Ethics of Long Term Care Research

Position Statement M03
Becomes Policy March 2003

Lisa Boult, MD, CMD; Bruce Dentler, MD, CMD; Ladislav Volicer, MD, CMD; Sharon Mead, MD, CMD and Jonathan M. Evans, MD, CMD writing for the AMDA Ethics Committee.

Summary: The primary goal of this statement is to encourage responsible and ethical research involving long-term care residents.

Background: This position paper expands upon AMDA's work at the 1995 Consensus Conference on the Humanistic Aspects of Research in Long-Term Care.

The Importance of Research Involving Human Subjects

The best practice of medicine rests on sound clinical evidence, which emerges only through the careful study of human subjects. Without the use of human subjects in research, the safe development and use of new diagnostic and therapeutic interventions, including medications, would be impossible. The United States Food and Drug Administration requires that clinical trials of new therapies demonstrate their safety and efficacy before approving their use for the public1.

In the past, certain populations, such as older adults in general, children, and residents of long-term care facilities in particular, were not included in most clinical trials. Consequently, many medications and other medical interventions currently used to treat these populations have never been specifically studied, and little is known about their safety and efficacy. Of necessity, clinicians have extrapolated findings from studies in limited populations such as healthy adult males to the needs of children and older people, even they are physiologically different from these studied populations in ways that may affect the safety and efficacy of their medical treatment. For example, older people differ from younger people in their rate of metabolism and excretion of drugs and in the composition of their bodies.

The growing and diverse population of long-term care residents presents a special challenge. At present, knowledge is lacking not only about the effects of medical, surgical, and diagnostic interventions on this population, but even about such simple epidemiological issues as the incidence and prevalence of specific conditions, and the interactions of their many and complex co-morbidities. For example, the relationship between moderate or severe dementia, which has a high prevalence in long-term care residents, and other diseases common in old age is just beginning to be explored. Likewise, the pediatric long-term care population is expanding and deserves special consideration. In addition, there are other groups of patients entering long-term care who are already involved in ongoing research studies, such as those with HIV infection, cancer, and Alzheimer's Disease.

If clinicians are to have information that is specific about the course of disease and the effects of medical interventions in long-term care residents who are frailer than, and physiologically different from the general population, they must be included in epidemiological studies and clinical trials. This is ultimately the only way an evidence-based body of medical knowledge will develop (Bowling 1999, Gurwitz 1992).

The Development of Standards and Federal Protections for Subjects of Clinical Research

Historically, concerns about research involving human subjects have focused on ethical conduct and on preventing harm. These concerns were prompted in part by a number of large and small research projects, which appeared to either directly cause harm, to neglect the care and safety of participants, or which were conducted without subjects' informed consent (Beecher 1966, Heller 1972, Jones 1991). As a result, safeguards were instituted to protect the human subjects of research. In the past 30 years, several national commissions have been convened to develop standards of conduct for research and to create mechanisms to protect human subjects participating in federally funded research.

In 1979, the Belmont Report, issued by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, outlined federal standards for conducting federally funded research projects involving human subjects (U.S. Department of Health, Education, and Welfare 1971, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979). The Belmont Report (and subsequent federal legislation prompted by that report) defined three principles essential to the ethical conduct of research: informed consent, risk/benefit assessment, and the appropriate selection of research subjects.

The report mandated that each federally funded research project involving human subjects must be approved by an independent Institutional Review Board (IRB) composed of scientists, clinicians, lay people, and community representatives. Similarly, each institution conducting federally funded research was required to create its own IRB that would provide initial approval for each project and then provide reviews of studies in progress. Since then, it has generally been standard practice in institutions conducting federally funded research on human subjects that all studies performed on human subjects be approved initially and at intervals by its IRB, irrespective of the project's funding source (Hayes 1995, General Accounting Office 1996). In addition to the federal requirements pertaining to IRBs, individual states may also have specific requirements that need to be fulfilled.

In 1994, the Clinton administration created the National Bioethics Advisory Commission to advise the federal government on bioethics and public policy issues related to research on human subjects. Prompted by a serious concern about the protection of human subjects, the commission resolved in 1997 that no person in the United States should be enrolled in research without the double protections of informed consent by an authorized person as well as an independent review of the risks and benefits of the research. A report by this commission in 1998 found that the legal protection of human subjects in research did not yet extend to all Americans, and that federal protections did not always include specific provisions for especially vulnerable populations of research subjects (National Bioethics Advisory Commission 2001). Residents of long-term care facilities were specifically identified in this report as one such vulnerable population.

Many long-term care residents are physically frail, with less physiological resilience than healthy adults. Cognitive impairment may prevent them from being able to describe symptoms or discomfort. In the research setting, cognitively impaired residents might not be able to describe distress caused by the research intervention itself. And for residents who cannot understand the goals of a particular research project, even a minor intervention such as the sampling of oropharyngeal or nasopharyngeal secretions for the purpose of culture, or the drawing of blood, can induce fear or distress that would not be present in a subject who comprehended the goals and the finite nature of the process.

Of particular importance, long-term care residency, by its very nature, creates a special vulnerability. Residents are dependent upon others to meet their physical, emotional and social needs.

Ethical Principles Relating to Research In Long-Term Care Facilities: Selection of Subjects, Informed Consent, and the Special Nature of the Nursing Home as a Research Environment

Performing clinical trials in the long-term care setting is an ethically complex undertaking (Kahn 1998, Lo 2000). Many residents of long-term care facilities lack decision-making capacity, as a result of dementia or other disease states. These residents are unable to make decisions about participation in research for themselves and require surrogate decision-makers to make the decisions for them.

For surrogate decision-makers, an ethical conflict is embedded in the question of whether to provide consent for an incapacitated person to participate in research. Though there is a great need for research on nursing home residents in general, participation may not provide any benefit, and may result in greater than minimal risk or harm to an individual resident who becomes a subject. The benefits of almost all research, unlike the risks, usually accrue to future populations. Thus, a surrogate decision-maker who gives permission for an incapacitated resident to participate in research is in the position of giving permission for something that could conceivably cause greater than minimal risk and may be unlikely to help, the individual resident.

The Belmont Report and the National Bioethics Advisory Commission suggest other criteria that should be met in order to perform ethical research. The basic principles of informed consent, risk/benefit assessment, and the selection of subjects of research need to be addressed, as do the ethical principles of autonomy, beneficence, substituted judgment, and best interest, which are outlined below. It is also important to note how these principles may conflict with one another, and how such conflicts may be resolved.

Autonomy and Informed Consent

The principle of autonomy requires that an individual who consents to participate in research be free from coercion and undue influence and have the decision-making capacity to consent to or refuse participation. Those individuals who do possess the capacity to make decisions about participation in research may decide to participate not only based upon their own best interest, but also based upon the principles of beneficence and social justice.

In long-term care facilities, often the majority of residents lack such decision-making capacity. When a long-term care resident is unable to provide informed consent to participate in a research project, then a designated surrogate must consent in writing. The principle of autonomy, the individual's right to make his or her own decisions without undue influence, also applies to the surrogate making the decision.

For informed consent, even by a surrogate, there must be full disclosure of procedures involved in the proposed research. For long-term care residents, especially those who lack decision-making capacity, this disclosure must include not only the known medical risks and benefits but also the consideration of components of the research that might cause the resident distress, whether from fear, disruption of schedule, or a non-routine procedure. Protection of privacy, like confidentiality, is always an issue in long-term care.

Ethical Principles: Beneficence, Justice, Substituted Judgment, and Best Interest

Beneficence

Beneficence is doing good, and it encompasses acts of kindness or charity that go beyond strict obligation2. In the context of research, it looks beyond the best interest of an individual patient and focuses on doing good for society in general. Though the ultimate benefits of a particular research project may not be realized directly by any of the study's participants, there are nonetheless benefits to society, in the form of knowledge derived from the research.

Justice

Also relevant to the participation of nursing home residents in research is the principle of justice, which requires that the benefits and burdens of research be allocated equally and fairly among all members of our society (Sachs 1993), and that standards for the protection of human subjects be applied equally as well. In recent years, concerns regarding justice have often focused on the need to allow members of groups such as children, women and the elderly, who were previously excluded from research the opportunity to participate in, and thus ultimately to benefit from research (Sachs 1993, Mastroianni 2001, Weijer 1999). The principle of justice thus requires that nursing home residents, including the mentally incapacitated, be allowed to participate in new or ongoing research studies that are relevant to their needs, and that research be done for their benefit. Federal and state-mandated protection of research subjects must extend to long-term care facility residents.

Substituted Judgment

When it is possible, surrogate decision-makers should be guided by the principle of substituted judgment. That is, they are expected to base decisions on what the incapacitated person would have chosen. Written advance directives provide a vehicle for communicating wishes directly and in advance. The idea of advance consent for participation in research, particularly in research about dementia, has been proposed (Sachs 1994). However, written advance directives rarely address the idea of participation in research, and preparing an advance directive that could meaningfully address participation in any one specific study would be extremely difficult, if not impossible.

It is unusual for people to discuss the question of research with designated surrogates before becoming incapacitated and many studies have shown that surrogates assumptions of what others would have chosen is often inaccurate (Secker 1991). When surrogates do have knowledge about a specific individual's attitudes toward research, they may be able to infer whether that person would have wanted to participate in a particular study. Otherwise, they must be guided by the principle of best interest.

Best Interest

Lacking information that would allow an accurate substituted judgment, surrogate decision-makers are expected to make the best and most reasonable decision for the resident that is possible given the information available. In the absence of a benefit to study participants, the principle of best interest does not, when considered in isolation, encourage surrogates to consent to mentally incapacitated persons' participation in research. Indeed, state laws may differ in what they allow surrogates to consent to for the purposes of research, and certain projects might involve too much risk to be allowed for a persons unable to make decisions for themselves. For this reason, court-appointed surrogates who are not family members (e.g., public guardians) may even be prohibited from giving consent for participation in research. Surrogates may feel that their overriding responsibility to protect the incapacitated person from harm, even the theoretical harm inherent in participating in research, supersedes any other consideration.

Institutional Responsibility

Although IRBs have the responsibility of ensuring that the research projects they approve be ethically conducted and that they not subject any participants to unnecessary risks, the special vulnerability of nursing home residents, particularly those who are mentally incapacitated, requires that extra measures be taken for their protection. Long-term care facilities have an additional responsibility to ensure that any research taking place in their facilities be conducted in an ethical and safe manner.

At a minimum, each facility should have an appropriate and consistent mechanism for addressing all proposed and ongoing research that includes review and approval by the facility's medical director. IRB approval is not an adequate substitute for approval by the medical director. The medical director's particular expertise will allow him or her to weigh the potential medical benefits of the research and the appropriateness of the research design to a long-term care setting as well as the potential risks to the residents. This may require consideration of residents' privacy, potential discomfort, disrupted schedules, and anxiety (Sachs 1993).

Whenever an individual resident is involved in a study that influences his or her medical care, it is necessary that investigators discuss the research project with the resident's attending physician. The primary physician may be aware of specific risks to the resident related to participation in a particular study. And without the knowledge and cooperation of the primary physician, there may be interactions between the research intervention and the elements of the resident's regular medical care.

Another important institutional responsibility is oversight of research projects specifically with regard to eliminating the potential for conflicts of interest. This important issue will be examined in further detail in a future position statement.

Positions

1. The Need for Research involving Long-Term Care Facility Residents
   The mission of AMDA (the American Medical Directors Association) is to improve the care of residents in long-term care (LTC) facilities. Because there is still much to learn about residents' special needs, physiology, responses to medication, and responses to diagnostic and therapeutic procedures, research on LTC residents is essential for improving their care. Each research project must be designed well enough to answer the research question, and the question must be worth investigating.
   • AMDA strongly supports the involvement of long-term care facility residents in responsible, ethical, and well-designed research.
2. Protection of Human Subjects
   Residents of LTC facilities should receive all protections required by federal and state statutes and regulations involving research in human subjects, irrespective of the source of funding for the proposed research. Because of LTC facility residents' special vulnerability, the standards for their protection should be even higher than for persons without cognitive impairment and persons living independently in the community. Protection can be assured by scrupulous oversight that involves the facility medical director.
   • Residents or their surrogates have the right to consent to, or to refuse participation in research.
   • Informed consent must be obtained from all subjects or their surrogates before participation in research projects.
   • Consent to participate can be revoked by the resident or surrogate at any time.
   • Residents have the right to refuse to participate in research at any time, even when a surrogate has given permission for participation.
   • Any research project involving LTC facility residents should be approved both by an IRB and by the Medical Director of the LTC facility.
   • The conduct of the research should be subject to continuous facility and IRB review.

References

1. See Food and Drug Administration Guidance for Institutional Review Boards and Clinical Investigators, 1998 Update. Available: http://www.fda.gov/oc/ohrt/irbs/default.htm.
2. Investigator Training in the Protection of Human Research Participants. University of Maryland, Baltimore County. Available: http://userpages.umbc.edu/~sparklin/sld001.htm.

Beecher HK. Ethics and clinical research. NEJM 1966; 273(24): 1354-1360.

Bowling A. Ageism in cardiology. BMJ 1999; 319:1353-1355.

General Accounting Office (GAO). Scientific research: Continued Vigilance Critical to Protecting Human Subjects. 1996. GAO/HEHS-96-72. Washington D.C: General Accounting Office

Gurwitz JH, Col NF, Avorn J. The exclusion of the elderly and women from clinical trials in acute myocardial infarction. JAMA 1992; 268:1417-22.

Hayes GJ, Hayes SC, Dykstra T. A Survey of University Institutional Review Boards: Characteristics, Policies, and Procedures. IRB: a review of human subjects research 1995; 17(3): 1-6.

Heller J. Syphilis Victims in U.S. Study Went Untreated for 40 Years. New York Times, July 26, 1972. pA1.

Jones JH. Bad blood: the Tuskegee syphilis experiment. 1981; New York, The Free Press.

Kahn JC, Mastroianni AC, Sugarman J eds. Beyond Consent: Seeking Justice in Research. Oxford University Press, New York 1998.

Lo B. Ethical issues in clinical research. In Hurley S, ed. Designing Clinical Research 2nd ed. Philadelphia: JB Lippincott; 2000.

Mastroianni A, Kahn J. Swinging the pendulum. Shifting views of justice in human subjects research. Hastings Cent Rep 2001; 31(23): 21-8.

National Bioethics Advisory Commission. Ethical and Policy Issues in Research Involving Human Participants. Bethesda MD: U.S. Government Printing Office 2001.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines in the Conduct of Research Involving Human Subjects. Washington, DC: U.S. Government Printing Office 1979.

Sachs GA. Advance consent for dementia research. Alzheimer Dis Assoc Disord 1994;8,Suppl 4:19-27.

Sachs GA, Rhymes J, Cassell CK. Biomedical and behavioral research in nursing homes: guidelines for ethical investigations. J Am Geriatr Soc 1993;41:771-777.

Seckler AB, Meier DE, Mulvihill M, Paris BEC. Substituted judgment: how accurate are proxy predictions? Ann Intern Med 1991; 115:92-98.

U.S. Department of Health, Education, and Welfare (DHEW) 1971. The Institutional Guide to DHEW Policy on Protection of Human Subjects. Washington, DC: U.S. Government Printing Office.

Weijer C. Selecting subjects for participation in clinical research: one sphere of justice. J Med Ethics 1999; 25(1): 31-6.