Research Methodology: III. Subjects

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III. SUBJECTS

Selecting individuals to participate in research involves not only scientific decisions about appropriate entry criteria but also ethical decisions about the distribution of benefits and burdens. In The Belmont Report (1979), the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research cited three ethical principles as the foundation of research ethics. The first, respect for persons, and the second, beneficence, have been analyzed more often and in greater depth than the third, justice. Investigators, regulators, and institutional review boards (IRBs) are accustomed to applying the principle of beneficence by examining the risk-benefit ratio and applying the principle of respect for persons by examining informed consent. But the third principle—the selection of subjects as a matter of justice—has often been considered last and in only one of its aspects, the protection of vulnerable groups from exploitation as subjects.

This situation is changing as persons and groups previously excluded from research on grounds of vulnerability seek access to what they perceive as research benefits, primarily the opportunity to try new drugs for serious and life-threatening illnesses. However, the concept of vulnerability is itself coming under greater scrutiny as being illdefined and too broad. In his 2001 paper, Vulnerability in Research Subjects, Kenneth Kipnis proposed a new taxonomy of vulnerability, which he defined as limitations on the ability to provide informed consent. He outlined six types of vulnerability, based on characteristics of the individual or society:

cognitive: the ability to understand information and make decisions;
juridic: being under the legal authority of someone such as a prison warden;
deferential: customary obedience to medical or other authority;
medical: having an illness for which there is no treatment;
allocational: poverty or educational deprivation; and
infrastructure: limits of the research setting to carry out the protocol.

According to the U.S. National Commission, justice is relevant to the selection of subjects at two levels: the social and the individual. At the individual level, "researchers [should] exhibit fairness: thus, they should not offer potentially beneficial research only to some patients who are in their favor or select only 'undesirable' persons for risky research" (U.S. National Commission, p. 7). At the social level, "distinctions [should] be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing further burdens on already burdened persons" (U.S. National Commission, p. 7). Specifically, on the grounds of social justice, classes of subjects should be ranked (e.g., adults before children) and some classes of potential subjects(e.g., prisoners and the institutionalized mentally infirm) should be selected only under certain conditions and should perhaps not be selected at all.

Very few philosophers or other scholars have proposed standards by which to establish priorities in the selection of subjects. Hans Jonas (1970) proposed a "descending order of permissibility" for the "conscription" of subjects. In his view, researchers themselves should be the first to test a new therapy, in that they can best understand the risks and benefits. Believing that very sick or dying patients are particularly vulnerable to researchers' invitations, Jonas opposed using them in research not directly related to their care.

Another approach has been to assert an obligation to participate in biomedical research. Arthur L. Caplan (1984) argued that research is a form of voluntary social cooperation that generates obligations of fairness and reciprocity. If a competent individual voluntarily seeks care in a hospital or institution that conducts biomedical research, he or she benefits from research and should share in its costs (i.e., participate). This obligation is a general one, not an obligation to volunteer for the first available trial or any particular trial.

Selecting the Least Vulnerable

Underlying these different views is the assumption that research is risky or at least burdensome. If this is true, subjects should be selected in a way that protects those whose social, demographic, or economic characteristics make them particularly vulnerable to coercion and exploitation. Volunteering for research is seen as either a duty to be discharged or an altruistic act to be applauded. This emphasis on protecting vulnerable persons is understandable given the signal event in the modern history of clinical research ethics—the cruel and often fatal experiments performed on unconsenting prisoners by Nazi doctors in World War II (Caplan, 1992). Public opinion in the United States also was shaped by the revelations of unethical experiments such as the Tuskegee Syphilis Study of poor black sharecroppers (Jones), the Willowbrook hepatitis B studies at an institution for mentally retarded children (Rothman, 1982), and the Jewish Chronic Disease Hospital studies in which live cancer cells were injected into uninformed elderly patients (Katz, Capron, and Glass). The most influential single article was one by Henry Knowles Beecher, a respected anesthesiologist, published in the New England Journal of Medicine in 1966; it described a series of studies at major research institutions that placed subjects at risk and in which the researchers failed to obtain informed consent (Rothman, 1991).

The view of research as inherently risky and of research subjects as inherently needing protection began to change in the early 1980s, but the pendulum may be swinging back to a more cautious view in the light of rare but highly publicized deaths of research subjects. In September 1999 Jesse Gelsinger, eighteen years old, died in a gene transfer. Ellen Roche and Hoiyan Wan, both young "normal, healthy volunteers," died in trials at Johns Hopkins University and the University of Rochester, respectively (Steinbrook, 2002a, 2002b). Research studies at several prominent medical centers were shut down temporarily after deficiencies in their procedures were identified.

The actual risk in most research studies is generally considered to be quite low, but there are no recent data. The U.S. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (1982) asked three large research institutions to summarize their experience with research-related injuries. Each group found a very low incidence of adverse effects. In one institution, out of more than 8,000 subjects involved in 157 protocols, only three adverse effects were reported, including two headaches after spinal taps. The definition of "adverse effect" is vague, however, especially among sick people, and it is possible that many adverse effects are not reported because they are deemed unrelated to the research study.

Sharing the Benefits of Research

The benefits side of the equation has assumed greater weight in individual decision making. Patients and advocacy groups are demanding more autonomy and less paternalism in the selection of subjects. Desperately ill patients forcefully argue that they are willing to trade a higher level of risk for the potential benefits of promising new procedures, devices, or drugs. Advocates for women and children point out that the typical exclusion or underrepresentation of these populations in clinical trials means that the drugs, when approved, will be prescribed for them with little direct data about dosage, efficacy, or side effects. These trends have been spurred by the vigorous, sometimes confrontational, efforts of persons with acquired immunodeficiency syndrome (AIDS). This advocacy also has stressed the inclusion of groups with poor access to trials, mainly women and minorities (C. Levine, 1988, 1993).

Increased emphasis on women's health issues has provided some information on subject recruitment. Examining the inclusion of women in clinical trials, the U.S. General Accounting Office reviewed the practices of the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) (Nadel; U.S. General Accounting Office, 1992). In both instances women were found to be underrepresented. The FDA review found that women were represented in every clinical trial of the fifty-three drugs approved by the FDA in the previous three and a half years. For more than 60 percent of the drugs, however, the proportion of women in the trial was less than the proportion of women with the relevant disease. Women were particularly underrepresented in trials of cardiovascular drugs, even though cardiovascular disease is the leading cause of death in women.

In arguing for wider inclusion criteria in clinical trials, patient advocates and some clinicians have noted that in the interest of good medical care, drugs should be tested on the populations that will use them. This belief runs counter to the more traditional research view of subject selection, which focuses on testing drugs in a small, homogeneous population in order to detect differences in efficacy and side effects as rapidly as possible.

Even with broadened inclusion criteria, not all patients who want access to promising new agents can be enrolled in clinical trials because they fail to meet the inclusion criteria, they live too far from a research center, or the trials are already closed. Several other mechanisms have been developed, such as the "parallel track," in which qualified patients who cannot enroll in clinical trials may obtain a promising drug through their physician ("Expanded Availability," 1992). Community-based research, especially in cancer and AIDS, also has made clinical trials more accessible to patients.

The NIH has formalized the movement toward broader selection of subjects by mandating that its research grant recipients include appropriate numbers of women and minorities (Kirschstein). The 1993 NIH Revitalization Act (Pub. L. 103–43) extended the revised NIH policy by requiring the NIH director to ensure that women and members of minority groups are included in each federally funded project. The director may waive the requirement if the inclusion is inappropriate for health reasons, the purpose of the research, or any other circumstance. Cost, however, is not considered a permissible reason to fail to include women and members of minority groups.

This trend has limits, however. The inclusion of pregnant women in clinical trials is still controversial unless the trial is specifically designed to benefit the fetus, such as trials to prevent maternal–fetal transmission of the human immunodeficiency virus (HIV), which is associated with AIDS. Some of the objections to including pregnant women rely on ethical concerns about, for example, placing a fetus, who cannot consent, at risk. Most of the concerns are based on fears of legal liability should the fetus be born with an injury that might be attributed to the investigational drug. Other subject groups for which protection is still deemed essential include children (Levine, 1991), prisoners, and mentally ill persons. Still other groups sometimes cited as vulnerable include elderly people, military personnel, pharmaceutical company employees, and medical students. Although for these individuals some conditions and some protocols might be coercive, in general they can make choices voluntarily. Special procedures have been set up in some instances to ensure voluntariness (see, e.g., Winter, on the U.S. Department of Defense).

From the societal perspective, equitable selection of subjects means that the groups bearing the burdens of research should also share in its benefits. Opponents of research in prisons argue that the fruits of the research—newly approved drugs—are rarely available in that setting. Similarly, although many drug trials have been carried out in Third World countries, these nations are often so poor or so lacking in healthcare services that they cannot afford to provide the tested drugs to their citizens.

More recently, representatives of Third World countries and of poorly served communities in the United States have been demanding a greater role in the distribution of benefits (Lurie et al.; U.S. National Commission on AIDS; Thomas and Quinn). Their agreement to participate in clinical drug trials is sometimes conditioned on a promise from trial sponsors to provide something of benefit to the population—the drug, if it proves efficacious, or the health infrastructure needed to deliver the therapy. Efficacy trials for vaccines, which require thousands of subjects, cannot be conducted without the goodwill and participation of a community's leaders. Community consultation, in which investigators and community spokespersons collaborate on the design and implementation of a trial, is becoming a frequent strategy for ensuring that the concerns of the pool of potential subjects and their representatives are addressed.

Recognizing the importance of social justice in the distribution of burdens and benefits, the Council for International Organizations of Medical Sciences (CIOMS) guidelines for international research state:

Before undertaking research in a population or community with limited resources, the sponsor and the investigator must make every effort to ensure that:

the research is responsive to the health needs and the priorities of the population or community in which it is to be carried out; and
any intervention or product developed, or knowledge generated, will be made reasonably available for the benefit of that population or community. (CIOMS, p. 19)

Principal 19 of the World Medical Association's most recent restatement of the Declaration of Helsinki (1964, revised 2000) states: "Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research."

The equitable selection of subjects now includes an assessment of both the need for protecting vulnerable individuals and groups and the importance of allowing them maximum choice in making the ultimate decision to participate. In the future, even more emphasis will be placed on the equitable distribution of the benefits of research.

carol levine

thomas w. ogletree (1995)

bibliography revised

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