There is a general perception that biomedical research has not given the same attention to the health problems of women that it has given to those of men, and that women may not have benefited from advances in medical diagnosis and therapy because of their lower rates of participation in clinical studies. These perceived inequities have recently become the focus of public attention and legislative action, as women's health advocates and others challenge the content of the national research agenda. Recent policy responses to these perceptions present very real challenges to Institutional Review Boards (IRBs) and investigators, in no small part because their requirements appear to constrain the independence of the scientific community.
At the request of the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH), the Institute of Medicine established a Committee on the Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies. It is within the context of public doubt about the equitable involvement of women and racial and ethnic groups in clinical research, skepticism about the methods and motives of investigators, and legislation enacted that attempts to address these concerns, that the committee executed its charge.
The committee was asked to examine the ethical and legal implications of policies that seek broader inclusion of women in clinical studies, including pregnant women and women of childbearing potential. In its analysis, the committee was asked to pay particular attention to the participation of
women in drug trials and the legal liabilities resulting from injuries to research subjects. The charge did not include a review of the state of scientific knowledge about gender differences, but the committee found that a basic understanding of the subject was necessary to its deliberations.
WOMEN'S PARTICIPATION IN CLINICAL STUDIES
The current concern about women's participation in clinical studies arises from the conflict of two public policy positions: protectionism and access. Emphasis on the need to protect research subjects burgeoned in the 1950s and 1960s in response to revelations of abuses of the research process. This emphasis was reinforced by the discovery of adverse outcomes in the children of women who had taken certain drugs during pregnancy. In the mid-1970s, legislation was passed that was designed to protect research subjects from unethical treatment. The regulations and guidelines stemming from this legislation also were designed to protect against fetal injury in their restrictions on the inclusion of pregnant women and women of childbearing potential in drug trials.
In recent years, guidelines and regulations put in place to protect research subjects have been challenged by claims that they are overprotective and overly exclusive, and therefore detrimental to the health of the very persons they were intended to protect. This shift in perspective developed in the early and mid-1980s, when women's health groups and Acquired Immune Deficiency Syndrome (AIDS) activists drew attention to inequities in the health research agenda and the exclusion of women and other groups from research studies. Since then, there has been a call for greater access to health care research for women, as well as members of diverse racial and ethnic groups. The shift in emphasis from protectionism to access gained momentum in 1990 with the release of a General Accounting Office (GAO) report that found that NIH had failed to fully implement its 1986 policy of greater inclusion of women in clinical studies, and that women were indeed ''underrepresented" in some clinical studies. The report lent credence to the claims that women's health needs were not being adequately addressed and has stimulated legislative efforts to correct the imbalance.
The National Institutes of Health Revitalization Act, passed on June 10, 1993, represents one such effort. The Act includes several provisions relating to clinical studies, one of which has stirred considerable controversy. This much-debated provision requires that each NIH-funded study include representative samples of subpopulations (particularly women and members of diverse racial and ethnic groups) unless their exclusion is justified; notably, cost is not a justifiable criterion for exclusion. The Act is clearly intended to promote justice in clinical research by changing the prevailing assumption of exclusion to one of inclusion, a move strongly supported by many in the research community and by the members of this committee. On
the other hand, many—this committee included—have expressed concern that if the act is too rigidly interpreted, it will make costly and unreasonable demands on the scientific research process and impede the implementation of its noble goal.
Before attempting to delineate how the goal of the NIH Revitalization Act might be more effectively achieved, the committee believed it was important to ascertain the current level of women's participation in clinical studies. Are women "underrepresented" in clinical studies, as many have claimed? Like others who had tried to assess women's participation in the whole of clinical research, the committee was frustrated by the lack of any systematic, centralized collection of data on the gender composition of study populations. Although the ORWH has begun such a collection at NIH, the results are not yet available. As an alternative approach, the committee undertook its own data collection and review of the published literature. The committee found the available data inadequate for determining whether women have participated in the whole of clinical studies to the same extent as men, and whether women have been disadvantaged by policies regarding their participation or a failure to focus on their health interests in the conduct of research. The literature detailing past research on heart disease and AIDS does, however, provide some evidence of gender inequity in these areas of study.
The committee can conclude from its survey that there are many unanswered questions about gender-based differences in response to treatment, and that, in general, investigators have not done one or more of the following: reported the results of gender analyses, performed gender analyses of study results, or recruited adequate numbers of women to support the kind of subgroup analysis that would be needed to resolve these questions.
That the committee was unable to draw conclusions about women's participation in clinical research as a whole from available data underscores the need for systematized collection of information. 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 is vital to achieving the above purposes and avoiding the potential waste of limited research dollars 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. 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.
JUSTICE IN CLINICAL STUDIES: GUIDING PRINCIPLES
Concerns about justice in the conduct of biomedical research involving human subjects received little attention until the publication in 1978 of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research's Belmont Report. This report outlined three ethical principles that should govern research: respect for persons, beneficence, and justice. With an understanding that calls to rectify women's alleged "underrepresentation" in clinical studies are based on concerns about un-
equal distribution of the benefits of biomedical research, the committee chose to form its analysis around principles of justice. Justice is not served when the nation's research agenda ignores important questions regarding the health of one gender when one gender does not participate in clinical studies, and when one gender is treated with interventions that have not been adequately tested in that gender. Based on these observations, the committee recommends three general principles of justice with regard to questions of gender in the conduct of clinical research:
- The scientific community and the institutions that support it must ensure that scientific advances in medicine and public health fairly benefit all people, regardless of gender, race, ethnicity, or age. Therefore, the national research agenda must ensure that medical research promotes the health and well-being of both women and men.
- Where it is established that specific health interests of women, men, or other groups have not received a fair allocation of research attention or resources, justice may require a policy of preferential treatment toward these specific areas in order to remedy a past injustice and to avoid perpetuating that injustice.
- Volunteers for clinical studies should be offered the opportunity to participate without regard to gender, race, ethnicity, or age. Women and men should be enrolled as participants in clinical studies in a manner that ensures that research yields scientifically generalizable results applicable to both genders.
There is a general belief among clinical researchers that, in most situations, women and men will not differ significantly in their response to treatment. The evidence to support this belief is not easily assembled, however, and there are countervailing concerns that gender differences have been insufficiently studied. Some of the known gender differences in response to treatments are related to physiological differences between the genders. Important examples include hormonal differences, particularly the variation in drug response by women during different stages of the menstrual cycle, the physiological changes that accompany pregnancy and lactation (conditions that carry the additional concern of the effect of drugs on the fetus and nursing infant), and pharmacokinetic effects such as differential rates of drug absorption and excretion. Hormonal contraceptives and
hormone replacement therapy in menopause may also have their own effects on the natural course of disease as well as on diagnosis and treatment interventions. Other differences are psychosocial in origin or are mediated by tendencies of men and women to act differently with respect to health care.
These true gender differences (and differences associated with gender, e.g., weight) have implications for the design of clinical trials, the subset of clinical studies that provides the most rigorous and reliable test of the effectiveness and safety of new drugs and treatment interventions. For example, greater heterogeneity among research subjects may permit the investigator to spot trends that might otherwise be missed, even if the numbers are too small for statistically reliable subgroup analysis. At the same time, greater homogeneity among research subjects reduces unexplained variance.
The committee has focused particularly on treatment trials in reaching its conclusions. The committee finds that the weight of scientific evidence, as well as practical considerations, supports the inclusion of both gendersand indeed all kinds of demographic subgroups—wherever possible. The most compelling scientific reasons for exclusion are found in investigations of diseases, conditions, or risk factors (including behavior) that are highly concentrated in a single gender. Some would argue that excluding women is justified in a study where there is no anticipated difference in how women and men respond to a treatment but where the disease is less common among women. These arguments rest on a false assumption that women's presence diminishes homogeneity and thereby lessens the ability to observe the main effect of the treatment (i.e., whether the treatment is effective for any subject). Person-years of follow-up are person-years of follow-up whether they are female or male years, unless the researchers have plausible hypotheses about gender differences in response. And if they do have convincing hypotheses about qualitative gender-specific differences, then this too argues for including both genders, but in sufficient numbers to test for gender-specific results.
This is not to say that there are no significant gender-specific diseases or treatment effects, nor does the committee mean to argue that sufficient attention has been paid to the possibility of gender-specific differences. The committee supports the need to examine these issues systematically where they are based on well-grounded scientific hypotheses, and we support attempts to encourage scientists and clinicians to consider and pursue such gender-related hypotheses. The committee acknowledges, however, that most treatments and most diseases do not differ significantly by gender. This observation reinforces rather than reduces the justification for a principle of inclusion: if indeed most treatment effects in the setting of treatment trials do not differ by gender, then it is reasonable for treatment trials to include both genders.
In general, the committee's findings are compatible with the goals of NIH's legislative mandate for greater inclusion of women and racial and ethnic groups in clinical studies, albeit with certain important exceptions. When there are no anticipated treatment effects by gender, however, a policy that requires scientists to include sufficient representation of both genders to permit subgroup analyses would require, at a minimum, that clinical studies significantly increase their size (to detect the main effect in each group) and proportionately increase their expenses. In an era of concern about the nation's resources, and about expenditures on health in particular, it is argued that a study-by-study application of this requirement makes for both questionable policy and questionable science. When no subgroup differences are anticipated, requiring scientists to enroll sufficient numbers to ensure the statistical power to detect unsuspected differences would produce little additional information at a greatly increased cost. Instead of this blanket requirement, the committee recommends a continuing review of the evidence on gender-specific effects and greater attentiveness to questions of gender at every level of the research process, from the design of individual studies to the setting of the national research agenda.
The committee recommends that NIH commission a study to identify known gender differences in drug response.
The committee recommends that investigators be attentive to factors associated with possible gender differences in drug response and design their studies accordingly. Further, NIH should commission a study that will assist investigators in their effort to detect such differences.
The committee recommends that in the design of studies investigators avoid exclusions based on demographic characteristics.
The committee recommends that investigators proposing research involving human subjects provide a reasonable review of the evidence and plausibility of gender-specific effects relevant to their research, and that studies be required to be designed with sufficient power to detect subgroup differences only when such a review indicates that such a design is warranted. When there is no information concerning possible gender differences, however, the investigator should, when feasible, include both genders in sufficient number to detect differences.
Strategies other than clinical trials, (e.g., surveillance techniques) are available to help devise hypotheses about the differential response of men and women
to medical interventions. These strategies may be significantly less costly than large-scale clinical trials that include sufficient numbers of men and women to detect gender differences in response.
The committee recommends that NIH assist investigators in this effort by: (1) identifying, developing, and disseminating alternative methods for detecting or formulating hypotheses about gender differences and (2) providing guidance for the use of these methods by investigators, initial review groups, and study sections.
SOCIAL AND ETHICAL CONSIDERATIONS
Clinical research is both shaped and constrained by the social and ethical context in which it takes place. While federal research regulations clearly delineate the ethical boundaries of research involving humans subjects, more subtle social influences—notably, biases—also play a role in determining the diseases and populations that are studied. In a society such as ours, composed of people of different races, ethnicities, and economic backgrounds, both unconscious and conscious biases may render those of lesser status "invisible" (or unimportant) to those of greater power and status. Accordingly, the health interests of persons of lower social status may not receive attention equal to that of the health interests of others. These biases may also operate with respect to gender, where women and their concerns have traditionally been assigned lower status. Two forms of unconscious gender bias have particular relevance for the design and conduct of clinical studies: male bias (observer error caused by adopting a male perspective and habit of thought) and the male norm (the tendency to use males as the standard and to see females as deviant or problematic, even in studying diseases that affect both sexes). Both have been thought to contribute to a predominant focus on men's health problems and on men as research participants.
Within the scientific community, there is no consensus concerning whether scientific objectivity can be achieved. Some scientists believe that the research process cannot easily be disentangled from the social world within which it is conducted. Societies stratified by gender, race, ethnicity, and socioeconomic status provide different "lenses" through which to see and understand social and scientific reality. These unconscious biases may permeate the entire scientific research process, influencing the research topics selected, the definition and operationalization of concepts examined, the study design, the method of data collection employed, and the research participants chosen for inclusion. Furthermore, such unconscious assumptions contribute to the view that men's physical makeup and experiences are the standard by which to measure and compare women's; to the extent that women's experiences differ from the established male norm, they may be
categorized as deviant. These biases impede the progress of the scientific enterprise and produce findings that are not valid for large segments of the population.
The committee recommends that NIH and IRBs engage in educational efforts that will ensure that investigators are aware of such gender biases and that studies are equitably conceived and designed with respect to gender.
One way to reduce the influence of such gender biases may be to have a greater number of women scientists active in the research enterprise, through, for example, identification and removal of any institutional barriers to their increased participation. The perspectives they bring to bear may differ markedly from those of their male colleagues, thus aiding in the dissolution of unwarranted and inaccurate assumptions about women in the research enterprise.
The committee recommends that NIH continue its efforts to encourage women of all racial and ethnic groups to become scientific researchers and to assume positions of authority within the scientific hierarchy.
Gender is not the only variable that science has been charged with ignoring. There are other important differences among groups—such as race, ethnicity, socioeconomic status—that are capable of affecting health and illness. The lack of attention to or inadequate conceptualization and measurement of these variables in clinical studies has resulted in findings that are inapplicable to particular racial, ethnic, and socioeconomic groups. For example, in order to accurately determine the effects of race on health and treatment outcomes, it is important to clearly distinguish the biological and sociological components of race. Standard methods of data collection may be inappropriate to certain cultural groups and may need to be modified to ensure that the information obtained is valid and for the risk-benefit ratio to be acceptable. Thus, studies must be planned, designed, and executed to produce valid and generalizable results to the populations under investigation. Investigators and IRBs should utilize the expertise of scholars with experience in studying these populations to avoid the weaknesses evidenced in earlier research.
The history of government-sponsored health research and health care efforts in racial, ethnic, and socioeconomic groups has not been unblemished—past unethical treatment has led individuals from these groups to be wary of participation in current studies. Because of the requirements of the NIH Revitalization Act of 1993, researchers now stand to gain or lose support in accordance with their success in recruiting and retaining participants
from these same groups, the federal mandate has the potential effect of exacerbating past problems of exploitation. Knowledge of the history of health research in relevant racial or ethnic groups and an awareness of the cultural and political frames of reference employed by the members of these groups will enable researchers to avoid perpetuating the problems.
Informed consent is the primary mechanism for protecting subjects from unethical treatment. NIH, IRBs, and investigators must work together to tailor the consent process so that it will be effective for every group that participates in clinical studies. This entails, for example, both understanding and avoiding what might constitute excessive inducement (monetary or otherwise) for members of a group. If the benefits of research are to accrue to all groups equally, then proper study design and fully informed consent are critical elements to the achievement of that end. Collaboration among clinical investigators, IRBs, and those with research expertise in these groups (e.g., social scientists) would facilitate the design of clinical studies that are socially, as well as scientifically, valid and ethically acceptable.
The committee recommends that NIH commission a study of attitudinal and institutional barriers to participation in research among women, racial and ethnic groups, and the poor.
The committee recommends that NIH train initial review groups (IRGs), technical evaluation groups (TEGs) and investigators in recruitment and retention issues; part of this training should emphasize methodological and ethical issues in conducting research with women of diverse racial and ethnic groups and poor women.
The committee recommends that investigators tailor study designs and recruitment and retention efforts to the specific populations to be included in the study. Investigators must consider the relevance of race, ethnicity, socioeconomic status, and other subgroup variables to their study and develop appropriate definitions, methods, and measurements, to ensure the validity of their research efforts among these groups.
The committee recommends that in designing recruitment and consent procedures, investigators be cognizant of concerns and needs of communities that have a history of exploitation or abuse in previous clinical studies. Investigators also must ensure that such information be presented and carefully explained, orally and/or in writing, in the potential participant's preferred language.
Health-related research and development in the United States is supported by the federal government (predominantly through the National Institutes of Health [NIH]), the pharmaceutical industry, and private foundations. This institutional structure can affect the conduct of research because it is the source not only of funding, but also of procedures for reviewing the ethics of scientific research—including whether a proposed plan for selecting research participants is just—and of the legal requirements applicable to research.
Current federal policies—in the form of statutes, regulations, and agency guidelines and memoranda—affect the achievement of equity in clinical studies. These policies govern research funded, conducted, or otherwise regulated by the federal government, its agencies, and departments. The policies vary: some appear to promote inclusion of both genders, others refer to inclusion of women and racial and ethnic groups, and others specify conditions applicable to women of childbearing potential and pregnant women. Application of a particular policy may depend on funding origin, type of research, condition studied, or fertility status of the proposed study participant. Particularly in the area of drug development, clinical studies receiving federal funding or performed at institutions supported by federal funding may be subject to a number of policies prior to a drug's entrance into the market. The many recent changes in relevant federal policies promote inclusion, rather than exclusion. As a result, policies have become more congruent. Consistency and, where possible, congruence among these policies is important to promote compliance and prevent confusion.
The committee recommends that NIH work closely with the FDA and with other Public Health Service (PHS) agencies to make regulations and policies on inclusion of women and racial and ethnic groups consistent with one another and, wherever possible, to make them congruent.
If the policies of federal agencies are harmonized, there will still remain the task of educating the research community concerning what is required, and motivating that community to comply. Enunciation of sound and congruent policies, in conjunction with a comprehensive educational program, will ensure that policies and the rationales for the policies are properly understood by the research community.
The committee recommends that NIH, in cooperation with FDA, should institute a comprehensive education program directed at in-
vestigators, institutions, and IRBs on policies concerning the inclusion of women and racial and ethnic groups in clinical studies.
The policies and activities of federal agencies are subject to constitutional challenge and review. It is unclear whether research policies that constrain the involvement of women in government-sponsored or government regulated research could be held to violate constitutional standards of liberty and equality. Such challenges could possibly be based in principles of decisional privacy and equal protection derived from the Fourteenth Amendment. For example, the Fourteenth Amendment's protection of ''life, liberty, and property" has been interpreted to provide decisional privacy with respect to terminating life-sustaining treatment and obtaining an abortion. It remains to be seen, however, how this protection could be read to imply a right to assume the risk of taking an experimental drug. Similarly, the Fourteenth Amendment guarantees all citizens "equal protection of the laws," which the Supreme Court has interpreted as prohibiting the government from treating similar individuals and groups differently. Research policies that result in the exclusion of women as a class might be found to contradict the equal protection clause unless a court found the justification for such exclusion to be adequate.
Both individuals and organizations involved in the conduct of research must deal with another set of legal considerations—liability. Fear of potential legal liability has been cited as one of the reasons that women of childbearing age and pregnant women have traditionally been excluded from clinical trials of drugs. The focus of liability concerns is on possible injury to potential offspring. Although recent evidence may indicate that exposure of a father to some chemicals may cause harm to a developing fetus, the focus has overwhelmingly been on the potential for harm to offspring resulting from the mother's exposure either before or after conception.
More recently, pharmaceutical companies have begun to recognize that they could also be liable for not including women in clinical research. For example, a pharmaceutical company may be liable if a drug that has never been tested in women is nevertheless marketed for use by both genders and prescribed for a woman who then suffers an adverse reaction. Similar approaches to liability could be used as well where men, or subpopulations of women or men, were not included in a study population but suffered an injury. This creates a paradox for clinical trial sponsors whose efforts to exclude women in order to protect themselves from liability may actually risk liability for exclusion.
The committee concluded that it is impossible to quantify the risk of tort liability from the inclusion of women in clinical studies at this time, because: (1) there is no complete compendium of unreported cases involving settlements and (2) pregnant women and women of childbearing age
have not been included in some major studies in the past. But, difficulties of prediction are compounded even more because tort law is governed by the individual states, with many variations on issues such as whether a woman's informed consent will serve to bar an independent action by a child injured as a fetus during such research. Analysis of existing legal rules and principles seems to indicate that the likelihood of successful damage actions is limited. Nevertheless, broadening the research population to include those groups previously excluded may also generate additional legal actions that will test existing legal doctrine.
Although there is a general lack of case law on liability for injuries to research participants, there is some precedent for liability for exclusion from research. The case law suggests that if a drug was found to cause injuries to women, and yet women had been excluded from clinical trials of the drug, the sponsor might be held liable for failing to test the drug in women. For some drugs, however, the potential for teratogenic or mutagenic effects is low or the negative effects are manifested after a long latent period. For these drugs, even adequate testing in all relevant populations unfortunately may not reveal their potential to cause harm.
The committee recognizes that, regardless of their basis or justification, fears about liability are real. On balance, however, the committee concludes that liability concerns should not represent an impediment to implementation of public policies that favor the broader inclusion of women in clinical studies.
A special set of concerns in the research area stems from the differing bases for liability according to which party is a defendant. A pharmaceutical company, for example, might be sued on the basis of strict liability, while a researcher ordinarily would be sued only on the basis of negligence in the informed consent process. With regard to the latter, the new federal policies calling for inclusion of women in clinical studies will help establish new standards that will be relevant to legal actions.
Many of the concerns voiced about liability in the context of research including women are the same as those with regard to the tort system in general. For example, expert scientific testimony is necessary to establish that a particular drug caused an injury. There are inherent difficulties in assuring the unbiased nature of such testimony in what are often highly technical cases.
The committee recommends that current and future initiatives toward general tort reform include attention to issues of research-related injury, including issues of proof of causation.
The question of whether there should be a special compensation scheme for injuries sustained by children as a result of a parent's participation in a
clinical study is similar to that raised in the context of research subjects in general. Because of the difficulty in quantifying the risk of liability, the committee does not recommend adoption—at this time—of a special compensation scheme limited to coverage of children injured prenatally or preconceptually. Any new compensation scheme focusing only on such injuries poses especially difficult problems with regard to establishing causation and averting large numbers of questionable recoveries.
The committee recommends that NIH thoroughly review the area of compensation for research injury in general and that consideration of implementation of any compensation scheme include attention to prenatal and preconceptual injuries to children resulting from a parent's participation in a clinical study.
Our current health care reimbursement system does not include coverage for medical care resulting from injuries sustained during research. This could be accomplished through a system of universal access with adequate coverage.
The committee recommends that health care reform efforts include considerations of medical care for research-related injury.
RISKS TO REPRODUCTION AND OFFSPRING
Historically, concern for the risks of new drugs has focused on women of reproductive potential, including pregnant and lactating women, but risks to the male reproductive system also may merit attention. Men and women of reproductive age get sick and take medications, and drugs intended for use by this population should therefore be tested in this population. Some of these drugs, however, have potential risks to reproduction or for the development of offspring. These risks give added importance to informed consent and contraceptive options. Risk assessment for reproductive and developmental toxicity may be complicated by the high background rates of infertility and birth defects, as well as the difficulty of identifying the specific effects of the drug under investigation. Techniques, such as animal studies, in vitro analysis, as well as surveillance for developmental effects, among others, can provide some information on potential hazards to humans. Laboratory animals and humans can differ in toxicokinetics, however, and the use of data from animals to determine health risks in humans must be assessed carefully.
Investigators should take these reproductive and developmental risks into consideration in the design and conduct of clinical trials. If men and women of reproductive potential are included in a trial in which they will be ex-
posed to a potential reproductive or developmental toxicant, the potential risks must be characterized as accurately as possible so they can make an informed decision about whether or not to participate. If they decide to participate, they also may wish to consider measures to prevent pregnancy. Information about toxicity risk can help participants determine the likelihood that the baseline incidence of adverse pregnancy outcomes will have been increased by study participation, should a pregnancy occur during the trial. When the study involves lactating women, the exposure and impact of the agent on the nursing infant also should be discussed.
The committee recommends that investigators and IRBs not exclude persons of reproductive age from participation in clinical studies. In the case of women of reproductive age, the potential or prospect of becoming pregnant during the study may not be used as a justification for precluding or limiting participation. Risks to the reproductive system should be considered in the same manner as risks to other organ systems. Risks to possible offspring of both men and women who are not pregnant or lactating should not be considered in the risk-benefit calculation. It is the responsibility of investigators and IRBs to assure that the informed consent process includes an adequate discussion of risks to reproduction and potential offspring, including, where appropriate, an adequate discussion of relevant considerations of birth control.
The committee recommends that the participant be permitted to select voluntarily the contraceptive method of his or her choice where there are no relevant study-dependent, scientific reasons for excluding certain contraceptives (e.g., drug interaction).
The committee recommends that pregnancy termination options be discussed as part of the consent process in clinical studies that pose unknown or foreseeable risks to potential offspring.
The committee recommends that investigators and IRBs not exclude women who are lactating from participation in clinical studies. It is the responsibility of investigators and IRBs to ensure that the informed consent process includes, wherever appropriate, an advisory to potential participants that there may be special risks to their children if nursing mothers participate. No nursing mother should be permitted to agree to participate without first receiving additional information about these special risks.
The inclusion of pregnant women in clinical studies, creates new con-
cerns and risks, but the lack of proven safe treatment options for ill pregnant women carries its own set of concerns and risks. The committee believes that it is important to encourage clinical research to advance the medical management of pregnant women who are or may become ill.
The committee recommends that NIH strongly encourage and facilitate clinical research to advance the medical management of preexisting medical conditions in women who become pregnant (e.g., lupus), medical conditions of pregnancy (e.g., gestational diabetes) and, conditions that threaten the successful course of pregnancy (e.g., preterm labor).
Clinical trials (as well as other studies) have limited power to detect some adverse effects due to the relatively small numbers of subjects included in research compared with the number of persons who eventually may use the drug under study. Adverse effects may not become evident until the drug is in widespread use. Therefore, systematic surveillance for developmental effects is essential to any plan to include pregnant women in clinical research. Together, both methods will further our understanding of the medical management of the ill pregnant woman.
The committee recommends that a review be undertaken of existing birth defects monitoring programs to critically define what they are capable of doing and suggest improvements and reasonable expectations for their use.
In the context of encouraging clinical research to advance the medical management of pregnant women who are or may become ill, the committee reviewed the current Department of Health and Human Services (DHHS) regulations concerning the involvement of pregnant women as research subjects. The committee's review of current DHHS regulations was limited to situations in which the pregnant woman is the subject of the research. It did not include situations involving fetal research (currently covered by the same regulation) since this topic was outside of the committee's charge.
The DHHS regulations begin with a presumption of exclusion—that is, "no pregnant woman may be a research subject" except under certain conditions; the regulations also classify pregnant women as a "vulnerable population" deserving of special protection. In this context, "vulnerable'' suggests that pregnant women are less autonomous or more easily exploited, by virtue of their pregnancy, than other persons—an inference that the committee has found no evidence to support. Removal of pregnant women from the regulatory category of "vulnerable" potential subjects would avoid any such inference.
The committee was unanimous in the view that pregnant women should be presumed to be eligible for participation in clinical studies. The committee also unanimously endorsed the importance of recognizing in public policy as well as in the deliberations of IRBs and investigators, that pregnant women should be treated as competent adults capable of making their own decisions about participation in research.
The committee recommends that pregnant women be presumed to be eligible for participation in clinical studies. It is the responsibility of investigators and IRBs to ensure that pregnant women are provided with adequate information about the risks and benefits to themselves, their pregnancies and their potential offspring. Even when evidence concerning risks is unknown or ambiguous, the decision about acceptability of risk to the pregnancy or to offspring should be made by the woman as part of the informed consent process.
It is critical to note that the committee is not advocating active recruitment of pregnant women into each and every clinical study. Rather, it is urging that the prevailing presumption regarding the participation of pregnant women in clinical trials and other intervention studies be shifted from one of exclusion to one of inclusion. The committee believes that a strengthened informed consent process can address specific concerns regarding the inclusion of pregnant women in clinical studies. This process should include a special disclosure statement detailing in lay language what is known about the risks and benefits of participation. The statement should be reviewed carefully with the pregnant woman and she should be encouraged to consult with her obstetrical care provider as well as with the potential baby's father. Only after the woman demonstrates an adequate understanding of the risks and benefits of participation should consent be solicited. It should be noted that the committee rejects any requirement that the consent of the potential baby's father be a condition of the participation of a pregnant woman in research.
The committee recognizes that, as in all clinical studies, there may be scientifically and medically valid reasons for excluding pregnant women from a particular study. A pregnant woman would be excluded if the medical condition of pregnancy disqualifies her as a subject in the same sense that anyone else, pregnant or nonpregnant, would be disqualified based on medical conditions that would interfere scientifically with the study. For example, a pregnant woman would be excluded from a study of hormone replacement or contraception.
Recording by the IRB in writing of both its reasons for permitting any exception to the general presumption of inclusion of pregnant women and
frequency with which it grants such exceptions would help the IRBs to implement properly any exceptions to the presumption. There was considerable discussion within the committee about whether there are any exceptional instances in which IRBs can be given the discretion to exclude pregnant women from participation for other than scientific reasons. Most committee members ultimately endorsed the following recommendation:
Investigators and IRBs may exclude pregnant women from participation only when the IRB finds, and records its finding in writing, that the following standard has been met: (1) there is no prospect of medical benefit to the pregnant woman, and (2) a risk of significant harm to potential offspring is known or can be plausibly inferred.
A finding that a risk of significant harm to potential offspring is "known or can be plausibly inferred" may be based on evidence from animal studies, in vitro studies, structure-activity relationship data, or previous clinical experience. Under the above standard, IRBs may exclude pregnant women from the earliest phases of many drug trials, but most clinical studies would remain open to pregnant women.
A few members of the committee, however, were not able to endorse the above standard. They wished to reserve for the IRB the discretion to exclude pregnant women from participation not only when there is no prospect of medical benefit to the women but also when there is the potential for benefit to them that could be characterized as minimal or insignificant.
The committee also struggled with how to accommodate within its support for the shift of the presumption to inclusion of pregnant women (from that of exclusion) a role for conscience and an individual investigator's moral commitments. It was agreed that, at a minimum, such a mechanism would require that the investigator provide the IRB with a written explanation of his or her concerns of conscience and that the IRB review any such requests in light of a presumption that favors the inclusion of pregnant women in clinical studies. It is because of the potential for abuse of a "conscience" exemption that the committee could not resolve whether or under what conditions such an exemption should be constructed.
At least a technical amendment to Subpart A, sec. 46.111(a)(3), eliminating the reference to pregnant women as a "vulnerable population" will be required by the recommended revision to Subpart B.
The committee recommends that OPRR revise and reissue subpart B of the DHHS regulations for the Protection of Human Subjects, titled "Additional Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human
In vitro Fertilization [45 C.F.R. 46, subpart B] in accordance with the committee's recommendation.
Policies requiring the inclusion of women and racial and ethnic groups in clinical studies are already in place. The present emphasis placed by NIH on the recruitment of diverse population groups into clinical research is a strong initial step in the pursuit of equity in clinical studies. Where earlier versions of the current NIH policy on inclusion of women in clinical studies simply encouraged investigators to include women in study populations, more recent policy statements require that "clear and compelling" rationales be given for the exclusion of women from proposed research. The challenge for those involved in clinical research is to achieve full implementation of these guidelines in a way that enhances the overall enterprise and deals with the various problems identified by this report. The committee believes that every level of the research structure must actively participate in the efforts to increase subgroup participation in clinical studies. However, the committee does not believe that the interests of justice in advancing the health of all people are best served by an exceptionless requirement that every clinical study be large enough to conduct valid analyses of every relevant subgroup comparison. As reflected in the committee's guiding principles 1 and 2 (see Chapter 3), the final burden for achieving justice falls on the national research agenda as a whole and cannot be implemented by a mechanical approach to the selection of subjects on a study-by-study basis.
The ultimate criteria for judging the success of a public policy to achieve justice and promote inclusion will be changes in research policy and clinical practice, and ultimately improvements in health status indicators, particularly in areas where unjustifiable disparities currently exist. Specific objectives include the following:
- Establish accountability for implementation at every level of the research enterprise, including levels well above that of the individual investigator;
- Provide the necessary database to shape adherence and identify gaps in knowledge;
- Establish a system for monitoring compliance with specific inclusion-based requirements and evaluating the extent to which fairness is being achieved;
- Use the preceding processes and data bases to educate, inform, and promote discussion among policy makers, bureaucrats, investigators, IRBs, IRGs, TEGs, and the general public.
The committee has attempted to frame its recommendations as actions that can be taken by all of the actors in the research process, some immediately and some in the longer term, to ensure the broad participation of women and other groups in clinical studies and to advance fairly the health of all persons. The committee strongly believes that tracking both the study populations' composition and topics of funded studies, and providing this information on a regular basis to all those involved in the research process, will in and of itself raise the level of awareness and activity concerning the issues of both study composition and attention to women's health concerns.
NIH already requires investigators to report the composition of study populations, which keeps investigators aware of the need to involve diverse populations. It is important that individual investigators be aware of both the state of the science and the state of clinical practice with respect to gender and other subgroup differences in their areas of research. In designing studies, investigators should conduct literature reviews to determine (1) the extent to which an evidentiary base exists for suspecting gender-specific and subgroup effect, and (2) the extent to which women and other groups have served as participants in relevantly similar research.
If there is a plausible basis for suspecting gender differences, investigators should make every effort to recruit sufficient participants of both genders to conduct analyses to detect these differences. In the absence of such an evidentiary base, investigators should recruit participants of both genders. Where sample size is large enough, investigators also should conduct analysis of gender differences in these studies. Investigators should strive to collect sufficient data on gender-related variables to permit a refined interpretation of any observed gender differences (e.g., potential confounders or mechanistic variables such as hormonal status of women, weight, and adiposity) and to reveal trends or suggest hypotheses.
As Soon as Feasible
Investigators should draw on the expertise available in the social science community to improve the ways in which the variables of gender, race, and ethnicity are conceptualized, operationalized and measured in their studies. Such collegial exchanges will enable investigators to tailor their study designs, recruitment and retention efforts, and informed
consent procedures to the study population selected, to avoid unwarranted exclusions of potential participants, and to be prepared to collect sufficient data on gender-related and subgroup variables to analyze for confounding effects.
Investigators clearly need broad-based support from the other actors within the research process in order to carry out their part of a comprehensive agenda. The committee recommends that IRBs, IRGs, TEGs, scientific advisory councils, and NIH management become more directly involved with investigators in activities that promote development of more inclusive study designs. Measures recommended by the committee, such as IRB review of protocols for study population composition and NIH provision of opportunities for investigator training and access to needed databases, facilitate investigator efforts to realize the goal of greater inclusion.
As part of the IRBs' responsibility for ensuring the just selection of persons to be participants in research, IRBs should require investigators to provide the proposed gender, racial, and ethnic composition for each study, as well as information about the distribution of the condition under study in the population at large and the composition of subjects in previous relevant research. It is the IRBs' responsibility to make a determination that the composition of the proposed study is equitable.
As Soon as Feasible
IRBs, in concert with NIH, should engage in educational efforts that will ensure awareness among investigators of gender and racial and ethnic biases. Research organizations could draw upon the expertise of social scientists experienced in the conceptualization, operationalization, measurement, and analysis of variables relevant to these issues to assist investigators.
The committee believes that providing feedback to IRBs concerning the characteristics of the study populations and research topics it has approved will serve to raise the level of awareness of IRBs to issues of justice and inclusion. The NIH Office of Protection from Research Risks (OPRR) should require IRBs to collect data on study population composition and research topics of all studies subject to IRB review. OPRR could monitor study population composition through, for example, a representative sample of general assurance IRBs.
IRGs and TEGs
Once NIH policies for inclusion of gender, racial, and ethnic groups are finalized, it is anticipated that IRGs and TEGs will have significant responsibility for monitoring their implementation. As with any new policy, it is expected that in the initial stages of implementation guidance will be needed. NIH should develop a mechanism for monitoring the actions taken by IRGs and TEGs in implementing policies for inclusion of gender, racial, and ethnic groups, and provide feedback to the IRGs and TEGs in order to ensure consistent and appropriate interpretation of these policies. Among other tools for evaluation, NIH might consider taking a random sample of justifications for exclusions. Central review and evaluation can standardize the implementation of the policy, and it will correct both unnecessarily strict and overly lenient policy interpretations by the peer review system. It will also provide illustrative material for education of IRG and TEG members as recommended below.
As Soon as Feasible
Each IRG and TEG should recruit members with expertise in the area of gender, racial, and ethnic differences or persons sensitive to gender and racial and ethnic concerns. Furthermore, every member of IRGs and TEGs should receive training and education on evaluation of study population composition and gender, racial, and ethnic differences. The very presence of qualified males and females from different racial and ethnic backgrounds is one way of increasing the likelihood that the relevant questions and appropriate conceptualizations are considered by investigators. A rough measure of sensitivity could be based on professional activities, such as research agenda, participation in committees of professional associations, publications, and service at one's institution.
Scientific Advisory Councils
As Soon as Feasible
Mechanisms should be developed for ensuring that principles of justice are central considerations in the setting of the nation's research agenda. Because clinical research carries both benefits and burdens, justice requires that no one group—gender, racial, ethnic, or socioeconomic—receive disproportionate benefits or bear disproportionate burdens of research. For the overall biomedical research agenda to comply with the requirements
of justice, studies must not only include women as well as men, but also women and men from different age cohorts and different racial and ethnic groups. In addition, the health needs of all women and men should receive their fair share of research resources and attention. Scientific advisory councils have the ultimate responsibility for determining priorities in the research agenda for the subject matter area they cover. These decisions should move toward establishing equity in U.S. research efforts for all populations over time. Databases compiled by NIH can be used by scientific advisory councils in making decisions about research priorities within the available funding and in determining what areas require requests for proposals (RFPs) or requests for applications (RFAs) to improve the balance of research across diseases and subgroups. The heads of the councils should confer periodically to assess the application of principles of justice across research areas. In developing research priorities, these councils should give special consideration as to whether the health needs of pregnant women are being adequately addressed by their institutes.
NIH should maintain the current policy emphasis on the inclusion of women in NIH-supported clinical studies. NIH should continue the practice of identifying research concerns of various subgroups (gender, race, ethnicity, socioeconomic status) and offer RFAs and RFPs for such studies. Where new requirements for subgroup analysis result in increases in study size and additional recruitment strategies, supplemental funds (e.g., from the NIH Office of Research on Women's Health) should be made available to meet these funding challenges.
NIH should commission studies to determine the present state of scientific knowledge on gender, racial, and ethnic differences to help investigators determine where subgroup analysis would be likely to identify clinically significant differences. These efforts should culminate in the establishment of a database that includes such information as differences in disease incidence and prevalence, as well as relevant physiological and cultural differences in subgroups. Investigators would be able to consult this database in developing strategies to identify and detect gender, racial, and ethnic differences.
NIH should require that proposals for clinical studies include in their literature reviews the following: the extent to which an evidentiary base exists for suspecting gender or other subgroup differences relevant to the proposed research; the demographic characteristics of subjects in past similar research; groups for which the proposed study might have
special relevance; how the preceding information justifies the population selected for the proposed study; and how that choice will address gaps identified in the literature. This requirement should be incorporated into the guidelines on the grant application (PHS 398 form).
NIH should widely disseminate to the scientific community methodological guidance on: (1) compliance with the legislative mandate regarding the inclusion of women and other subgroups in clinical research and (2) considerations for valid subgroup analysis.
As Soon as Feasible
NIH should pursue the current dialogue with Congress and the research community on the policy of inclusion and the commitment to justice. The objective is to develop mechanisms that merge public policy goals with scientific advice to promote legislation that is at once socially responsible, practical, and consistent with good science. Such action would extract the scientific community from a current dilemma: if NIH is strictly responsive to the law, clinical studies may become larger and more expensive in order to be in compliance, with no guarantee that this is either the most efficient or effective way to advance the health interests of women or other groups. If this results in an inability to fund an adequate range of biomedical research, it is likely that the health interests of all people will suffer, and thus justice will not be served.
As part of the registry of clinical studies it is currently evaluating, NIH should establish a database cross-referenced by: (1) categories of disease and physiological or psychological factors and (2) study population composition of ongoing and published studies. This database should be compiled in a way that ensures easy accessibility to the data included by subgroup classification. Reporting requirements for all studies should be comprehensive and uniform and at a minimum include: the research questions addressed and the gender, race, ethnicity, socioeconomic status, age, and hormonal status (i.e., pregnancy, stage of menstrual cycle) of the study population.
To facilitate the collection of data about inclusion and justice from non-federally supported research, NIH should encourage journal publishers to require presentation of data on demographic characteristics. Currently, there is no national norm that compels pharmaceutical manufacturers and other investigators to submit their data to a registry or other data repository.
NIH should assist investigators in the effort to detect gender differences by: (1) identifying, developing, and disseminating alternative methods for detecting or formulating hypotheses about gender differences and (2) providing guidance for the use of these methods by investigators, IRGs, and TEGs. The new legislative mandate makes it especially critical
that both investigators and review committees clearly understand the interrelationship of sample sizes and the power to draw statistically significant inferences about differences between subgroups. A proactive strategy of development and dissemination would help investigators in complying with regulations. It would also help to prevent the introduction into the literature of analyses based on insufficient data—analyses that could ultimately do a disservice to subgroups by fostering seemingly valid but erroneous conclusions.