1
Introduction

BACKGROUND

Women make up just over half the US population (US Census Bureau, 2009) and should not be considered a special, minority population, but rather an equal gender whose health needs require equal research efforts as those for men. Historically, however, the health needs of women have lagged in medical research. In 1985, the Public Health Service Task Force on Women’s Health Issues, formed in light of the changing role of women in society, highlighted the need for research in women’s health and issued Women’s Health: Report of the Public Health Service Task Force on Women’s Health Issues (HHS, 1985). It 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.

Since the publication of that report, there has been a transformation in women’s health research—including changes in government support of research, in policies, in regulations, and in organization—that has resulted in the generation of new scientific knowledge of women’s health. Offices on women’s health in the National Institutes of Health (NIH) and in the Substance Abuse and Mental Health Services Administration were mandated by law. Other offices focusing on women’s health were established in the Department of Health and Human Services (HHS), in its Food and Drug Administration (FDA) and Health Resources and Services Administration, and in other government agencies, and are now codified under the Patient Protection and Affordable Care Act of 2010 (Public Law [PL] 111-148).

A number of nongovernment organizations have also provided leadership in



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1 Introduction BACKGROUND Women make up just over half the US population (US Census Bureau, 2009) and should not be considered a special, minority population, but rather an equal gender whose health needs require equal research efforts as those for men. Historically, however, the health needs of women have lagged in medical research. In 1985, the Public Health Service Task Force on Women’s Health Is - sues, formed in light of the changing role of women in society, highlighted the need for research in women’s health and issued Women’s Health: Report of the Public Health Serice Task Force on Women’s Health Issues (HHS, 1985). It 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. Since the publication of that report, there has been a transformation in women’s health research—including changes in government support of research, in policies, in regulations, and in organization—that has resulted in the generation of new scientific knowledge of women’s health. Offices on women’s health in the National Institutes of Health (NIH) and in the Substance Abuse and Mental Health Services Administration were mandated by law. Other offices focusing on women’s health were established in the Department of Health and Human Ser- vices (HHS), in its Food and Drug Administration (FDA) and Health Resources and Services Administration, and in other government agencies, and are now codified under the Patient Protection and Affordable Care Act of 2010 (Public Law [PL] 111-148). A number of nongovernment organizations have also provided leadership in 

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 WOMEN’S HEALTH RESEARCH research in women’s health. Women as advocates, research subjects, researchers, clinicians, administrators, and US representatives and senators played a major role in building a women’s health movement. 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 sub - stance, the variability in hormonal status in women, comorbidities, the assump - tion 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 immunodefi - ciency 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 1 NIH definition of clinical research: “1. Patient-oriented research. Research conducted with hu - man subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. Patient-oriented research includes: a. Mechanisms of human disease, b. Therapeutic interventions, c. Clinical trials, and d. Development of new technologies. 2. Epidemiologic and behavioral studies. 3. Outcomes research and health services research” (HHS, 2009). 2 In 2004, the agency name was changed to Government Accountability Office. 3According to GAO (1990), “although the policy first was announced in October, 1986, guidance for implementation was not published until July, 1989, and the policy was not applied consistently before the 1990 grant review cycles.”

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 INTRODUCTION 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 devel- opments in the early 1990s discussed below (Carnes et al., 2008). Table 1-1 high- lights some of the milestones in women’s health research at the federal level. The National Institutes of Health Revitalization Act of 1993 (PL 103-43, Subtitle B, “Clinical Research Equity Regarding Women and Minorities”) re - quired 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 be - ing 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 moni - tor 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 signifi- cant progress toward the goal of including women and minorities in research. 4The National Institutes of Health Revitalization Act of 1993 essentially reinforced the existing NIH policies but with four major differences: (1) that NIH ensure that women and minorities and their subpopulations be included in all clinical research, (2) that women and minorities and their subpopula- tions be included in phase III clinical trials in numbers adequate to allow valid analyses of differences in intervention effect, (3) that cost not be allowed as an acceptable reason for excluding these groups, and (4) that NIH initiate programs and support for outreach efforts to recruit and retain women and minorities and their subpopulations as participants in clinical studies (HHS, 2008). 5According to NIH (2008), phase I trials are “initial studies to determine the metabolism and phar - macologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and/or patients”; phase II trials are “controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indica - tion or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks”; and phase III trials are “expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide an adequate basis for physician labeling.” 6 ORWH, in collaboration with the Office of Extramural Research and the Office of Intramural Research, monitors efforts for compliance, including convening a “trans-NIH” Tracking and Inclusion Committee. Inclusion of women and minorities in NIH-supported clinical research is documented by fiscal year in a series of reports, which are available to the public at http://orwh.od.nih.gov/inclusion/ inclreports.html (accessed June 17, 2010). ORWH has also helped to develop outreach documents for investigators and study staff of NIH-supported research that include guidance on inclusion, recruit - ment, and retention of women and minorities in clinical research (ORWH, 2009).

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 WOMEN’S HEALTH RESEARCH TABLE 1-1 Key Federal and Legislative Milestones in Women’s Health Research from 1977 to Present Year Event 1977 FDA restricts women of childbearing potential from participating in clinical research because of thalidomide and diethylstilbestrol tragedies 1985 Women’s Health: Report of the Public Health Serice Task Force on Women’s Health Issues concludes that “the historical lack of research focus on women’s health concerns had compromised the quality of health information available to women as well as the health care they receive” 1986 NIH establishes policy to increase women’s health research 1987 NIH issues guidelines urging inclusion of women for first time in NIH Guide to Grants and Contracts Nurses’ Health Study focus is expandeda 1989 1990 Women’s Health Equity Act is passed Breast and Cerical Cancer Mortality Preention Act establishes the CDC’s National Breast and Cervical Cancer Early Detection Program GAO review of inclusion of women in clinical research concludes that • NIH policy on inclusion of women in clinical trials was not well communicated or understood within NIH or research community, was applied inconsistently among institutes, and was applied only to extramural research • There was “no readily accessible source of data on the demographics of NIH study populations,” so it was impossible to determine whether NIH was enforcing its own recommendations 1990 NIH Office of Research on Women’s Health is established by NIH and requires inclusion of women in clinical research 1991 HHS establishes Office on Women’s Health WHI, largest clinical study in women, is launched by NIHb NIH ORWH launches strategic planning process to define research priorities for women’s health research in NIH 1992 GAO issues report on inclusion of women in clinical trials used by FDA in evaluating drugs for marketing approval. The report finds that • Although women were sometimes included in drug trials, they were significantly underrepresented • Even when women were included, data were not analyzed to determine whether women’s responses to drugs differed from those of men The report recommends 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” Mammography Quality Standard Act is signed into law. It links accreditation of mammography facilities to evidence that facilities met standards for personnel, equipment, quality-assurance procedures, clinical images, phantom images, and dose

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 INTRODUCTION TABLE 1-1 Continued Year Event 1993 NIH Revitalization Act is signed into law. It requires inclusion of women in all clinical research and analysis of results by sex for phase III clinical trials and formalizes NIH ORWH in law 1993 FDA reverses its 1977 guidelines barring women of childbearing potential from participating in clinical research and publishes new guideline, Guideline for the Study and Ealuation of Gender Differences in the Clinical Ealuation of Drugs. The new guideline • Encourages inclusion of women in phase I and II studies • Requires inclusion of women in efficacy studies • Requires analysis of data on sex differences • Encourages consideration of effects of menstrual cycle on drug effect, effects of exogenous hormone therapy on drug effect, and effect of drug on the effects of oral contraceptives, when feasible 1994 Offices of women’s health are established in FDA and CDC SWAN, the first study on the natural history of menopause, is established c NIH guidelines on the inclusion of women and minority-group members as subjects in clinical research (first issued in 1990 and supported by 1993 NIH Revitalization Act) become effective on publication in Federal Register of March 28, 1994; guidelines state that NIH must: • “Ensure that women and members of minorities and their subpopulations are included in all human subject research; • For Phase III clinical trials, ensure that women and minorities and their subpopulations must be included such that valid analysis of differences in intervention effect can be accomplished; • Not allow cost as an acceptable reason for excluding these groups; and, • Initiate programs and support for outreach efforts to recruit these groups into clinical studies.”d 1996 HHS OWH launches National Centers of Excellence in Women’s Health; first six centers are established; program was later terminated 1998 NIH ORWH launches second strategic planning process to define research priorities for women’s health research in NIH, and releases report, Agenda for Research on Women’s Health for the st Century FDA publishes its final rule permitting agency to place clinical hold on investigational new drug application if men or women were excluded because of potential risk of reproductive or developmental toxicity 1999 AHRQ Centers for Education and Research of Therapeutics program begins. The Centers address a variety of topics over time including the following which were specific to women: hip fractures, irregular heart rhythms and the menstrual cycle, gaps in osteoporosis treatment, arthritis resources, prescription drug use by pregnant women, and hormone therapy continued

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0 WOMEN’S HEALTH RESEARCH TABLE 1-1 Continued Year Event 2000 GAO issues followup audit of NIH that concludes that although women are in clinical trials at rates proportional to their numbers in general population, “NIH has made less progress in implementing the requirement that certain clinical trials be designed and carried out to permit valid analysis by sex, which could reveal whether interventions affect women and men differently” NIH ORWH initiates Building Interdisciplinary Research Careers in Women’s Health program to support research career development of junior faculty members, known as Interdisciplinary Women’s Health Research scholars, who have recently completed clinical training or postdoctoral fellowships and are commencing basic research, translational research, clinical research, or health-services research relevant to women’s health 2001 Interim report released in January on GAO audit of FDA records reveals that 8 of last 10 drugs withdrawn from market caused more adverse effects in women than in men; 4 of those drugs were more often prescribed to women than to men, so the higher number of adverse events in women was not unexpected; other 4 drugs were prescribed equally to men and women, but number of adverse events was higher in women, and this suggested a true sex difference in incidence of adverse effects GAO final report on audit of FDA records reveals that • 30% of study documents examined failed to fulfill requirements for presentation of outcome data by sex • Nearly 40% of study documents examined did not include required demographic information Auditors conclude that “FDA has not effectively overseen the presentation and analysis of data related to sex differences in drug development.” 2003 Study by FDA’s OWH found that nearly equal numbers of men and women were participating in clinical trials but noted that data were not being analyzed by sex NIH establishes Specialized Centers of Research on Sex and Gender Factors Affecting Women’s Health program to develop innovative approaches to advancing research on role of sex and gender factors in health and disease AHRQ begins the annual release of National Healthcare Quality Report and the National Healthcare Disparities Report that address various health care issues, including the following that were specific to women: disparities among women, including race, ethnicity, and socio-economic status; disparities between men and women; and trends and variations over time 2008 HHS implements strategic plan for 2010 through 2015

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 INTRODUCTION TABLE 1-1 Continued Year Event 2009 NIH OWHR launches third strategic planning process to identify research priorities in women’s health for NIH 2010 Patient Protection and Affordable Care Act (Public Law 111-148) formally codifies the Offices of Women’s Health within HHS. It also formally establishes an Office of Women’s Health in the director’s office of AHRQ, CDC, FDA, HRSA, and SAMHSA. It formally establishes an HHS Coordinating Committee on Women’s Health and the National Women’s Health Information Center. Each agency is appropriated such sums as may be necessary for FY 2010 through 2014 aThe Nurses’ Health Studies are among the largest and longest-running observational investigations of factors that influence women’s health. They were started in 1976 to investigate potential long-term consequences of use of oral contraceptives and expanded in 1989. Information provided by 238,000 nurse-participants has led to many insights into health and disease. Prevention of cancer is still the primary focus, but the studies have also produced landmark data on cardiovascular disease, diabetes, and many other conditions. Most important, these studies have shown that diet, physical activity, and other lifestyle factors can powerfully promote better health. bWHI is major 15-year research study to address most common causes of death, disability, and poor quality of life in postmenopausal women: cardiovascular disease, cancer, and osteoporosis. One major goal was to assess the effect of hormone therapy on those clinical end points. cSWAN is a multisite longitudinal epidemiologic study designed to examine health of women during their middle years, including the menopausal transition. Study examines physical, biologic, psychologic, and social changes during this transitional period. The goal of SWAN’s research is to help scientists, health-care providers, and women to learn how midlife experiences affect health and quality of life during aging. dNIH defines a phase III clinical trial as “a broadly based . . . clinical investigation usually in - volving several hundred or more research subjects, for the purpose of evaluating an experimental intervention in comparison with a standard or control intervention or comparing two or more existing treatments.” ABBREVIATIONS: AHRQ, Agency for Healthcare Research and Quality; CDC, Centers for Disease Control and Prevention; FDA, Food and Drug Administration; FY, fiscal year; GAO, Government Ac- countability Office (formerly General Accounting Office); HHS, Department of Health and Human Services; HRSA, Health Resources and Services Administration; NIH, National Institutes of Health; ORWH, Office of Research on Women’s Health; OWH, Office of Women’s Health; SAMHSA, Sub - stance Abuse and Mental Health Services Administration; SWAN, Study of Women’s Health Across the Nation; WHI, Women’s Health Initiative.

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 WOMEN’S HEALTH 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 responsibili - ties 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 reproduc- tive 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 clini- cal 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 differ- ences 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 7A clinical hold is an order issued by FDA to the sponsor of an investigational new drug to delay or to suspend a clinical investigation.

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 INTRODUCTION potential are excluded from participation only because of the risk or potential risk of reproductive or developmental toxicity associated with use of the investi - gational 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 de- scriptions 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 differ- ent 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. 8 In addition, in 2002, the FDA Office on Women’s Health funded an internal review of participation of women in clinical trials and sex analysis of data on biologics (such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins) for which a new product or biologic license application was approved by the Center for Biologics Evaluation and Research during calendar years 1995–1999. The review found that nearly equal num - bers of men and women were participating in the trials. However, analysis of data by sex occurred for only a small number of the studies reviewed (FDA, 2009).

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 WOMEN’S HEALTH RESEARCH 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 ap - pear 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 reproduc - tive 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 recom- mendations in Box 1-1 (IOM, 2001): 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. BOX 1-1 Recommendations from Exploring the Biological Contributions to Human Health: Does Sex Matter? Recommendations for Research • romote research on sex at the cellular level. P • tudy sex differences from womb to tomb. S • ine cross-species information. M • nvestigate natural variations. I • xpand research on sex differences in brain organization and function. E • onitor sex differences and similarities for all human diseases that affect M both sexes. Recommendations for Addressing Barriers to Progress • larify use of the terms sex and gender. C • upport and conduct additional research on sex differences. S • ake sex-specific data more readily available. M • etermine and disclose the sex of origin of biological research materials. D • ongitudinal studies should be conducted and should be constructed so L that their results can by analyzed by sex. • dentify the endocrine status of research subjects. I • ncourage and support interdisciplinary research on sex differences. E • educe the potential for discrimination based on identified sex R differences.

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 INTRODUCTION 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, in- cluding 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. CHARGE TO THE COMMITTEE Given the differences that have been identified between men and women with regard to health and given the transformation in approaching women’s health and the increase in women’s health research conducted over the last 2 decades, in the Consolidated Appropriations Act of 2008 (PL 110-161) Congress provided the HHS Office on Women’s Health (OWH) with funds for the IOM “to conduct a comprehensive review of the status of women’s health research, summarize what has been learned about how diseases specifically affect women, and report to the Congress on suggestions for the direction of future research.” In response to that congressional language, the HHS OWH requested that the IOM conduct a study of women’s health research; the charge to the committee for the project is presented in Box 1-2. In response to that request, the IOM convened a committee of 18 members who have a wide variety of expertise, including expertise in biomedical research, research translation, research communication, disabilities, epidemiology, health- care services, behavioral and social determinants of health, health disparities, nutrition, public health, women’s health, clinical decision making, and such other medical specialties as cardiovascular disease, mental health, endocrinology, geriatrics, and immunology. BOX 1-2 Charge to the Committee An Institute of Medicine committee will examine what the research on women’s health has revealed; how that research has been communicated to providers, women, the public and others; and identify gaps in those areas. The committee will identify examples of successful dissemination of findings paying particular atten- tion to how the communication has influenced women’s use of care and preventive services. The committee will make recommendations where appropriate.

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 WOMEN’S HEALTH RESEARCH This consensus report is the result of the committee’s research and deliberations. THE COMMITTEE’S APPROACH TO ITS CHARGE In light of the expansive nature of its charge, the broad expertise of the committee, and the audience for this report, the committee recognized the need to focus its information gathering, the need to ensure that terms are defined and used consistently, and the need to have an organizational framework. The committee’s information gathering approach, definitions, and framework are described below. 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 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, outcomes, or treatments in women; it includes the study of factors that are determinants of health (biologic, psychologic, environmental, and sociocultural), especially factors that might affect women disproportionately or uniquely. Sex “The classification of living things, generally as male or female according to their reproductive organs and functions assigned by chromosomal complement.” (IOM, 2001) Gender “A person’s self-representation as male or female, or how that person is re- sponded to by social institutions on the basis of the individual’s gender presenta- tion. Gender is shaped by environment and experience.” (IOM, 2001) Research Translation The application of the knowledge and findings from research (such as basic experimental research, observational and clinical studies, and research on health- care services) to health-care practices and public-health policies. Health Communication The dissemination of research findings to the public.

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 INTRODUCTION “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 fe- male 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, environ - mental, and sociocultural factors), especially factors that might affect women disproportionately or uniquely. 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 re - productive 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 pre - sentation. 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 recommenda - tions 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 00 (HHS ODPHP, 2009): Health communication encompasses the study and use of communication strate- gies to inform and influence individual and community decisions that enhance health. It links the domains of communication and health and is increasingly rec- ognized as a necessary element of efforts to improve personal and public health [Jackson and Duffy, 1998; NCI, 1989; Piotrow et al., 1997]. Health communi - cation 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 educa-

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 WOMEN’S HEALTH RESEARCH tion 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 ses- sions 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 dur- ing which policies were implemented to promote women’s health research. The committee’s evaluation included research on biologically determined sex dif- ferences in health and research on the influence of social, behavioral, and envi - ronmental 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, sum - maries 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 health- care 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 addi - tion, 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.

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 INTRODUCTION Focus of Charge Given the breadth of its charge, the committee developed a series of ques- tions to focus deliberations and ensure appropriate response to the charge. Al - though 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. 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 knowl- edge, 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 fac- tors 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 inter- nists, oncologists, cardiologists, epidemiologists, psychologists, and nutrition - ists). 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 determi - nants are discussed in the context of an ecologic framework that distinguishes BOX 1-4 Committee Questions to Focus Deliberations 1. s women’s health research studying the most appropriate and relevant deter- I minants of health? 2. s women’s health research focused on the most appropriate and relevant I conditions and end points? 3. s women’s health research studying the most relevant groups of women? For I example, are women with sociodemographic characteristics that place them at higher risk adequately studied? 4. re the most appropriate research methods being used to study women’s A health? 5. re the research findings being translated in a way that affects practice? A 6. re the research findings being communicated effectively to women? A

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0 WOMEN’S HEALTH RESEARCH individual-level determinants of health (such as biologic and physiologic factors and health behaviors) from broader determinants of health (such as environmen - tal and social determinants) (see, for example, Dahlgren and Whitehead, 1991; Evans and Stoddart, 1990; IOM, 2000). Such an approach is better suited to un - derstanding 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 com - mittee 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 dis- abled 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. 9The IOM is currently preparing a report on lesbian, gay, bisexual, and transgender health issues as well as research gaps and opportunities.

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 INTRODUCTION ORGANIZATION OF THIS REPORT The remainder of this report is organized in five chapters and three appen- dixes. Chapter 2 focuses on findings over the last 2 decades related to the determi- nants of health outcomes and diseases in women. Chapter 3 provides an overview of some of the major research advances of the last 1–2 decades in understanding the biology of women’s health, including the biology of conditions relevant to women and diagnosing and treating those health conditions. Those two chapters present the evidence that supports the committee’s conclusions regarding ques - tions 1, 2, and 3 in Box 1-4, that is, whether women’s health research is focused on the most appropriate and relevant determinants of health, the most appropriate and relevant health conditions, and the most relevant groups of women. In Chap- ter 4, the committee looks at the methods that have been used in women’s health research on pathology and health determinants and draws conclusions related to question 4 in Box 1-4, that is, whether, the most appropriate research methods are being used to study women’s health? The committee addresses questions 5 and 6, about how well research findings in women’s health have been translated into practice and communicated to women, in Chapter 5. The committee’s findings are synthesized in Chapter 6, which presents the committee’s responses to its six questions, a summary of the basis for its responses, and its overall conclusions and recommendations on women’s health research. The report includes three appendixes. Appendix A presents the agendas of the open sessions held by the committee. Appendix B summarizes data on the overall causes of morbidity or causes of mortality in women. The committee used the latter information to focus its review of research on women’s health on issues that have the greatest impact on women. A number of large research studies or trials have been conducted in women in recent years, such as the Nurses’ Health Study and the Women’s Health Initiative. The findings of those studies are dis- cussed in almost all the chapters in this report. To facilitate the discussions and avoid repetition of the descriptions of the study designs, Appendix C, which is included on the enclosed compact disk, describes those large trials. REFERENCES Atkin, C. K., and L. M. Wallack. 1990. Mass Communication and Public Health: Complexities and Conflicts. Edited by Anonymous, Sage focus editions. Newbury Park, CA: Sage Publications. Backer, T. E., E. M. Rogers, and S. Pradeep. 1992. Designing Health Communication Campaigns: What Works? Newberry Park, CA: Sage Publications. Carnes, M., C. Morrissey, and S. E. Geller. 2008. Women’s health and women’s leadership in aca - demic medicine: Hitting the same glass ceiling? Journal of Women’s Health 17(9):1453–1462. Dahlgren, G., and M. Whitehead. 1991. Policies and Strategies to Promote Social Equity in Health. Stockholm, Sweden: Institute for the Futures Studies. Eng, T. R., and D. H. Gustafson, eds. 1999. Wired for Health and Well-being: The Emergence of Interactie Health Communication. Washington, DC: Office of Disease Prevention and Health Promotion.

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