Government Activities

In 1986, NIH established a policy for the inclusion of women in clinical research;¹ guidelines for the implementation of the policy were included in its 1987 Guide to Grants and Contracts. A similar policy encouraging enrollment of minority-group members was issued in 1987 (ORWH, 2009). Before that, little clinical research on women’s health was conducted, for reasons that included concern about ethical issues of possible fetal exposure to an experimental substance, the variability in hormonal status in women, comorbidities, the assumption that results of research on men could be extrapolated to women, and legal issues. Several developments led to a questioning of the exclusion of women from clinical trials: with the onset of the epidemic of the acquired immunodeficiency syndrome, clinical trials explicitly solicited only men, thereby denying to women the potential of a life-saving treatment; results of clinical trials in men were not being extrapolated to women, as seen in the initial unequal application of stents, beta blockers, and cholesterol-lowering drugs; and the male model did not always corresponds to health and disease status in women, especially with regard to cardiovascular disease (McCarthy, 1994; Merkatz and Junod, 1994). As a result of congressional inquiries, particularly from the bipartisan Congressional Caucus on Women’s Issues (Carnes et al., 2008), in the early 1990s the General Accounting Office² (GAO) reviewed how well NIH had implemented its 1986 policy³ to encourage the inclusion of women in research study populations (GAO, 1990). GAO found that the policy was not well communicated within NIH or the research community; there were inconsistencies in application of the policy in the grant-review process; the policy applied only to extramural research, and the smaller intramural research program had no policy; and NIH officials took little action to encourage researchers to analyze results by sex. GAO also concluded that there was “no readily accessible source of data on the demographics of NIH study populations” and it was “impossible to determine the impact of the policy.” The resulting public outrage and response by Congress led to many of the developments in the early 1990s discussed below (Carnes et al., 2008). Table 1-1 highlights some of the milestones in women’s health research at the federal level.

TABLE 1-1

Key Federal and Legislative Milestones in Women’s Health Research from 1977 to Present.

The National Institutes of Health Revitalization Act of 1993 (PL 103-43, Subtitle B, “Clinical Research Equity Regarding Women and Minorities”) required that NIH grantees include women and minority groups in human-subjects research and, for clinical trials, “ensure that the trial is designed and carried out in a manner sufficient to provide for a valid analysis of whether the variables being studied in the trial affect women or members of minority groups, as the case may be, differently than other subjects in the trial.”⁴ Cost was not allowed as an acceptable reason for exclusion. In addition, NIH developed a database to monitor compliance with the law. However, the law for clinical trials applied only to phase III trials.⁵ The act also formalized the NIH Office of Research on Women’s Health (ORWH), which was established in September 1990, and charged it with reporting on progress related to the law throughout NIH.⁶ Inclusion guidelines for complying with the law were published in 1994 and effectively stated that “that NIH could not and would not fund any grant, cooperative agreement or contract or support any intramural project … which did not comply with this policy” (NIH Tracking/Inclusion Committee, 2009).

In 2000, a second analysis by GAO documented that NIH had made significant progress toward the goal of including women and minorities in research. However, for the policy to have its intended effect, GAO emphasized that NIH needed to expand its focus beyond simple inclusion to ensure that, when it is scientifically appropriate, clinical trials be designed and carried out to allow for analysis by sex (GAO, 2000). NIH concurred with GAO’s recommendations and stated they would make efforts to improve tracking of statistical analysis of data on women in clinical trials (GAO, 2000).

In addition to the activities related to NIH discussed above, there have been several activities related to FDA. One of FDA’s primary regulatory responsibilities is to review applications for new drugs, biologics, and medical devices before they are marketed to the public. As part of that responsibility, the agency provides guidance for manufacturers that are conducting clinical trials and evaluating the safety and efficacy of new medical products. In 1977 guidance to manufacturers, FDA precluded women of childbearing potential from participating in phase I and early phase II trials (FDA, 1977) to avoid the possibility of exposing a fetus to a drug that had not satisfied preliminary safety and efficacy testing. Women of childbearing potential were permitted to participate in clinical trials that were conducted after evidence of a drug’s effectiveness in humans was obtained (that is, in late phase II and phase III trials) and after data from animal reproductive studies were examined to see whether the drug caused birth defects; but in practice, women were underrepresented in the later phases as well (GAO, 1992). However, there were concerns that if FDA approved drugs on the basis of clinical trials in which women were underrepresented, their effectiveness and safety in women would not be known (GAO, 1992; Haseltine and Jacobson, 1997). For example, a drug dose established in small early-phase clinical trials that used mostly men might be too high for women, especially because men typically weigh more than women.

Concerns led to a GAO review (1992) that found that although women were included in phase III clinical trials for all the drugs surveyed, they were generally underrepresented, especially in trials of cardiovascular drugs (GAO, 1992). The report recommended that FDA ensure that drug companies consistently include “sufficient numbers of women in drug testing to identify gender-related differences in drug response and that such sex differences are explored and studied.” In 1993, FDA issued a Federal Register (FR) notice (58 FR 39406), “Guideline for the Study and Evaluation of Gender Differences in Clinical Evaluation of Drugs,” which reversed the 1977 guidance and recommended inclusion of women in early-phase clinical trials. FDA also amended its regulations to require efficacy and safety data on sex, age, and racial subgroups (21 Code of Federal Regulation [CFR] Parts 312 and 314, February 11, 1998. Final Rule: Investigational New Drug Applications and New Drug Applications). The final published rule permits the agency to place a clinical hold⁷ on one or more studies that is the subject of an investigational new drug application if men or women with reproductive potential are excluded from participation only because of the risk or potential risk of reproductive or developmental toxicity associated with use of the investigational drug (21 CFR 312, June 1, 2000. Final Rule: Investigational New Drug Applications: Amendment to Clinical Hold Regulations for Product Intended for Life Threatening Disease).

In 2001, GAO again reviewed the inclusion of women in clinical drug trials submitted to FDA and found that women made up a majority (52%) of the trial participants in the new drug applications (NDAs) examined and that every NDA included enough women in the pivotal studies to make it possible to determine statistically whether the drugs were effective in women (GAO, 2000, 2001).⁸ However, GAO had three concerns (GAO, 2001):

1.

There was a relatively small proportion of women in early small-scale safety studies, which provide important information on a drug’s toxicity and safe dosages for later stages of clinical development.

2.

Although “most of the NDAs included analyses to detect differences between men and women, fewer of the NDAs explicitly included descriptions of both safety and efficacy analyses that compared women taking the drug with a comparison group of women taking a placebo or an alternative treatment,” and “NDA sponsors did not recommend different dosage levels for men and women based on the sex differences they detected.” Furthermore, GAO found “no evidence that any of the sex differences reported in any NDA on any dimension—safety, efficacy, or pharmacokinetics—even when statistically significant, were judged to be clinically relevant by either the NDA sponsors or the FDA reviewers, and no dose adjustments based on sex were recommended” (because NDA summary documents are not required to include analyses of sex differences, many of them do not, and FDA reviewers do not consistently request that information).

3.

FDA lacks appropriate management systems to document the number of women in clinical trials, to comply with regulations for presenting outcomes data by sex, and to confirm that its reviewers have adequately addressed sex-related issues in their reviews.

Previous Institute of Medicine Report—Does Sex Matter?

In 2001, the Institute of Medicine (IOM) published Exploring the Biological Contributions to Human Health: Does Sex Matter? The committee that prepared the report focused on the basic differences between males and females that appear to have primarily biologic origins (that is, sex differences). Although it acknowledged the importance of social factors (such as female role expectations and socialization—that is, gender differences), it did not review data on those factors as health determinants. It also did not discuss the influence of reproductive factors (such as pregnancy, parity, and parenthood) on health (IOM, 2001), believing that these deserve a separate evaluation.

After a review of the evidence and discussions with scientific experts, that committee came to the following three overarching conclusions and the recommendations in Box 1-1 (IOM, 2001):

BOX 1-1

Recommendations from Exploring the Biological Contributionsto Human Health: Does Sex Matter? Recommendations for Research Promote research on sex at the cellular level.

1.

Sex matters. Being male or female is an important basic human variable and should be considered in designing and analyzing studies in all areas and at all levels of biomedical and health-related research.

2.

The study of sex differences is evolving into a mature science. There is sufficient knowledge of the biologic basis of sex differences to validate their scientific study and to allow the generation of hypotheses.

3.

Barriers to the advancement of knowledge about sex differences in health and illness exist and must be eliminated. Scientists conducting research on sex differences are confronted with barriers to progress, including ethical, financial, sociologic, and scientific factors.

Since that report, a large amount of research on women’s health has been conducted with a variety of research approaches, methods, and studies.

Definitions Used by the Committee

In Box 1-3 the committee defines a number of terms that will be used throughout this report. In 1946, the World Health Organization defined health as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity” (WHO, 1946). The committee agrees that health is not merely the absence of disease and disability. The committee approached women’s health as a concept that has expanded beyond a narrow focus on the female reproductive system to encompass other conditions that create a significant burden in women’s lives. It confines its discussion of women’s health research to the scientific study of health conditions that are specific to women, are more common or more serious in women, have distinct causes or manifestations in women, or have different outcomes or treatments in women; and it includes the study of factors that are determinants of health (biologic, psychologic, environmental, and sociocultural factors), especially factors that might affect women disproportionately or uniquely.

BOX 1-3

Key Definitions. Women’s Health Research Women’s health research is confined for this report to the scientific study of health conditions that are specific to women, are more common or more serious in women, or have distinct causes, manifestations, (more...)

Being a man or a woman has a substantial influence on health as a result of biologic and sociocultural differences. It is important to distinguish sex-based differences and gender-based differences. The committee uses those terms as they were defined in the IOM report Exploring the Biological Contributions to Human Health: Does Sex Matter? (IOM, 2001). That report defined sex as “the classification of living things, generally as male or female according to their reproductive organs and functions assigned by chromosomal complement.” Gender is defined as “a person’s self-representation as male or female, or how that person is responded to by social institutions on the basis of the individual’s gender presentation. Gender is shaped by environment and experience.”

The committee is charged not only with highlighting what has been learned from women’s health research but with providing conclusions and recommendations related to the translation and communication of those research findings. For the purposes of this report, the committee defines research translation as the application or implementation of the findings of research studies in changes in health-care practice and public-health policies, and it defines health-research communication as the dissemination of the findings of research studies related to women’s health to the general public. As discussed in Healthy People 2010 (HHS ODPHP, 2009):

Health communication encompasses the study and use of communication strategies to inform and influence individual and community decisions that enhance health. It links the domains of communication and health and is increasingly recognized as a necessary element of efforts to improve personal and public health [Jackson and Duffy, 1998; NCI, 1989; Piotrow et al., 1997]. Health communication can contribute to all aspects of disease prevention and health promotion and is relevant in a number of contexts, including (1) health professional-patient relations, (2) individuals’ exposure to, search for, and use of health information, (3) individuals’ adherence to clinical recommendations and regimens, (4) the construction of public health messages and campaigns, (5) the dissemination of individual and population health risk information, that is, risk communication, (6) images of health in the mass media and the culture at large, (7) the education of consumers about how to gain access to the public health and health care systems, and (8) the development of telehealth applications [Atkin and Wallack, 1990; Backer et al., 1992; Eng and Gustafson, 1999; Freimuth et al., 1989; Harris, 1995; Jackson and Duffy, 1998; Maibach and Parrott, 1995; Northouse and Northouse, 1998; Ray and Donohew, 1990].

Information Gathering

The committee met six times, including two open information-gathering sessions at which the members heard from stakeholders and researchers. Appendix A presents the agendas of those public meetings. During that time, the NIH ORWH held a series of scientific workshops and public hearings involving a variety of stakeholders (health-care providers, public-policy experts, advocates, and the general public) to gather information to update its women’s health research agenda. Committee members or IOM staff attended portions of those meetings so that they could be aware of ORWH research–priority development and hear further stakeholder input on research priorities in women’s health.

The committee conducted extensive literature searches related to women’s health research and on the translation and communication of research findings in numerous databases, including PubMed and Embase. The committee focused on research published in the last 15–20 years, which is roughly the period during which policies were implemented to promote women’s health research. The committee’s evaluation included research on biologically determined sex differences in health and research on the influence of social, behavioral, and environmental factors on women’s health. Searches were conducted both on studies of women’s health research in general and on specific diseases, conditions, and determinants of health. Because of the large number of published articles, summaries and review articles were used when possible. Data from a broad spectrum of research were reviewed, including clinical trials, observational studies, basic research (spanning human, animal, and cellular studies), and research on healthcare services, such as women’s use of and access to high-quality health care. The committee focused on research relevant to the health of US women and to differential effects in groups of women.

In light of the breadth of the topic and the enormous base of published scientific articles, reviews, and summaries, the committee does not provide a comprehensive summary of findings of research related to women’s health but instead identifies selected conditions in which there has been progress. In addition, health issues in which progress has been lacking or narrowly limited and in which additional research is needed are mentioned; the committee focuses on a few examples that make it possible to identify overarching lessons and recommendations.

Focus of Charge

Given the breadth of its charge, the committee developed a series of questions to focus deliberations and ensure appropriate response to the charge. Although not officially outlined in the statement of task, the questions provided more specific tasks for the committee to use in addressing its overall charge. The questions are presented in Box 1-4. The committee refers to those questions in this report to link the information in the various chapters to its charge.

BOX 1-4

Committee Questions to Focus Deliberations. Is women’s health research studying the most appropriate and relevant determinants of health? Is women’s health research focused on the most appropriate and relevant conditions and end points? (more...)

Framework for the Committee’s Work

Women’s health research (like health research in general) traditionally has been conducted with an organ- or disease-based approach. With advancing knowledge, however, it has become apparent that a woman’s health encompasses more than the sum of the absence or presence of discrete disease states and is much more complex. Moreover, health and disease are influenced by a number of factors and the interplay among them, including genetics; physiologic, psychologic, social, and environmental forces; and growth, development, and aging. Health research has expanded to be interdisciplinary and collaborative among specialties (for example, a clinical trial might be developed and conducted jointly by internists, oncologists, cardiologists, epidemiologists, psychologists, and nutritionists). The present committee was faced with a decision of whether to work with a disease-based framework, in keeping with the conduct and funding of most of the research reviewed, or to take an interdisciplinary approach by incorporating multiple determinants of health and considering health outcomes in addition to disease. The committee used both approaches. In Chapter 2, health determinants are discussed in the context of an ecologic framework that distinguishes individual-level determinants of health (such as biologic and physiologic factors and health behaviors) from broader determinants of health (such as environmental and social determinants) (see, for example, Dahlgren and Whitehead, 1991; Evans and Stoddart, 1990; IOM, 2000). Such an approach is better suited to understanding not only the pathophysiology of a health outcome but also preventive measures that can help to ensure optimal health. When summarizing advances in the understanding of the biology and pathology related to women’s health in Chapter 3, however, the committee organized findings by health outcome in light of the nature of the literature reviewed.

The committee did not conduct a comprehensive review of all research on all diseases, disorders, and conditions that are women’s health issues. It reviewed data on the status of women’s health in terms of morbidity and mortality, and it assessed improvements in those respects in the context of research that has been conducted on the various diseases and health issues. The overall leading causes of death in women from 1989 through 2006 are presented in Appendix B. The committee focused its review in Chapter 3 on progress that has been made in reducing mortality or morbidity associated with specific conditions. The committee also highlights a few conditions or diseases in which little progress has been made so that it can identify lessons learned and future needs.

Because the incidence and prevalence of conditions and the leading causes of mortality in women vary with age, it is important to remember that the main causes of death in women overall do not necessarily reflect the main health concerns and issues at different points in a women’s life cycle and that events that occur in one stage can affect health later in life. Furthermore, women have a longer life expectancy than men so many diseases of aging are of a greater concern for women than men.

The population of women in the United Sates is diverse and growing more so. As can be seen in Appendix B, demographic groups vary in the prevalence, incidence, and severity of conditions and their determinants. The committee has reviewed the data on disparities to determine whether research is being conducted on appropriate populations of women. The committee recognizes that different groups of women (such as lesbians,⁹ military and veterans, prisoners, and disabled women) can have different health needs or benefit from different means of meeting their health needs. The committee has not compiled a comprehensive list of such populations but discusses the needs of particular groups as appropriate when data are available. Finally, in addition to health conditions, the committee considered such emerging issues as genetics and the effect of health information technology.