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--> 3 Justice in Clinical Studies: Guiding Principles CONCEPTIONS OF JUSTICE Concerns about justice in the conduct of biomedical research involving human subjects received little attention until the publication of the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1978). In that document, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) outlined three ethical principles that should govern research: Respect for persons reflects two basic convictions: "first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection." Beneficence is understood as the obligation to maximize possible benefits and minimize possible harms in conducting research. Justice, the third of these basic principles, is the main focus of this chapter. The Belmont Report states that "injustice arises from social, racial, sexual and cultural biases institutionalized in society." Women as a class were not the primary concern of the National Commission's work. In sketching the historical background related to justice in research, its report cited the following examples of injustices:
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--> During the 19th and early 20th centuries the burdens of serving as research subjects fell largely upon poor ward patients, while the benefits of improved medical care flowed primarily to private patients. Subsequently, the exploitation of unwilling prisoners as research subjects in Nazi concentration camps was condemned as a particularly flagrant injustice. In this country, in the 1940s, the Tuskegee syphilis study used disadvantaged, rural black men to study the untreated course of a disease that is by no means confined to that population. These subjects were deprived of demonstrably effective treatment in order not to interrupt the project, long after such treatment became available. The conception of justice embodied in the Belmont Report is essentially that of distributive justice, a notion pertinent to situations that call for the fair allocation of society's benefits and burdens. Other conceptions of justice may apply in differing situations. For example, procedural justice applies to a wide variety of social, legal, and institutional matters in which achieving a fair or unbiased result is dependent on adherence to a set of well-ordered procedures, such as the legal requirements of due process. The notion of compensatory justice goes beyond that of fairness in distribution in an attempt to remedy or redress past wrongs. An example from the history of human subjects research is that of monetary payments made to survivors of the Tuskegee syphilis study or to their relatives, to compensate them for the harm or wrong done by the study. The Distributive Paradigm Of these conceptions of justice, the most widely applicable to human subjects research is distributive justice. Clinical studies, especially those in the earliest stages where safety or toxicity is being measured, often involve substantial risks to human subjects. Those risks should be allocated fairly. It is impossible to arrive at a precise general definition of fair allocation, however, because the criteria for fairness may differ from one context to another. Some situations require an equal distribution (for example, one person, one vote), while others call for an equitable distribution (such as from each according to ability, to each according to need). The precise definition of fairness in allocation is determined by the context. In the context of clinical studies, fair allocation is best characterized as equity. That is, because research carries both benefits and burdens, fairness requires that no one group—gender, racial, ethnic, or socioeconomic group—receive disproportionate benefits or bear disproportionate burdens of research. It is not readily apparent, however, what is to count as "proportionate" or "disproportionate" benefits and burdens. If justice requires an appropriate representation of women in the conduct of clinical studies, there remains the problem of elucidating what is to
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--> count as "appropriate representation." Does it mean that women should be included in research in numbers equal to their representation in the population as a whole? Should it be viewed as including women in proportion to their representation among those afflicted by the disease or condition in question? Or does it mean that the research results should pertain equally to all afflicted groups, and hence that the research population must be constructed to assure appropriate analyses for providing this information? This difficulty in defining the kind of representation required by distributive justice influenced the committee's consideration of issues relating to the composition of study populations (see Chapter 4). It should be emphasized that the general concept of distributive justice, and thus the principle of appropriate representation, applies to classes of people rather than to individuals. Therefore, it would not be a violation of the principle of justice if particular individuals in a class were not recruited as research subjects. Only if the benefits or burdens of research are found to accrue systematically to specified classes of people to the exclusion of other classes would the research violate the principle of distributive justice. One aspect of justice in research is thus the requirement of a "fitting" match: the population from which research subjects are drawn should reflect the population to be served by the actual or projected results of the research. The chief concern over the past several decades has been that some groups, such as incarcerated men, have been "overstudied". The Belmont Report addressed this concern by urging that: The selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied. More recently, attention has turned away from the problem of unduly subjecting certain groups to disproportionate risks and toward the problem of denying the benefits of research to certain classes of people who have not frequently been the subjects of research. This observation has been made with regard to heart disease in women (see Chapter 2), but the same concern applies to subgroups of women such as women of color, diverse ethnic groups, and older women. 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. If clinical studies are intended to benefit the population as a whole, then the systematic exclusion of women from such studies places them at an unfair disadvantage. Conversely, justice also demands that (in the words of the Belmont
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--> Report) "research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research." This requirement pertains not so much to women in general as to poor women and women of racial and ethnic groups. The same holds true for U.S.-sponsored research conducted in other countries. If people in developing countries are recruited as participants in research, two conditions must be fulfilled to meet the requirements of the distributive conception of justice: The design and determination of acceptable risk-benefit ratios must be evaluated with the same standards as when such research is carried out in the United States. Beneficiaries of the research outcomes must include people in the developing countries where the research is conducted, as well as in the United States. In short, justice is to be construed as a universal requirement, not confined within the borders of any one nation. Application to Clinical Studies According to the basic conception of distributive justice, a categorical exclusion of women from clinical studies would surely violate the principle of justice. But even when women are not categorically excluded, justice may still be violated in particular research programs or in the overall national research agenda. This violation of justice can take several different forms. First, studies of diseases or conditions that affect both genders but that have included a disproportionately small number of people of one gender are presumptively unjust (an example is that of heart disease, as noted above). Second, some conditions or diseases that affect only or primarily one gender have received far less research attention than the numbers of people affected would appear to warrant. An example commonly put forward for women is that of menopause; another is the manifestations of human immunodeficiency virus (HIV) disease in women (see Chapter 2). An example that applies to men is the study of functional impotence in older men. Another long-standing failure to meet the requirements of justice has been the exclusion from certain drug studies of women "of childbearing potential," a category broadly construed to include the vast majority of women for a substantial portion of their lives. What are the consequences of violating the principles of justice when conducting clinical studies? Exclusion or underrepresentation affects both women during the time they are denied access to studies and women who receive the treatment that was under investigation following the completion
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--> of clinical studies. In the most general sense, the failure to match study groups with target user groups can cause the unstudied or understudied group to receive no medical treatment, ineffective treatment, or even harmful treatment. If the drug has not been tested at all on pregnant or lactating women during the research phase, for example, then information is lacking about the safety and efficacy of the drug for the women themselves, as well as for the fetus. This may result in undertreatment of pregnant or lactating women until postapproval studies are available. Even when some data are collected about women's responses to a particular treatment—including pregnant and lactating women—information may still be lacking about how a proposed treatment will affect specific subgroups of women with clinically relevant characteristics, such as women who have disabilities or are elderly or poor. According to the traditional conception of distributive justice, this sort of discrimination is unjust and may have the consequence of providing less effective health care for some women than for comparable men because the knowledge base that guides health care practices is unfairly skewed. Under the distributive paradigm, what steps might be required to remedy the injustice of excluding women from clinical studies? The minimum measure required is the appropriate inclusion of women in future clinical studies, as described above. According to the mainstream conception of distributive justice, current inequities are to be rectified by abandoning policies or practices that have deliberately or unwittingly excluded women from the study of diseases or disorders that afflict both men and women. Beyond that step, however, other views may come into play. Justice and the Research Agenda: Oppression and Power The distributive paradigm is not the only conception of justice, despite its preeminence in the Belmont Report and ensuing literature. For example, Iris Marion Young and other writers presenting a feminist view have argued that oppression qualifies as a concern of justice, and that some important aspects of oppression are not purely matters of distribution (Young, 1990). These scholars have argued that it is not random or accidental that women are disadvantaged in this way, but rather a result and further dimension of women's generally oppressed status in society. For example, the research agenda has historically neglected many important questions regarding women's health needs, yet there has been a substantial body of research directed at gaining control over women's reproductive capacity (Sherwin, 1994). This concentration on women's reproductive role not only assumes the conventional view that women are, by nature, to be responsible and available for reproductive activities; it has the
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--> further consequence of legitimizing, reinforcing, and further entrenching such views and the attitudes that accompany them. This feminist critique also explains what some contend is a corresponding lack of attention to problems of peri- and postmenopausal women as topics of research. There are other consequences that flow from this broader conception of justice. One of the reasons that women traditionally have been excluded from clinical studies of conditions that affect both men and women is that "their hormonal fluctuations 'confound' or 'confuse' research results" (DeBruin, 1994). Acceptance of the view that men are the norm, and women deviant or problematic for the conduct of biomedical research, serves to perpetuate the practice of excluding women so that the scientific results of studies are not "confounded" (see discussion of male norm in Chapter 5). According to this view, remedies for past injustices would require paying special attention to women in the research agenda. To some extent, this could be understood as an instance of compensatory justice (see above). In one form or another, however, it would amount to granting women preferential treatment in biomedical research. Going beyond the distributive model, in which women must be represented fairly in relation to their health risk in clinical studies likely to benefit the subject population, this conception of justice holds that those who are currently oppressed in society should have a privileged place in studies that are likely to be of specific benefit to members of the group investigated. A final model of justice goes beyond considerations of distribution and oppression to address questions of power and influence over the process of setting the research agenda. Although it may seem that the notions of "benefit" and "burden" can be objectively defined, different groups may construe the burdens of being a research participant in a variety of ways. Moreover, the health priorities of a study population may not be the same as the priorities of those who set the research agenda. Being part of the process that establishes a research agenda can be construed as a requirement of procedural justice. This point is illustrated by the history of acquired immune deficiency syndrome (AIDS) research. Much of the initial research on AIDS understandably focused on gay and bisexual men, because they were the first population identified as having the disease in sizable numbers. This focus is not only gender-specific. Even after male intravenous drug users were known to be afflicted with AIDS, only rarely were they recruited as research subjects. When research interest first focused on women with HIV infection, the concern was largely for their role as "vectors" rather than as patients: "the original interest in HIV-infected women centered on their relation to pediatric AIDS through perinatal transmission. A search of the medical literature yields only a handful of papers focusing on the consequences of the infection in nonpregnant women" (Mitchell et al., 1992; see also C. Levine, 1990; Faden et al., in press).
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--> This picture of enrollment in AIDS research reveals equal class and gender bias. Because the primary population initially infected was gay men, it is understandable that a much larger proportion of men than women were subjects. At some point, however, the failure to focus on the health interests of women affected by the epidemic is considered by many to have become inappropriate. Most of the women who have acquired HIV disease from intravenous drug use or from having sexual relations with IV drug users are also poor and members of diverse racial and ethnic groups; they have been inadequately represented in AIDS research not only as women, but also (along with male IV drug users) as poor members of racial and ethnic groups. For the nation's research agenda to be just, it must ensure that medical research promotes the health and well-being of both men and women. Where it is established that women or other groups have not received a fair allocation of research attention or resources, justice may require that the research agenda provide preferential treatment in these areas. To set a just research agenda for the nation may thus require more than a reordering of priorities. It may also require substantial changes in the way funding priorities are established, to ensure that the objectives of a research program coincide with the health benefits sought by specific communities of potential research participants. Changes also may be required in the way funds are allocated generally and for women's health issues specifically, as well as some administrative restructuring of funding agencies. We will have more to say about how to implement these principles of justice in Chapter 8. LIMITS TO THE REQUIREMENTS OF JUSTICE There is an important limit to the requirements of justice with respect to gender in the conduct of clinical studies. If it is true that women or members of poorer groups or some racial and ethnic groups have not been included in research in appropriate numbers, do the demands of justice now impose on them an obligation to serve as subjects? Does redressing past imbalances or ensuring justice in the future require that groups that have been excluded must now be recruited? The answer to these questions marks the boundary between ethical and unethical recruitment. The requirements of distributive justice demand that recruitment efforts fulfill the criteria outlined in this chapter, but the ethical requirement of voluntariness of participation in research sets limits on what might actually be achievable. The obligations of justice for inclusion of different groups in research are thus imposed on the scientific community and its sponsors, not on the subject populations to be enrolled. Researchers may now stand to gain or lose directly in accordance with their success in recruiting a diverse study sample. The gain, if in compli-
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--> ance with inclusiveness, may be a higher priority for funding or the ability to receive continuation funds. The penalty for noncompliance may be losing research funds. This situation will produce strong incentives to researchers to enroll a diverse study sample. The participants themselves, however, may not benefit from the research. Even in studies that promise enhanced benefits from an investigational drug, a control group receiving a placebo or the standard treatment will not receive the enhanced benefits by serving as research subjects. It is the investigator's responsibility to see that the needs and rights of potential participants are balanced against the need to have them in the study. To guard against potential exploitation and manipulation in the recruitment of particularly "desirable" subjects, every effort must be made to balance the pressure to encourage the inclusion of women—and particularly women from diverse racial and ethnic groups and the poor—with the equally appropriate pressure to heighten investigators' awareness of the importance of soliciting valid, voluntary consents. The requirement of valid consent does not preclude appropriate compensation to participants for time lost from work, costs of travel to the research site, baby-sitting expenses, or any other out-of-pocket costs incurred by research subjects. If justice requires recruitment of research subjects from all social, economic, and ethnic groups, it also requires that volunteers be compensated for any financial losses they incur from serving as subjects. At the same time, incentives for participation should not be so great as to constitute an undue inducement to participate. If investigators offer monetary or other incentives to poor people that unduly influence them to enroll, what is gained by meeting the requirement of distributive justice is lost by diminishing the voluntariness of participation (see Chapter 5). STATEMENT OF GUIDING PRINCIPLES Based on the foregoing examination, the committee recommends three general principles of justice with regard to issues of inclusion of both genders 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
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--> 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. These principles guide the committee's deliberations in the following chapters, which examine the challenges to applying these principles, and achieving equity in clinical studies, that arise from four specific areas: scientific considerations (Chapter 4); social and ethical considerations (Chapter 5); legal considerations (Chapter 6); and issues surrounding risks to reproduction and offspring (Chapter 7). REFERENCES DeBruin, D.A. 1994. Justice and the inclusion of women in clinical studies: A conceptual framework. In: Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. Faden, R., Kass, N., and McGraw, D. In press. Women as vessels and vectors: Lessons from the HIV epidemic. In: Feminism and Bioethics: Beyond Reproduction, S. Wolf, ed. New York: Oxford University Press. Levine, C. 1990. Women and HIV/AIDS research: The barriers to equity. Evaluation Review 14(5):447-463. Mitchell, J.L., et al. 1992. HIV and Women: Current controversies and clinical relevance, Journal of Women's Health 1 (1):35-39. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1978. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, D.C.: Government Printing Office. Special Programme of Research, Development and Research Training in Human Reproduction and International Women's Health Coalition. 1991. Creating Common Ground: Women's Perspectives on the Selection and Introduction of Fertility Regulation Technologies. Geneva: World Health Organization. Sherwin, S. 1994. Women in Clinical Studies: A feminist view. In: Women and Health Research: The Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. Young, I.M. 1990. Justice and the Politics of Difference. Princeton, N.J.: Princeton University Press.
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