTON, The Pennsylvania State University JOANNE LYNN, Dartmouth Medical School LYNN ROSENBERG, Slone Epidemiology Unit, Boston University School of Medicine DIANE B. STOY, The George Washington University Medical Center Staff SUSAN THAUL, Study Director DANA HOTRA, Research Associate FELICE LEPAR, Research Assistant DONNA ALLEN, Project Assistant * Member, Institute of Medicine

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An Assessment of the NIH Women's Health Initiative FOOD AND NUTRITION BOARD M.R.C. GREENWOOD * (Chair), University of California, Davis EDWIN L. BIERMAN * (Vice Chair), University of Washington School of Medicine PERRY L. ADKISSON, * Department of Entomology, Texas A&M University LINDSAY H. ALLEN, Nutritional Sciences, University of Connecticut DENNIS M. BIER, Pediatric Endocrinology and Metabolism, Washington University School of Medicine HECTOR F. DELUCA, † Department of Biochemistry, University of Wisconsin, Madison MICHAEL P. DOYLE, Department of Food Science and Technology, University of Georgia JOHANNA T. DWYER, Frances Stern Nutrition Center, New England Medical Center Hospital, Boston JOHN W. ERDMAN, JR., University of Illinois, Urbana CUTBERTO GARZA, Division of Nutritional Sciences, Cornell University Department of Pediatrics, University of Colorado Medical Center, Denver JANET C. KING, Department of Nutritional Sciences, University of California, Berkeley LAURENCE N. KOLONEL, Cancer Center of Hawaii, University of Hawaii, Honolulu SANFORD MILLER, Graduate School of Biomedical Sciences, University of Texas, San Antonio ALFRED SOMMER, * School of Hygiene and Public Health, The Johns Hopkins University VERNON R. YOUNG, * Laboratory of Human Nutrition, Massachusetts Institute of Technology STEVE L. TAYLOR (Ex Officio), Department of Food Science and Technology, University of Nebraska ARTHUR H. RUBENSTEIN * (IOM Council Liaison), Department of Medicine, The University of Chicago Staff CATHERINE E. WOTEKI, Director MARCIA LEWIS, Administrative Assistant SUSAN WYATT, Financial Associate * Member, Institute of Medicine †   Member, National Academy of Sciences

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An Assessment of the NIH Women's Health Initiative BOARD ON HEALTH SCIENCES POLICY J. CLAUDE BENNETT * (Chair), Department of Medicine, The University of Alabama School of Medicine, Birmingham DAVID R. CHALLONER, * University of Florida RAMZI S. COTRAN, * Harvard Medical School, Department of Pathology DEBORAH COTTON, * Health Policy & Management, Harvard School of Public Health EMILIO DADDARIO, * Attorney, Washington, D.C. WILLIAM N. HUBBARD, JR., * Retired President, The Upjohn Company, Hickory Corners, Michigan THOMAS INUI, * Department of Ambulatory Care and Prevention, Harvard Medical School RICHARD J. JOHNS, * Department of Biomedical Engineering, The Johns Hopkins University School of Medicine ERIC R. KANDEL, * Center for Neurobiology & Behavior, Columbia College of Physicians and Surgeons PATRICIA A. KING, * Georgetown University Law Center ELAINE L. LARSON, School of Nursing, Georgetown University JOSHUA LEDERBERG, * The Rockefeller University ROBERT I. LEVY, * Wyeth-Ayerst Research, Philadelphia MARY LAKE POLAN, Department of Obstetrics and Gynecology, Stanford University JOHN D. STOBO, Department of Medicine and Physician-In-Chief, The Johns Hopkins Hospital JOHN E. WENNBERG, * The Center for the Evaluative Clinical Sciences, Dartmouth Medical School JEAN DONALD WILSON, Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas Staff VALERIE P. SETLOW, Director RUTH E. BULGER, Senior Program Officer JOSEPH CASSELLS, Senior Program Officer PHILOMINA MAMMEN, Administrative Assistant * Member, Institute of Medicine

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An Assessment of the NIH Women's Health Initiative Preface For many years women have not been included in large prospective trials examining the benefits and risks of therapeutic interventions in diseases with significant morbidity and mortality that are common to both men and women. Such exclusion was not due to a lack of concern for the health of women, but rather an assumption that results obtained in men could be extrapolated to women. Other reasons for excluding women from clinical trials included concerns about the difficulty of recruiting and retaining women as compared with men and the need to increase sample size and costs. Implicit in the argument for larger sample sizes, ironically, is the need for a separate analysis by gender, which undercuts the assumption that the results can be extrapolated from males to females. More recent research with drug therapy has shown important pharmacokinetic differences between males and females, as well as differences in risks and, in some cases, benefits. Thus, it is appropriate to conduct large scale studies in women who have or acquire diseases that are common to both sexes. In addition, women are at great risk for diseases like osteoporosis and breast cancer, for which additional prevention strategies are sorely needed. The National Institutes of Health (NIH) has invested considerable resources in the past few years to rectify the inequities in research involving women and much useful information is expected to accrue from these efforts. The Women's Health Initiative (WHI) goes beyond NIH's earlier efforts—it is an attempt to not only gather data from over 100,000 women, but also to influence a change in lifestyles toward a healthier future. The committee constituted by the Institute of Medicine (IOM) to review the WHI protocol faced a challenging task of reviewing a study that already had awarded large multi-year contracts and that was to begin participant recruitment during the IOM committee's review period. There is a tension evident throughout this report. Had this committee been asked to design a plan for women's health research, it would not have designed this WHI. Although some committee members would have preferred that the WHI be cancelled, others were more willing to take the gamble. The committee focused on what aspects of the WHI

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An Assessment of the NIH Women's Health Initiative it did and did not consider scientifically justifiable and feasible. As will be seen, the committee recommended that the ongoing WHI could proceed but should be modified. The committee wishes to express its appreciation to the many people who made important contributions to this report by providing source materials or special written reports, sharing their views during meetings, commenting on drafts, or otherwise serving as resource persons. In particular, the committee wishes to thank Dr. Louise Brinton, National Cancer Institute; Dr. M.R.C. Greenwood, University of California at Davis; Dr. J. Christopher Gallagher, Creighton University Medical Center; Dr. David Hunter, Harvard University; Dr. William Insull, Lipid Research Clinic, Houston, TX; Gayle Mowbray, The Johns Hopkins University; Paul Phelps, a free-lance editor and writer; Dr. John Potter, University of Minnesota; and Dr. Christopher Sempos, National Center for Health Statistics. Many people at NIH shared generously of their time to supply the committee with the documents necessary to perform this review. Susan Clark, Project Officer; Dr. Caroline Clifford, Chief, Diet and Cancer Branch, National Cancer Institute; Laurence Freedman, Acting Chief, Biometry Branch, NCI; Linda Gardner, Contracts Specialist; Dr. William Harlan, Co-Director, WHI; Dr. Carrie Hunter, Special Assistant to the Director, Office of Research on Women's Health; and Dr. Jacques Rossouw, Project Officer, WHI Clinical Trial and Observational Study went to special efforts to assist IOM staff. The committee would also like to thank Dr. Ross Prentice, Principal Investigator of the WHI Clinical Coordinating Center, and the representatives from the Vanguard Clinical Centers, who were able to join the committee on extremely short notice for its July 1993 meeting and provided valuable information about details of the WHI. The necessity for rapid review required herculean efforts on the part of the IOM staff, particularly the Study Director, Dr. Susan Thaul, to prepare background material and to formulate the issues for review. The committee itself had only three meetings, at monthly intervals, to debate the issues and to prepare draft statements on several topics. At these meetings, and also behind the scenes, Dr. Thaul and Dr. Catherine E. Woteki, the Director of the IOM's Food and Nutrition Board, provided skillful guidance and input. The study report itself was thoroughly prepared by Dr. Thaul and Dana Hotra, Research Associate. They not only had to synthesize the discussions that took place at the meetings but also to interpret a multiplicity of comments and recommendations into a report with which all members could agree. In addition, they made major contributions to the report using their own expertise. The committee could not have accomplished its goals in the brief period allotted to it without their dedicated efforts. The committee also wishes to thank Dr. Ruth Bulger, the past Director of the IOM Health Sciences Policy Division, who was instrumental in developing this project for the IOM; Claudia Carl, Administrative Associate in the IOM Reports and Information Office; Robert Earl, Program Officer; Michael Edington, Managing Editor, Reports and Information

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An Assessment of the NIH Women's Health Initiative Office; Geraldine Kennedo, Project Assistant; Felice LePar, Research Assistant; Marcia Lewis, Administrative Assistant; Dr. Valerie P. Setlow, Director of the Health Sciences Policy Division of the IOM; Susan M. Wyatt, IOM Financial Associate; and the staff of the Food and Nutrition Board for their support. Finally, much appreciation is also due to Donna Allen, Project Assistant, who smoothed the way for the committee members and the rest of the IOM staff. Marion J. Finkel, M.D. Chair

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An Assessment of the NIH Women's Health Initiative Contents     Executive Summary   1      The Women's Health Initiative,   2      The IOM Study,   3      Findings and Suggestions,   4      Clinical Trial,   4      Observational Study,   9      Community Prevention Study,   9      Recommendations,   10      Clinical Trial,   10      Observational Study,   11      Community Prevention Study,   12      Responses to the Statement of Task,   13  1   Introduction   19      Description of the NIH Women's Health Initiative,   20      History of Institute of Medicine Involvement,   20      Committee Selection and Participation,   21      Statement of Task,   21      Committee Activities,   23  2   Clinical Trial   25      Introduction,   25      Rationale,   26      General Issues,   26        Integration of the CT with Other Components of the WHI,   28      Design and Methods,   29      Factorial Design,   29      Sample Characteristics,   30      Proposed Analytic Techniques,   34      Ethics: Consent and Stopping Rules,   35      Minority Analysis Plan,   39

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An Assessment of the NIH Women's Health Initiative      Specifying the Relationship of Intervention and Effect,   40      Outcome Definition and Measurement,   40      Recruitment and Retention,   41      Adherence,   44      Secular Trends,   45      Provision of Health Care Services to Participants,   45      Study Management,   46      Dietary Modification Branch,   47      Rationale,   47      Design and Methods,   49      Weighing Benefits and Uncertainties of the Breast Cancer Arm,   51      Hormone Replacement Therapy Branch,   52      Rationale,   52      Design and Methods,   53      Threats to Completion of HRT Branch,   54      Use of HRT in Elderly Women,   56      Calcium and Vitamin D Supplement Branch,   59      Rationale,   59      Design and Methods,   60      Threats to Successful Completion of CaD Branch,   61      Clinical Trial Cost,   61      Data Available to Committee Deliberations,   62      WHI Cost Relative to Other Large Studies,   63      Clinical Center Funding,   64      Total Cost,   65      Potential Causes of Budget Shortfalls,   66      Summary,   68      Findings and Suggestions,   69      Recommendations,   73  3   Observational Study   77      Rationale,   77      Design and Methods,   78      Cost,   79      Recommendations,   80

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An Assessment of the NIH Women's Health Initiative  4   Community Prevention Study   81      Introduction,   81      Rationale,   81      Design and Methods,   82      Cost,   83      Recommendations,   83  5   Concluding Remarks   85      Response to the Statement of Task,   85      Societal Context,   88      Efficacy and Effectiveness,   88      Public Health Choice Versus Individual Choice,   89      Considerations Beyond Science,   90     References   91  Appendix A   Clinical Trial Exclusion Criteria   97  Appendix B   U.S. House of Representatives Appropriations Committee   101  Appendix C   Statement of Task   103  Appendix D   Documents Received by the Institute of Medicine from the National Institutes of Health   105  Appendix E   Meeting Participants June, July, and August 1993   109  Appendix F   Primary and Subsidiary Hypotheses of the Women's Health Initiative Clinical Trial   113  Appendix G   Women's Health Initiative Committees   115  Appendix H   NIH-Sponsored Women's Health Studies   117  Appendix I   NIH Cost and FTE Summary for Vanguard Clinical Centers   123  Appendix J   NIH Power Calculations   127

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An Assessment of the NIH Women's Health Initiative  Appendix K   Women's Health Initiative Clinical Coordinating Center and Vanguard Clinical Centers Principal Investigators   133  Appendix L   Abbreviations and Acronyms   135  Appendix M   Committee and Staff Biographies   137

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An Assessment of the NIH Women's Health Initiative List of Figures  1   Objective Prescheduled Reassessment (OPR) Time Frame,   17  2-1   Outcomes for WHI Clinical Trial,   27  2-2   Women's Health Initiative Clinical Trial Partial Factorial Design,   30  2-3   NIH Organization for the WHI,   47  2-4   Objective Prescheduled Reassessment Timeline,   76

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