Ethical Issues for Research Involving Participants with Diminished Capacity to Consent

Alzheimer’s Disease continues to be a common disorder of aging. In the United States, it is estimated that about 6 million Americans have Alzheimer’s Disease, which underscores the need for continued research on this form of dementia. The controversial approval in 2021 of the drug Aducanumab to treat Alzheimer’s Disease by the U.S. Food and Drug Administration (FDA) illustrates both the high interest, as well as the difficulties, in identifying potentially effective medications for this devastating disease. Studying patients with Alzheimer’s Disease or with other neurological conditions raises a number of ethical issues, including how to adequately obtain informed consent of these patients to participate in human subjects research.

The Belmont Report principle of respect for persons defines three key features of the informed consent process: information, comprehension, and voluntariness. However, subjects with impaired decision making may not be able to comprehend the information that is provided, raising questions about their ability to voluntarily agree to participate in research. This blog reviews the revised Common Rule protection of human subjects regulations and other guidance related to issues of capacity to provide informed consent.

The Federal human subjects protection regulations have long recognized the need for additional protections for subjects who are vulnerable due to coercion or undue influence, including those with impaired decision making. When adult subjects cannot provide informed consent, the regulations allow a legally authorized representative or LAR to provide consent for them. The 2018 revised Common Rule clarified who can be considered an LAR, particularly if there are no applicable laws in the jurisdiction where the research is being conducted.

The revised Common Rule does not provide details about how to design or review research studies involving participants with impaired decision-making. However, there are other sources of guidance for this important issue, including recommendations from the Office for Human Subjects Protections (OHRP)’s Secretary’s Advisory Committee on Human Research Protections (SACHRP); the Presidential Commission for the Study of Bioethics’ 2015 Report “Gray Matters,” which includes a chapter on informed consent capacity; 2014 guidance from the FDA on informed consent; and a 2009 NIH document with points to consider on this topic. Key take-aways from these various guidance documents include:

1. The inclusion of participants with questionable capacity to consent in research must be well-justified.
2. Researchers should develop clear plans for how consent capacity will be determined, which may depend on factors such as:
   1. What types of procedures a study involves: For example, is it simply making use of existing data and biospecimens or is it a complex randomized clinical trial?
   2. The ability of a potential participant to absorb and comprehend information presented during the informed consent process, to use that information to make a reasoned choice about participation, and to be able to clearly express their choice.

3. Often, assessments for consent capacity are made informally. However, a number of formal tools to assess capacity to consent have been developed. The one that has been most well-studied in terms of validity is the MacArthur Competency Assessment Tool for Clinical Research (MacCAT-CR) but it is long and can be complicated to administer. A shorter option is the University of California Brief Assessment of Capacity to Consent (UBACC).
4. Researchers should recognize that the ability to provide informed consent may fluctuate over time. Consideration should be given to periodic reassessment of decision-making capacity and allowing participants to provide consent at a later time, if they become able to do so.
5. Care should be taken to ensure that study subjects are not coerced into participation by an LAR:
   1. Even with the permission of an LAR, most ethicists agree that participants should be allowed to assent or to refuse to participate. This is similar to the requirement for research with children in which children who are able provide assent to participate in research after their parents have given permission.
   2. Alternatively, an independent subject advocate can be used to help determine if a participant should be enrolled, or the Institutional Review Board (IRB) or an independent monitor can observe the consenting process to ensure it is being done appropriately.

6. The risks and benefits of a research study should be carefully analyzed. It may be easier to justify approval of inclusion of participants who cannot consent for themselves in studies that pose minimal risks or greater than minimal risks but with the prospect of direct benefit.
7. Consider the use of a research advance directive for potential research subjects whose decisional abilities may decline over time to enable them to state in advance whether they wish to participate in future research and to set limits on the types of research they are willing to participate in. The NIH Clinical Center uses such an approach.

While there is broad agreement about the importance of research on Alzheimer’s Disease and other conditions characterized by cognitive impairment, the ethical treatment of participants in such studies deserves special consideration and additional protections to ensure their safety and well-being. The revised Common Rule and related guidance can assist both investigators and IRBs in the design and oversight of research with participants with diminished capacity to provide consent.

Resources:

Secretary’s Advisory Committee on Human Research Protections (SACHRP) Subcommittee on Inclusion of Individuals with Impaired Decision-making Recommendations Regarding Research Involving Individuals with Impaired Decision-making (SIIIDR) March 2008 and 2009.

Gray Matters: Topics at the Intersection of Neuroscience, Ethics, and Society. Washington, D.C. Presidential Commission for the Study of Bioethical Issues. March 2015

U.S. Food and Drug Administration (FDA). (2014). Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors. Draft Guidance  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent#impaired

National Institutes of Health (NIH) Office of Extramural Research. (2009). Research Involving Individuals with Questionable Capacity to Consent: Points to Consider.

NIH Clinical Center: 8 NIH. (n.d.). NIH Advance Directive for Health Care and Medical Research Participation, NIH-200 (10-00)