2
Women's Participation in Clinical Studies

In recent years, both scientific and public attention has focused on the level of women's participation in clinical studies and on the position of women's health issues in the national research agenda. In a spate of articles in professional journals, authors have criticized "gaps in medical knowledge" about women, questioned how the "white male [came] to be the prototype of the human research subject," and commented on "gender disparit[ies] in our scientific and medical knowledge base" (Cotton, 1990b; Dresser, 1992; Sherman, 1993; see also Cotton, 1990a, 1992; Healy, 1991; Gurwitz et al., 1992; Johnson, 1992). Coverage in newspapers and popular magazines, including the New York Times, Washington Post, and Washingtonian, has added to the level of interest in these issues (Kolata, 1990; Okie, 1990; Herman, 1992; Stevens, 1992; McGuire, 1993).

The current concern about women's participation in clinical studies arises from the conflict of two public policy positions: the need to protect research participants and the "rights" of participants to access clinical studies. The roots of protectionism go deeper than those of greater access. For example, in the wake of revelations that government-funded research projects engaged in unethical treatment of participants (see below), policies were formulated to protect human volunteers. Policies grounded in protectionist considerations contributed to the later exclusion of pregnant women and women of childbearing potential from some clinical studies, most notably, early phase drug trials. Protectionist policies do not adequately account, however, for what many perceive to be the relative inattention to the study



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--> 2 Women's Participation in Clinical Studies In recent years, both scientific and public attention has focused on the level of women's participation in clinical studies and on the position of women's health issues in the national research agenda. In a spate of articles in professional journals, authors have criticized "gaps in medical knowledge" about women, questioned how the "white male [came] to be the prototype of the human research subject," and commented on "gender disparit[ies] in our scientific and medical knowledge base" (Cotton, 1990b; Dresser, 1992; Sherman, 1993; see also Cotton, 1990a, 1992; Healy, 1991; Gurwitz et al., 1992; Johnson, 1992). Coverage in newspapers and popular magazines, including the New York Times, Washington Post, and Washingtonian, has added to the level of interest in these issues (Kolata, 1990; Okie, 1990; Herman, 1992; Stevens, 1992; McGuire, 1993). The current concern about women's participation in clinical studies arises from the conflict of two public policy positions: the need to protect research participants and the "rights" of participants to access clinical studies. The roots of protectionism go deeper than those of greater access. For example, in the wake of revelations that government-funded research projects engaged in unethical treatment of participants (see below), policies were formulated to protect human volunteers. Policies grounded in protectionist considerations contributed to the later exclusion of pregnant women and women of childbearing potential from some clinical studies, most notably, early phase drug trials. Protectionist policies do not adequately account, however, for what many perceive to be the relative inattention to the study

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--> of health problems experienced primarily by women. This alleged inattention may arise from subtler (yet powerful) forces such as gender and race biases that permeate both society and scientific research (see Chapter 5). Contributing to the current focus on access to health care and health research are a wide range of factors, including the emergence of human rights movements to represent the concerns of diverse racial and ethnic groups, women, gays, lesbians, and persons with disabilities; the growing funding of biomedical research; the advent of new medical technologies to diagnose, prevent, and cure disease; and the public availability of information about these medical advances. In particular, the spread of acquired immune deficiency syndrome (AIDS) and the activism of health advocacy groups representing diverse populations have served to focus attention on the extent of scientific knowledge and research concerning the health problems of women and racial and ethnic groups. HISTORICAL BACKGROUND As part of its study of federal policies, the committee traced the evolution of the current standards governing the participation of women (and men) in clinical studies. The history begins with the early attempts to deal with ethical aspects of the use of human research participants. These efforts led to a period of public policy dominated by a protectionist agenda that is now being replaced by an emerging emphasis on expanded access to clinical studies. The present, rapidly changing policy environment is a product of professional and governmental policy responses to: (1) identified abuses in the use of human participants; (2) more recent changes in the public policy dialogue and in drug development and the corresponding governmental policy responses, primarily by the Food and Drug Administration (FDA); and (3) the role of both women's health and AIDS advocates in drawing attention to what they perceived to be inequitable research practices and the relative absence of women and racial and ethnic groups from the research agenda. This historical context gave the committee a better understanding of the rationale behind its charge, and therefore a better understanding of some the subtleties of the legal and ethical issues. Evolution of Protectionist Policies Policy development in the area of protection of human research subjects began in 1949 with the issuance of the Nuremberg Code, which outlined standards for the judgment of flagrantly abusive human experimentation conducted by the Nazis in World War II. The code articulated ten basic principles regarding moral, ethical, and legal requirements of research involving human subjects, including the provisions that research subjects must

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--> have the legal capacity to give consent, the ability to exercise free power of choice, and sufficient knowledge and comprehension to be able to make an informed decision. The code also dictated that experiments involving human subjects should yield useful results that cannot be achieved by other methods, avoid unnecessary suffering and injury, assure that risk does not exceed importance, and be done by scientifically qualified persons with adequate facilities for subject protection. Further, the code stipulated that human subjects be at liberty to withdraw from the study at any time and that the scientist be prepared to terminate the experiment if continuation is likely to result in injury, disability, or death to the subject. The Nuremberg Code provided a model for later statements regarding research on human subjects, including the Declaration of Helsinki Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects, first adopted in 1964. A more immediate reaction to the Nuremberg Code, however, was evident in the formulation of guidelines for clinical research at the Clinical Center of the NIH, a research hospital opened in 1953. Titled "Group Considerations for Clinical Research Procedures Deviating from Accepted Medical Practice or Involving Universal Hazards," these guidelines were the first federal guidelines for human studies research and the first official statement requiring committee review of human studies protocols. Research Abuses In the 1960s and 1970s, several unfortunate events demonstrated that serious problems remained with regard to the protection of human research subjects. Landmark research abuses, including those involving elderly, debilitated patients and African Americans, signaled the desperate need for the clarification and, more important, the formalization of existing guidelines for human subjects research. While the Nuremberg Code and Declaration of Helsinki were well known, they included no explicit provisions for enforcement. The vulnerability of the elderly to research abuse was highlighted in 1963, when it was discovered that a physician at the Jewish Chronic Disease Hospital in Brooklyn, New York, was experimentally injecting live cancer cells into elderly debilitated patients without proper informed consent. Review proceedings indicated that the study, designed to explore the immune system's role in defense against cancer, had not been presented to the hospital's research committee and that several physicians responsible for the subjects' care had not been consulted before the injections were given (Faden and Beauchamp, 1986). It was also revealed that the physicians who had been consulted prior to the experiment had argued against

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--> the research on the basis that the patients were incapable of giving informed consent. The failure to properly obtain consent at the Jewish Chronic Disease Hospital was not an isolated case. In 1965 Henry K. Beecher, a Harvard anesthesiologist, gave a highly publicized speech that highlighted cases in the published literature of neglect of the consent process in human subjects research. In this speech, and in a subsequent paper, he recounted several examples of studies in which subjects had not received satisfactory explanations of risks. Beecher stated, ''it must be apparent that they would not have been available if they had been truly aware of the uses that would be made of them" (Beecher, 1966). Although Beecher realized that he risked criticism for exposing these abuses, he believed strongly that such abuses not only had grave consequences for the subjects, but for the medical profession as well. In February of the following year, Surgeon General William H. Stewart responded to these revelations by requiring that all extramural research supported by the U.S. Public Health Service be subject to review by an independent committee of institutional associates. These committees were to include members of the community as well as scientists, and they would assure that the proposed informed consent procedures were adequate. These requirements did not, however, have the force of regulations. In the early 1970s, the abuses of the infamous Tuskegee Syphilis Study were revealed, adding fuel to arguments that human research subjects were not being adequately protected by the existing guidelines, and that more formal regulations were in order. This observational study of untreated syphilis, begun in 1932, involved approximately 400 African American men, many of whom were allowed to remain untreated for the disease, even after antibiotic treatment was widely available (Jones, 1981; King, 1992). There was no evidence that informed consent was received from the subjects. Because the study was initiated before the Nuremberg Code, it had not been subject to any "ethical" review; funding for the study had simply been renewed over the years in accordance with the recommendations of the investigators. Shortly after these abuses were revealed, a congressional panel was convened to review the study's history and to recommend appropriate action by the federal government. In its final report the panel concluded that the study had been ethically unjustifiable from its inception, that it should be immediately disbanded, and that all surviving study subjects should be located and treated (USDHEW, 1973). The panel also expressed concern that "no uniform departmental policy for the protection of research subjects exist[ed]" for government-sponsored research. Finally, the panel recommended that the Department of Health, Education, and Welfare (DHEW)

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--> standards regarding informed consent of research subjects be clarified and that an effective enforcement mechanism be devised. On May 30, 1974, existing guidelines for the protection of human research subjects finally took the shape of federal regulations. Promulgated by DHEW, the regulations established the institutional review board (IRB), a more formal version of the research review committee, as one mechanism for the protection of human research subjects. The responsibilities given to IRBs included the reviewing of risk-benefit ratios, confidentiality protections, informed consent processes and documents, and procedures for selection of subjects (to ensure that selection is equitable). Responses to Fetal Injury In the 1960s and 1970s, as the country was coping with the events at the Jewish Chronic Disease Hospital and Tuskegee, problems caused by two medications, thalidomide and diethylstilbestrol (DES), would amplify public sentiment about the need for greater protection for fetuses from risks in science and medicine. These concerns were ultimately translated into protective policies directed toward women of childbearing potential, including pregnant women. Thalidomide, approved for marketing in 1958, was used primarily as a sedative and antidote for nausea in early pregnancy. The drug was approved for over-the-counter sale in 20 countries (not including the United States) and was widely used. While marketing approval had been delayed in this country, many U.S. women received thalidomide from "investigating" doctors who had been given the drug by the manufacturer. As thalidomide was being widely distributed, physicians began to note a startling increase in the number of children born with a rare set of deformities, the most prominent features of which were severe limb malformations (Christie, 1962). By 1962, when sufficient statistical evidence had accumulated to establish thalidomide as the causative agent of these deformities, approximately 8,000 children had been affected. The blame for what is often referred to as the "thalidomide disaster" is alleged to reside in inadequate research standards, a failure of the drug's manufacturer to acknowledge early evidence of side effects and reports that were critical of the drug, and physicians' uncritical acceptance of promotional claims (Levine, 1993). The response from the U.S. science establishment was the creation of new legislation: the Kefauver-Harris amendments of 1962. These amendments to the drug approval laws instituted a rigorous preapproval process at the FDA. Although the "thalidomide disaster" did not result from women's participation in research, the experience had a powerful emotional impact that created an aversion to involving pregnant

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--> women and women of childbearing age in drug research (Levine, 1993). The DES experience would bolster this aversion. DES is a synthetic hormone that was widely prescribed in the 1940s and 1950s to prevent miscarriage (see DES Case Study in Appendix C). Enthusiastic physicians overlooked large, controlled clinical trials indicating that DES was ineffective. They focused instead on smaller studies in which the drug appeared to show promise (Levine, 1993). It was not until 20 years later, in the late 1960s and early 1970s, that the side effects of the drug would become evident: the daughters of women who had taken DES during pregnancy began to experience a rare adenocarcinoma of the vagina. Public trust in science and medicine was shaken once again, and a protectionist stance toward including fertile women in drug trials became further entrenched. Although the DES claims were based on injuries incurred in the context of medical practice, not in the context of formal research, the substantial costs incurred by pharmaceutical companies through DES-related litigation encouraged the practice of excluding pregnant and potentially pregnant women from clinical research. FDA guidelines issued in the late 1970s would serve to reinforce this exclusionary practice. In July of 1974, Congress passed the National Research Act (P.L. 93348), which called for the establishment of a National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) to "identify ethical principles" and to "develop guidelines" for research involving human subjects. This commission operated between 1974 and 1978 and issued many reports. In 1975, guidelines developed by the National Commission for research on fetuses and pregnant women were incorporated into DHHS regulations for research on human subjects. These federal regulations, still in effect today, identify the limited conditions under which an IRB may approve research on pregnant women and fetuses (see Chapter 6). Subsequent regulations instituted to protect children and prisoners from research abuses have served to group pregnant women in the category of ''vulnerable populations," a designation that is reinforced by current regulatory language (see 45 C.F.R. 46. 11 [a][3]). This grouping has been criticized for its implication that pregnant women are incapable of making responsible decisions for themselves and future offspring. Although DHHS included restrictions on the inclusion of women of childbearing potential in earlier drafts of the regulation concerning pregnant women, these references were eliminated from the final regulation. In 1977, however, FDA issued guidelines for drug development that recommended that women of childbearing potential be excluded from early phases of drug trials (except in the case of life-threatening diseases).

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--> Advent of Inclusionary Policies The publication of the National Commission's Belmont Report in 1978 was a watershed event in the shift away from practices and policies that some might label "paternalistic" toward greater valuation of the autonomy of research subjects. The Belmont Report identified three comprehensive ethical principles that provide an analytical framework for scientists, physicians, research subjects, and reviewers of research proposals to understand the ethical issues inherent in humans subjects research. The three principles were: (1) respect for persons (individuals should be treated as autonomous agents and persons with diminished autonomy are entitled to protection); (2) beneficence (maximize possible benefits and minimize possible harms); and (3) justice (fairness in the selection of subjects for clinical research) (National Commission, 1978). Events of the following decade would sharpen this focus on the rights of research subjects. In the 1980s, AIDS activists working to promote access to experimental AIDS therapies offered the first formal challenge to the protectionist policies of the preceding decades (Rothman and Edgar, 1992). Frustrated with the length of time required for new drugs to move through the FDA approval process, these activists called for a new mechanism for earlier release of AIDS drugs in the development process (Levi, 1991). In May of 1987, the FDA issued regulations that expanded access to experimental drugs used to treat serious and life-threatening illnesses (Rothman and Edgar, 1990). As described below, the success of AIDS activists would serve to energize the women's health movement. At roughly the same time the AIDS "movement" was born, advocates for women's health began to call for more focused research on health problems unique to women. Women had united around health concerns in the 1970s, a movement exemplified by the publication of Our Bodies, Ourselves (Boston Women's Health Book Collective, 1973), a women's health care manual created in reaction to a health care system that many women perceived to be unresponsive to their needs. In the 1980s, however, women gained sufficient political power to forcefully confront the science and health bureaucracy. In the late 1980s, women of the baby boom generation began to reach mid-life and to experience menopause and breast and reproductive cancers. The perception of a relative lack of attention to women's health in the scientific and medical establishment became of increasingly salient concern to this group of women. Better educated and employed in more powerful positions than their predecessors, baby boom women began to take action by supporting female political candidates, fund-raising for women's issues, and forming interest groups to educate themselves and to pressure unresponsive bureaucrats—the very strategies AIDS activists had used with suc-

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--> cess. In addition, dramatic increases in medical school enrollment among women during the 1970s (AMA, 1991) began to produce a vocal group of medical professionals who questioned current priorities and policies in women's health research. Many observers have pointed to the 1985 report of the U.S. Public Health Service Task Force on Women's Health Issues as the cornerstone of the current focus on biomedical research in the women's health movement (Auerbach, 1993; Johnson, 1994). This task force concluded that: The historical lack of research focus on women's health concerns has compromised the quality of health information available to women as well as the health care they receive [U.S. Public Health Service, 1985]. The accompanying recommendations ultimately provoked NIH to announce a new policy in 1986 that urged funding applicants to include women in clinical research. The policy also stated that applicants should provide a clear rationale for proposed exclusions of women and that investigators should evaluate gender differences in their findings. The Alcohol, Drug Abuse, and Mental Health Administration, another agency of the U.S. Public Health Service, cosponsored the policy (GAO, 1990). Public attention to the issue of women's inclusion in clinical research and the implications of this inclusion for the status of women's health gained tremendous momentum in 1990 when the General Accounting Office (GAO) released a report in which it evaluated the efficacy of the 1986 NIH policy. In congressional testimony regarding this report, a GAO representative stated that the unautomated, decentralized recordkeeping at NIH had prevented GAO from systematically evaluating the effectiveness of the NIH policy. He concluded that "NIH [had] no way to measure the policy's impact on the research it funds" (GAO, 1990). GAO also reported that the 1986 policy had not been well disseminated internally to individual institutes or centers, nor to prospective grant applicants, and therefore probably had not been implemented consistently, if at all. In addition, the GAO pointed to some of the larger, more expensive NIH-funded clinical studies that had included only men as evidence of the ineffectiveness of the policy. One of the examples was the Physician's Health Study, an all-male study of the role of aspirin in the prevention of heart attacks. NIH Office of Research on Women's Health and Recent Changes Following the release of the 1990 GAO report, women's health advocacy groups and other organizations initiated their own efforts to clarify the picture of women's participation in clinical research (AMA Council on Ethical and Judicial Affairs, 1991; IOM, 1991a; PMA, 1991). A significant shift in popular opinion, however, already had begun to develop. Practices

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--> and policies once presented as protective were now labeled as paternalistic and discriminatory. The rationales behind a number of clinical studies that had proceeded without question were now being challenged. Why had the NIH-sponsored Multiple Risk-Factor Intervention Trials (MRFIT) of heart disease not included women when women as well as men were dying of heart disease? How could the Baltimore Longitudinal Study of Aging include no women when the elderly population in this country is disproportionately female? In September 1990, largely in response to the impact of the GAO report, Acting NIH Director William Raub announced the creation of the NIH Office of Research on Women's Health (ORWH). Located within the director's office, ORWH was given a three-part mandate: to strengthen and enhance research related to diseases, disorders, and conditions that affect women and to ensure that research conducted and supported by NIH adequately addresses issues regarding women's health; to ensure that women are appropriately represented in biomedical and behavioral research studies supported by NIH; and to foster the increased enrollment of women in biomedical research—especially in pivotal decisionmaking roles within both clinical medicine and the research environment [NIH, 1992b]. Although the ORWH began its work almost immediately, it would not be statutorily authorized until June 1993. The legislation that would eventually authorize the ORWH as a permanent entity began as part of the Women's Health Equity Act (WHEA), an omnibus legislative package first introduced in July 1990 by Representatives Schroeder and Snowe. Reintroduced in 1991, the WHEA contained 22 bills that addressed research, care, and prevention issues in women's health. During the 1991-1992 legislative year, six of the research-related provisions of the WHEA (including the provision to permanently authorize the ORWH) were incorporated into the NIH Revitalization Act, which reauthorizes the programs of the NIH. These provisions authorized additional funding for breast cancer, ovarian and other reproductive cancers, and osteoporosis and related bone disorders; they also called for the establishment of three contraceptive research centers and two fertility research centers. One of the provisions included a policy regarding inclusion of women and racial and ethnic groups in NIH-sponsored or -funded clinical research. The NIH Revitalization Act passed both the Senate and the House of Representatives, only to be vetoed by President Bush in June 1992 because of provisions that called for lifting of the moratorium on federally funded fetal tissue transplantation research. With strong support from Senate Majority Leader George Mitchell, the bill was introduced, with the women's health provisions intact, in January 1993. President Clinton, who had vowed

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--> during his presidential campaign to overturn the fetal tissue transplantation moratorium, signed the NIH Revitalization Act into law on June 10, 1993. In 1991 both NIH and the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA)1 issued special instructions to grant applicants directing that women and racial and ethnic groups be included in clinical study populations. The instructions also stated that clear and compelling rationales for the exclusion of women and racial and ethnic groups should accompany proposals that do not include these groups. NIH also devised a plan to facilitate the implementation of the new policy; it included educational programs for reviewers, investigators, and NIH staff and for a coding system to track gender and racial and ethnic group representation in extramural clinical studies. (See Chapter 6.) Later in 1991, Bernadine Healy, the first woman director of NIH, announced NIH's plans to initiate a major longitudinal study of women's health, called the Women's Health Initiative (WHI). A 14-year, $625 million research initiative, the WHI would address the preventive effects of smoking cessation, exercise, hormone therapy, diet, and dietary supplements on osteoporosis, cancer, and cardiovascular disease in postmenopausal women. In addition to the policy changes at NIH, events outside the federal science and health establishment stirred public sentiment about paternalism, protectionism, and discrimination. In 1991, the U.S. Supreme Court heard International Union, UAW v. Johnson Controls, a case involving a battery manufacturing company (Johnson Controls, Inc.) that had a policy barring women of reproductive age from performing certain jobs because of the potential risk of fetal injury and subsequent company liability. The Court ruled that this policy constituted sex discrimination and was therefore unconstitutional (see Chapter 6). Many policy analysts would add that the sexual harassment hearings that preceded Clarence Thomas' confirmation to the Supreme Court also heightened sensitivity to issues of gender in politics (Auerbach, 1993). Since the initiation of this committee's deliberations in the fall of 1992, a number of additional events have taken place that have influenced women's inclusion in clinical studies. In October 1992, FDA cosponsored a conference with the Food and Drug Law Institute (FDLI) on issues related to the inclusion of women in clinical trials of FDA-related products (Women in Clinical Trials of FDA-Regulated Products, Washington, D.C., 5 October). A primary purpose of the conference was to discuss the FDA's 1977 guidelines, particularly as they pertained to exclusion of "women of childbearing potential" from early phases of most new drug trials. Later in October of 1992, the GAO released a second report that addressed the inclusion of women in clinical studies. The report examined the FDA's policies and the pharmaceutical industry's practices regarding experimental drug testing in women. The report's conclusions were based on

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--> the results of a questionnaire sent by the GAO to each pharmaceutical company that had secured FDA approval for a new drug between January 1988 and June 1991. The questionnaire requested information about the extent of women's inclusion in new drug studies and efforts to detect and analyze gender differences (GAO, 1992). The GAO states in the report that although women were included in most of the drug studies reported, "for more than 60 percent of the drugs, the representation of women in the test population was less than the representation of women in the population with the corresponding disease" (GAO, 1992). Representation of women was found to be particularly poor in cardiovascular drug trials, a finding the GAO noted "with particular concern" because this is an area in which gender differences in drug response had been observed. In addition, the GAO indicated that pharmaceutical manufacturers frequently failed to analyze trial data for gender differences, despite an FDA guideline that encourages gender analysis. Although FDA and industry representatives have expressed some agreement with GAO's findings, particularly with respect to the conduct of gender analyses, many have disputed GAO's definition of "representative" numbers of women (FDA, 1992). On March 24, 1993, the FDA announced the lifting of the 1977 restriction on the inclusion of women of childbearing potential in early clinical trials, including pharmacology studies and early therapeutic studies. Issued officially in the Federal Register on July 22, 1993, the revised FDA policy also formalized its expectations regarding analysis of clinical data by gender, assessment of potential pharmacokinetic differences between genders, and, where appropriate, assessment of pharmacodynamic differences and the conduct of specific additional studies in women (FDA, 1993b). A major intent of the new guideline is to give more flexibility to IRBs, investigators, and subjects in determining how best to ensure the safe and scientifically valid participation of women of reproductive potential in clinical studies. NIH has also been active. In March 1993, ORWH sponsored a public hearing on recruitment and retention of women in clinical studies. A task force on recruitment and retention of women in clinical studies has worked throughout the year to develop recommendations to NIH. Another relevant NIH report currently under way is an official progress report on the inclusion of women and racial and ethnic groups in NIH-sponsored research, a report prepared as a follow-up to the 1990 GAO report. This report will include an analysis of data collected from all NIH institutes since the institution of the 1991 policy regarding the inclusion of women and racial and ethnic groups in clinical studies. Recently NIH announced plans to convene a conference to discuss the establishment of a database for tracking and monitoring clinical trials data, including data on gender composition. These efforts are a response to a

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--> ate. Concern also has been expressed about the possibility that what is known about the natural history of the diseases and their treatment in men is inapplicable to women. Recent research efforts, however, have begun to address these concerns. Heart Disease Every year 2.5 million American women are hospitalized for heart disease (Wenger et al., 1993). Of this number, 500,000 die, half of them (approximately 250,000) from coronary heart disease (CHD) (Field, 1993). CHD is the single most frequent cause of death among women. Yet despite these compelling statistics, a perception persists among the public and physicians that women do not contract heart disease as often as men, and that when they do, it is not as serious. Part of this perception is based on results obtained by the Framingham study, a longitudinal study launched in 1948 that followed a cohort of male and female subjects between the ages of 36 and 68 over a period of 12 years. It found that mortality rates for CHD were much higher among men than women-approximately three male deaths for every female death. Based on the results from this and other studies, males in their middle years appeared to be especially vulnerable to CHD; women were assumed to be relatively protected from this disease. It has since been shown that women are not protected from CHD, but rather that they develop the disease (and die from it) later in life. Rates of heart disease increase gradually in postmenopausal women until they begin to manifest myocardial infarction (MI) at the same rate as men. There is evidence to suggest that this increase is caused by the loss of the protective effect of estrogen, and that hormone replacement therapy might restore this protective factor (Fackelmann, 1993). Estrogen replacement therapy in postmenopausal women, however, has produced mixed results. Coronary events are rare in women under age 65: women in the 75-84 age group exhibit a significantly higher rate of CHD than women in the 3544 age group (NHLBI, 1990). Moreover, women comprise 59 percent of the population over age 65 and 64 percent of the population over age 74; there are 182 women for every 100 men over 75 years of age (Gurwitz et al., 1992). Thus, a failure to include people over 65 in clinical studies of heart disease has serious ramifications for women, who develop the disease later than men and are 20 years older at their first MI. It suggests that women's manifestations of heart disease may not have been adequately studied. The major identified risk factors for heart disease (including hypertension, cigarette smoking, and obesity) are reliable predictors for both men and women, but men and women differ in their manifestations of CHD. For men the most common initial manifestation is MI, but for women it is

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--> uncomplicated angina pectoris (Wenger et al., 1993). For example, 69 percent of the women but only 30 percent of the men in the Framingham study had angina pectoris as their initial manifestation of CHD (NIH, 1990). In addition, women may continue to have angina for a number of years without experiencing an MI. Thus, angina pectoris came to be viewed as relatively benign: even though it was the most common manifestation of CHD for women, it was not as widespread or as immediate in its effects as MI was for men. This provided yet another reason for regarding CHD as fatal primarily for men, and not for women, despite the fact that some evidence from the Framingham study indicates that an initial MI is more likely to be fatal in women than in men (NIH, 1990). Several well-known studies of cardiovascular disease have not included any women participants. These include the MRFIT, the Coronary Drug Project (CDP), Lipid Research Clinic, and the Physicians' Health Study, all of which have had widespread influence on the treatment and prevention of heart disease (Healy, 1991). MRFIT was a study of 12,866 men between the ages of 35 and 57, designed to assess the efficacy of intervention for individuals at high risk for coronary heart disease because of elevated serum lipids, hypertension, and cigarette smoking (Multiple Risk Factor Intervention Trial Research Group, 1977). CDP was a randomized, controlled clinical trial designed to evaluate the efficacy of several different lipid-influencing drugs in prolonging the lives of men (age 30 through 64 at entry) with a prior history of myocardial infarction (Meinert, 1986). The Physicians' Health Study was a randomized controlled trial of 22,071 male physicians designed to determine whether low-dose aspirin therapy decreases the risk of myocardial infarction and whether beta-carotene reduces the risk of cancer (Steering Committee of the Physicians' Health Study Research Group, 1989). Because these studies did not include women, they could not produce definitive information about prevention and treatment of heart disease in women. Critics have claimed that the extrapolation to women of the male-generated findings of MRFIT, CDP, and PHS is potentially faulty because it ignores the importance of estrogen in women as an antiatherogenic agent (Healy, 1991) and because the natural history of CHD is different in men and women. They have also claimed that such gender-exclusive research reinforces the myth that cardiovascular disease is a uniquely male affliction (Healy, 1991), when cardiovascular disease is the leading cause of death in both women and men. Those who defend the male-only design of MRFIT, CDP, and the Physicians' Health Study point to the epidemiology of heart disease at the time the studies were initiated: a perceived epidemic of heart disease among middle-aged men explains the studies' focus on males. The failure to detect the actual rate of heart disease in women may have resulted from gender bias; recent studies show evidence of a sex bias in the management of

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--> coronary heart disease (Ayanian and Epstein, 1991; Steingart et al., 1991). The age differential may also have played a role in women's exclusion women are typically affected by heart disease 10 to 15 years later than men. Recruiting older persons, male or female, complicates recruitment strategies (that is, required recruitment at large numbers of retirement communities as well as major medical centers) and poses a challenge to retention of subjects (as a result of comorbid conditions, for example). It is also conceivable, however, that age bias played a primary role in the male-only design of the studies. AIDS AIDS research is another area in which claims have been made that women and women's health interests have been understudied. When the scientific community first became aware of AIDS in 1981, it was considered a disease of homosexual men, and indeed the absolute number of cases of AIDS in men continues to be greater than the absolute number of cases in women. Nevertheless, the first cases of AIDS in women were reported in 1981, and the number of cases in women has been increasing rapidly since 1986. The response of the federal research enterprise has not kept pace with the spread of the disease among women; only now, in 1994, are comprehensive studies looking at the epidemiology of the disease in women. The delay in examining how AIDS manifests itself in women has resulted in women's conditions being conspicuously absent from the list of conditions defined by the Centers for Disease Control and Prevention (CDC) to constitute AIDS, and this in turn has resulted in the denial of benefit and treatment programs to women. Finally, in clinical trials of AIDS drugs, which often may provide significant sources of first-rate medical care and access to experimental treatments for persons with AIDS, the numbers of women participating lags behind expectations for a disease that is increasing the most rapidly among women. Perhaps more important, where women have been the focus of clinical research the primary research question has been how to reduce or prevent a vertical transmission of human immunodeficiency virus (HIV) from a pregnant woman to a fetus or newborn, not how to treat the female-specific manifestations of HIV diseases. Moreover, until very recently there has been almost no research explaining the mechanisms of male-to-female transmission of HIV and little research directed at the development of antiviricidal preparations that could be used by women to reduce their chances of contracting the infection through sexual activity (Faden et al., in press).

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--> Women of Childbearing Age in Early Phases of Drug Trials The FDA recently revised its policy on the exclusion of women of childbearing potential from early phases of drug trials (FDA, 1993). The 1977 guideline had recommended that a ''woman of childbearing potential" be excluded from Phase I and early Phase II drug trials except under limited circumstances, for example, when the use of an investigational drug was considered to be a life-saving or life-prolonging measure, such as cancer therapies, and, more recently, AIDS therapies. The guideline broadly defined a woman of childbearing potential as a "premenopausal female capable of becoming pregnant" (FDA, 1977). Included in the definition were women on oral, injectable, or mechanical contraception; women who were "single"; and women whose partners had been vasectomized or were using mechanical contraception. Women prisoners could be excluded from the guideline's restriction because they were "not in the appropriate environment to become pregnant" during a study. (See Chapter 6.) FDA concluded that the guidelines have limited the collection of drug response information that would have been useful in designing later phases of trials and may have slowed detection of gender-related variations in drug effects (FDA, 1993a). As a result, FDA issued a revised guideline in July 1993 describing the earlier restriction as an "unnecessary Federal impediment to the inclusion of women in the earliest stages of drug development" (FDA, 1993b). As currently written, the 1993 guideline does not now mandate the inclusion of women of childbearing potential, or women in general, in particular types of trials, relying instead on the "interplay of ethical, social, medical, legal and political forces" to encourage greater participation of women in the earlier stages of clinical trials (FDA, 1993b). It is unclear how this change in FDA guidelines will change the behavior of those performing trials. Clinical Trial Registries The inability of the committee to draw conclusions from available data underscores the need for systematized collection of information by, at the very least, all federal agencies that conduct or support research involving human subjects. While these sorts of efforts have been undertaken in the past, they have not been wholly successful or enduring. In 1974 NIH established a centralized registry of NIH-funded clinical trials that operated for almost five years before it was abandoned in 1979 as a cost-saving measure (Dickersin and Min, 1993). In 1985 the registry was reestablished in NIH Office of Medical Applications of Research (OMAR) in response to a need for a single source of information on clinical trials, as well as to assist in responding to reporting requirements of the Stephenson-

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--> Wydler Technology Innovation Act of 1980² (NIH, 1992a). For two reasons, however, the information contained in the OMAR registry is not considered to be complete: (1) reporting of clinical studies is not mandatory, and (2) it was not until 1988 that the registry began collecting data on the gender of study participants, data that is not yet available in aggregate form. Strategies for redesigning the OMAR registry so that it is more accessible to researchers who want to submit data and to others who want to extract data are currently being explored (personal communication with J. Ferguson, OMAR Director, August 1993). The NIH Revitalization Act of 1993, passed in June 1993, promises to enhance the availability of information about women's participation in clinical studies. One provision of the act requires the directors of NIH, ORWH, and the National Library of Medicine (NLM) to collaborate in establishing a "data system for the collection, storage, analysis, retrieval, and dissemination of information regarding research on women's health that is conducted or supported by the national research institutes." The act also requires that the data system include a registry of clinical trials of experimental treatments that have been developed for research on women's health, as well as information about subject eligibility criteria, gender, race, ethnicity, age, and the location of the trial site(s). The act also stipulates that principal investigators of clinical trials provide this information to the registry within 30 days after it is available, and, once a trial is completed, provide the registry with information about the results, including potential toxicities or adverse effects associated with the treatments evaluated. At the time of this writing, a conference on future strategies for clinical study registration was being planned by NIH. There are numerous clinical trial registries throughout the world. Most of these are focused on specific medical conditions, such as AIDS or cancer, or on specific fields of medicine, such a neurosurgery or perinatology. An ongoing University of Maryland project to identify clinical trial registries around the world counted 27 registries in existence as of June, 1992 (Dickersin and Garcia-Lopez, 1992). The goals of the project are to provide information to researchers and interested parties and to form an international network of registers. CONCLUSIONS AND RECOMMENDATIONS Over the past 50 years the scientific and political communities have grappled with the question of just how far they should go in protecting the human subjects of medical research, especially pregnant women. Reaction to the atrocities of the Nazis was reinforced by further abuses in the 1960s and 1970s and by the tragedies of thalidomide and DES. Early federal

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--> policies and regulations in this area were stringent and protectionist, grouping pregnant women with other "vulnerable" populations—children, prisoners, and the mentally impaired. Following the example of AIDS activists, however, women's health groups have successfully lobbied for changes that encourage and, more recently, require investigators to include an "appropriate" number of women in their study populations. The pendulum now appears to be swinging toward the "inclusionist" side of the argument, where a consensus seems to be emerging in the scientific and political communities, and among the general public as well. Other chapters of this report review the ethical and scientific arguments that bolster this consensus, as well as the social and legal issues it raises. The committee, however, has identified an important underlying consideration: the lack of reliable, comprehensive information on the actual participation of women and various subgroups of women in clinical studies, today or in the past. Information on gender, racial, and ethnic composition of study populations is not currently available in any accessible form. The NIH Revitalization Act's mandate that ORWH create a registry focused solely on women's health and the collection of women's health data is too narrow—without information on men's health issues and men's levels of participation in such studies, monitoring of the relative levels of participation in the future will be difficult and open to bias. The committee supports the efforts of NIH to establish a registry of clinical studies and recommends that such a registry include information on the participation of women and men and on the racial and ethnic composition of participants in such studies, as well as the research questions addressed, that such information be reasonably accessible to investigators and the public, and that the scope of the studies included in the registry be comprehensive. The committee views this registry as a potentially valuable resource in the development of national research agendas, preparation of reports to Congress, preparation of grant requests by investigators, recruitment of study participants, and development of cooperative efforts among institutes and other study sponsors, including multicenter studies. Such a registry would facilitate the development of the NIH research agenda. Another purpose might be to provide data for reporting to Congress on implementation of the legislative mandate to include women and racial and ethnic groups in clinical studies. A comprehensive scope (i.e., who is required to report to whom and what is required to be reported to the registry) is vital to achieving the above purposes and avoiding the potential waste of limited research dollars

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--> on duplicative research. At a minimum, the registry should include ongoing studies as well as published studies. The committee recommends that NIH work with other federal agencies and departments that conduct clinical research to ensure reporting of all federally funded clinical studies. The committee further recommends that representatives of NIH initiate discussions with FDA concerning the feasibility of including privately funded studies in such a registry. The kinds of information to be included and reported to the registry should be uniform. In addition to gender composition of the study population, the registry might include an abstract of the study, the investigator name, and other study population characteristics, such as age and racial and ethnic identification. The committee proposes in Chapter 8 that this information be collected by IRBs; the current legislation concerning the establishment of a clinical trials registry for women's health proposes that such information be collected by investigators. In implementing such a registry, NIH should consider the costs, reporting pathways, accessibility of information, enforceability of reporting requirements, and quality control. NIH should also consider and take precautions against problems that might be posed by such a registry, particularly with private industry involvement, including considerations of confidentiality, insurance reimbursement implications, endorsement of studies through inclusion in registry, access to non-peer-reviewed studies, administrative burden, and cost considerations. NOTES 1.   The three institutes that comprised ADAMHA—the National Institute of Mental Health (NIMH), the National Institute of Drug Abuse (NIDA), and the National Institute of Alcoholism and Alcohol Abuse (NIAAA)—were joined, in their capacity as research institutions, with the NIH in October, 1992. The service components of ADAMHA now operate under the name of Substance Abuse and Mental Health Services Administration. 2.   The Stephenson-Wydler Technology Innovation Act of 1980 called for efforts to "ensure the full use of the results of the nation's federal investment in research and development." One section of the act specifies that "each federal agency which operates or directs one or more federal laboratories shall prepare biennially a report summarizing the activities performed by that agency and its Federal laboratories."

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