Approximately 10 percent of elders older than 65 years and 22 percent older than 80 years have dementia. Furthermore, a majority of nursing home residents have some form of cognitive impairment (Cassel, C., 1988). In addition, many elders experience delirium during hospi-talizations for acute illnesses (Rummans, T., et al., 1995). Many of these patients are incapable of giving valid informed consent. Nevertheless, to better understand illnesses that uniquely afflict elders including those illnesses that impair decision-making capacity, research that involves decisionally impaired elders may be necessary. Restrictive approaches that bar subjects with impaired capacity from research may cause harm; these individuals would be deprived of research-derived medical advances on the very conditions that limit their capacity and be deprived of the benefits of participating in research. Nevertheless, informed voluntary consent to research requires decision-making capacity. Hence, is it ever legitimate to enroll in research studies individuals with impaired decision-making capacity?
The permissibility of enrolling decisionally impaired persons in research has evolved over time. The authors of the Nuremberg Code did not allow for the involvement of decisionally impaired persons in research even if such research was potentially therapeutic. The prevailing view was that studies involving subjects with impaired capacity that do not directly benefit or are potentially harmful to the subjects should not be done (Capron, A., 1999). The Declaration of Helsinki, however, allowed for legally recognized surrogates of decisionally impaired persons to provide consent for therapeutic research (Capron, A., 1999; Michels, R., 1999). Later the National Commission went beyond the Nuremberg Code and the Declaration of Helsinki by claiming that prohibiting such research might harm an entire class of decisionally-impaired persons by depriving them of potential benefits of research (Michels, R., 1999). Indeed, proxy consent for minimal risk studies and greater than minimal risk studies with potential direct benefits to subjects is now widely accepted (Capron, A., 1999).
The National Commission, however, noted that investigators may need to make special provisions for protecting subjects with impaired decision-making capacity. Later, in 1983, the President's Commission reiterated the National Commission's concern (Shamoo, A. and Khin-Maung-Gyi, F., 2002). Nevertheless, despite the reports of these two commissions, specific federal regulations aimed to protect research subjects with impaired decision-making capacity have not been adopted. Even so, the Common Rule (45 CFR 46) does state that ''if an IRB regularly reviews research that involves a vulnerable category of subjects, such as ... mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects'' (Department of Health and Human Services). Nevertheless, in the absence of federal regulations, IRBs must decide what constitutes impaired decision-making capacity, what constitutes greater than minimal risk, and when decision-ally impaired subjects are not at excessive risk of harm (Shamoo, A. and Khin-Maung-Gyi, F., 2002).
In 1998, the National Bioethics Advisory Commission (NBAC) issued its report, ''Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity,'' in which it stated that a ''case can be made for requiring additional special protections in research involving subjects persons with impaired decision making capacity'' (National Bioethics Advisory Commission, 1998). Specific recommendations made by NBAC include: (a) IRBs involved in reviewing protocols involving populations with impaired decision-making capacity should contain at least two members who are familiar with the disorders causing the impaired capacity and with the concerns of the population being studied; (b) for greater than minimal risk protocols, IRBs should require independent and professionally qualified assessment of potential subjects' capacity to consent; (c) for greater than minimal risk protocols that offer no prospect of direct medical benefit to subjects, the protocol should be referred to a national Special Standing Panel for a decision. NBAC advised that its recommendations become part of the Common Rule and that, until the recommendations become federal regulations, IRBs adopt voluntarily the recommendations. To date, these recommendations have not become part of the Common Rule (Sachs, G. and Cohen, H., 2003).
2. Advance Directive for Research Advance care planning consists of informal and formal healthcare planning by a decisionally capable person to guide healthcare decision-making for a future time in which they no longer have decision-making capacity. A discussion with family members, friends and healthcare providers is an example of informal advance care planning. A written advance directive for healthcare decisions is an example of formal planning (Sachs, G., 1994). For research involving persons with impaired decision-making capacity, NBAC recommended that these subjects could be enrolled in research studies if the subject gave prospective authorization via an advance directive for research completed at a time when the subject had decision-making capacity, and in the absence of an advance directive for research, consent from a legally authorized proxy is obtained and the subject assents to the research study (National Bioethics Advisory Commission, 1998).
Like the advance directive for healthcare decisions, the advance directive for research (also known as advance consent) is a legal document executed by a decisionally capable person that authorizes their enrollment in research studies for the time the person lacks decision-making capacity (Kapp, M., 1994; AGS Ethics Committee, 1998). In an advance directive for research, persons can designate their proxy decision-maker, the types of research and risks that would be acceptable, and other values (e.g., religious values) and goals (Sachs, G., 1994).
The advance directive for research, however, has important limitations. First, only 10-20% of Americans adults have advance directives for healthcare treatment decisions (Sachs, G., 1994; Hanson, L. and Rodgman, E., 1996), and it is likely that even fewer have advance directives for research. Many people who complete advance directives for healthcare decisions are motivated to avoid invasive procedures and burdensome life-sustaining treatments (e.g., respirators) at the end-of-life and to prevent prolongation of the dying process. There is no equivalent motivating factor for completing an advance directive for research. Second, by the time it is recognized that a person has lost decision-making capacity, it is unlikely that she or he can complete a detailed advance directive for research. Finally, requiring a written advance directive for research in order for persons with impaired decision-making capacity to participate in research would substantially limit the number of potential subjects and deprive them of the benefits of being research participants and deprive others with their condition of the benefits derived from the discovery of new knowledge (Sachs, G., 1994).
3. Proxy Consent for Research In the absence of an advance directive for research, investigators must obtain consent for research from a legally authorized proxy (AGS Ethics Committee, 1998; Alzheimer's Association, 2004). Typically, the person at the top of the decision-making hierarchy is a court-appointed guardian followed by the person or persons named in an advance directive. If no advance directive exists, investigators should identify and seek consent from a legally authorized proxy. Notably, hierarchies of proxy decision-making vary from jurisdiction to jurisdiction (Karlawish, J., 2003).
Proxies should base their decisions to enroll the decisionally impaired subjects they represent in research studies on the subjects' previously expressed wishes, values and goals (i.e., substituted judgment). However, as with healthcare decision-making, proxies frequently do not know the previously expressed wishes, values and goals of subjects and, hence, do not consistently make substituted judgments for enrollment in research (Sachs, G., 1994; Karlawish, J.,2003). Indeed, in a study (Warren, J., et al., 1986) of proxy consent, investigators examined the decisions by proxies for 168 nursing home residents about whether to permit the residents' participation in a minimal risk study. In all but one instance, the proxies were family members. Fifty-five proxies were of the opinion that the residents that they represented would refuse to participate (if capable) in the study. Of these proxies, however, 17 (31%) gave consent to participate. Another study (Sachs, G., et al., 1994) involving patients with dementia, proxies and well elders found that some demented patients were capable of giving informed consent and most were capable of identifying a proxy decision-maker. The investigators commented that many patients regard designating a trusted proxy as more important than the decisions a proxy would make and that designating a proxy requires less decision-making capacity than the informed consent process for research. Finally, using research scenarios, the investigators found that proxies were more likely to take risks for themselves and protect patients from greater than minimal risk studies (e.g., trials involving drugs and procedures). On the other hand, proxies made decisions contrary to what the patient would want in scenarios in which the risk was perceived to be low and the benefit for others perceived to be present. The results of these studies and others suggest that while proxies do not always use substituted judgments for enrollment in research, they do make decisions that minimize harm to patients. In addition, evidence suggests that patients care more about who is making the decisions for them than the decisions being made (Sachs, G., 1994).
Despite impaired decision-making capacity and proxy consent, subject assent is essential and subjects should be allowed to refuse to participate. Assent can be judged based on subject behavior and cooperatives. Subject dissent should be respected, and when it occurs, subjects should be withdrawn from the study (Capron, A., 1999; Alzheimer's Association, 2004). Notably, in some situations, assent is not possible (e.g., coma and persistent vegetative state). In these situations, investigators must rely solely on the proxy decision-maker for consent.
5. Acceptable Risks of Research Involving Elders with Impaired Decision-Making Capacity
The American Geriatrics Society (AGS Ethics Committee, 1998), the Alzheimer's Association (Alzheimer's Association, 2004) and NBAC (National Bioethics Advisory Commission, 1998) have provided similar guidelines regarding acceptable risks of research involving individuals with impaired decision-making capacity. Provided that informed consent (via an advance directive for research or proxy consent) has been obtained and subject assent, subjects with impaired capacity may be enrolled in research if involvement in the study offers direct health-related benefit to the subject, and, if not, then the study should not expose the subject to more than a minor increment above minimal risk and should have the prospect of yielding generalizable new knowledge about the subject's illness or condition. Enrollment in studies of greater than a minor increment above minimal risk should be offered only to persons who have decision-making capacity or to persons with impaired capacity who have an advance directive for research that allows enrollment in such a study. However, the AGS and NBAC recommend a national panel for considering, on a case-by-case basis, approval of especially promising studies that pose risks greater than a minor increment above minimal risk involving subjects lacking decision-making capacity who have not executed an advance directive for research. To date, such a panel has not been established.
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