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

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

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