Importance of Research Involving Individuals with Impaired Decisionmaking Capacity.

Research is essential to improve our understanding of and ability to treat human diseases and disorders that place great burdens on individuals and their families. The quest for new knowledge, however, should never take precedence over the welfare of the research participant. Research may at times involve individuals with limited decisionmaking capacity. The NIH is committed to helping researchers and Institutional Review Boards (IRBs) carry out this research in an ethical manner, protecting the rights and welfare of research participants while advancing treatment opportunities and vital knowledge. Critical to this research process are appropriate safeguards that ensure legally effective⁽¹⁾ informed consent and protect the confidentiality and dignity of the individuals participating in research.

Individuals in a wide variety of situations may have impaired decisionmaking capacity. For example, impairment may occur at times of great stress. Impaired capacity is not limited to individuals with neurologic, psychiatric, or substance abuse problems; conversely, individuals with neurologic, psychiatric, or substance abuse problems should not be presumed to be decisionally impaired. Some research questions may only be answered by research that involves persons with impaired decisionmaking capacity; precluding this research would contribute to needless suffering. The most severely impaired individuals have the greatest need for the benefits of research on etiology and treatment. While this area is controversial, limiting research to the least impaired individuals would hamper research on the underlying causes and potential therapies of many disorders. Not all research will directly benefit the individual participant but may offer future benefits to others who have or will develop the condition or disorder. For example, genetic studies, biochemical measures, or other non-therapeutic approaches may benefit subsequent generations.

Unlike research involving children, prisoners, pregnant women, and fetuses, no additional Department of Health and Human Services (DHHS) regulations specifically govern research involving persons who are cognitively impaired. While limited decisionmaking capacity should not prevent participation in research, it is important to keep in mind that additional scrutiny by IRBs and researchers is warranted for research involving this population.

In developing this statement, members of several NIH Institutes consulted a broad array of experts on clinical research, bioethics, mental health, substance abuse, and age-related conditions. The Office for Protection from Research Risks and representatives from professional and lay advocacy communities, former research participants and IRB members, and others concerned about clinical research and human subject protections also provided valuable perspectives. Together, we have carefully considered clinical research situations in which the additional safeguards described in the DHHS regulations for the protection of participants in research⁽²⁾ might be used by IRBs and by clinical investigators to protect potentially vulnerable individuals.

The NIH offers the following Points to Consider to assist IRBs and clinical investigators in their effort to protect participants in research who are, or may be, or may become decisionally impaired:

Conflicting Roles and Potential Conflicts of Interest. Potential and actual research participants, especially those with permanent or transient cognitive impairments, may find it difficult to understand the difference between research and treatment, and to understand researchers' multiple roles, making "therapeutic misconceptions" particularly problematic, and possibly creating confusion among participants and their families.

• It is essential that the consent process (including consent documents) clearly indicate differences both between individualized treatment and research and between clinician and clinical investigator.

IRB Membership. IRBs that regularly review research involving vulnerable subjects (such as the decisionally impaired) are required by DHHS and FDA regulations to consider including one or more individuals who are knowledgeable about and experienced in working with these subjects (45 CFR 46.107; 21 CFR 56.107). When reviewing research involving individuals with questionable capacity to consent, additional options in the makeup of the IRB should be considered:

• Include at least one voting member, independent of the research and investigators, with appropriate professional background, knowledge and experience in working with individuals with questionable capacity;

• Include additional voting members from the community; these members may include representatives of patient advocacy groups and others not affiliated with the research institution.

Assessing Capacity to Consent. Individual's capacities, impairments, and needs must be taken into account, in order to develop practical and ethical approaches to enable them to participate in research. Since well-validated and practical methods to assess capacity to consent are clearly needed, the NIH is supporting and will continue to support research addressing these issues. A clear understanding of the implications of various cognitive impairments, along with a careful consideration of proposed clinical research methodology, is required. Assessment is complex; simply answering a certain number of factual questions about a protocol may not be an adequate assessment. A key factor in participants' decisionmaking is their appreciation of how the risks, benefits, and alternatives to participation in the study apply to them personally.

• Limited decision making capacity covers a broad spectrum. A healthy person in shock may be temporarily decisionally impaired. Another may have been severely mentally retarded since birth, while yet a third who has schizophrenia may have fluctuating capacity. Researchers should be sensitive to the differing levels of capacity and use assessment methods tailored to the specific situation. Further, researchers should carefully consider the timing of assessment to avoid periods of heightened vulnerability when individuals may not be able to provide valid informed consent.

• Both IRBs and clinical investigators must keep in mind that decisionmaking capacity may fluctuate, requiring ongoing assessment during the course of the research. The consent process should be ongoing.

Responsibilities of Investigators and IRBs:

Not all research projects proposing to involve decisionally impaired persons should be approved by IRBs, and indeed, not all such persons should be enabled to participate in research studies.

• Principal investigators and members of the research team bear primary responsibility for protecting research participants. Responsibilities of IRBs also are significant, including the review of the informed consent forms and processes and research design as presented in the research proposal. They should exercise heightened vigilance in the review of protocols involving individuals with questionable capacity in accordance with 45 CFR 46.111(b).⁽³⁾

• As impairment increases, along with risks and discomforts, safeguards should increase according to a sliding scale, i.e., protections should be proportional to the severity of capacity impairment, or to the magnitude of experimental risk, or both. Provisions for additional safeguards should be in place prior to involving individuals with questionable decisionmaking capacity in research that poses greater than minimal risk.

• Educational efforts should be ongoing to enhance research participants' understanding and appreciation of their role in the research.

Options for Additional Safeguards. A sliding scale involving assessment of risks, benefits, and capacity to consent should guide the IRB's decisions regarding additional safeguards. Many strategies are available as options for investigators as they develop their research protocols and for IRB members as they evaluate them. In considering increasing levels of risk and/or impairment, investigators should be creative in choosing appropriate protections, seeking strategies used successfully in other situations.

• Use of an Independent Monitor. When reviewing greater than minimal risk research involving individuals with questionable capacity to consent, IRBs should discuss and document the potential value of an independent monitor. A monitor can be appointed to be present when investigators invite individuals with impaired decisionmaking capacity to participate in a research study. The consent process should be visible throughout, and IRBs have a right to observe recruitment, assessment, the informed consent process, and debriefing of research participants (and/or their family/surrogates).

• Use of a Surrogate. Where permitted by law, individuals with impaired capacity may have a family member or other legally authorized representative serve as a surrogate for research decisions, with this role documented during the consent process. Surrogates should be informed of the risks, benefits, and alternatives to the research when they are providing permission for an individual to participate. Whenever possible, surrogates should make research decisions based on substituted judgment, reflecting the views of the individual expressed while decisionally capable. Best interest standards should be used if the values of the individual are not known. It is important that surrogates receive some education about their own role, the cognitive and health status of the research participant, as well as about the study in which the participant may be involved.

• Use of Assent in Addition to Surrogate Permission. The autonomy of individuals with impaired decisionmaking capacity should be respected. Their assent to participation in research should be obtained whenever possible and their decision to withdraw from a study at any time should be honored.

• Use of an Advance Directive. Where State or other applicable law permits, use of an advance directive for research may be considered.

• Use of Informational/Educational Techniques. Because informed consent is an ongoing process throughout the course of the protocol, assessing and enhancing comprehension at each stage is essential. Single sheet summaries of important information about key elements of a study may be useful when provided on a regular basis. Questions from potential participants and family members should be encouraged, and handouts of frequently asked questions and answers regarding specific human subject protections can be prepared. Model consent forms and procedures can be developed. Communication between members of the research team and participants and their families is key to successful research participation.

• Use of Waiting Periods. Individuals who are decisionally impaired may need more time to consider the information they are given about a research protocol. Information should be provided incrementally to facilitate understanding. Planning built-in waiting periods within the consent process also may be useful to allow potential participants time to consult with family members about whether or not to participate.

In conclusion, in all human research, varied degrees of research risk and decisional impairment call for varied levels of scrutiny and safeguards; additional protections (e.g., involvement of family surrogates where State or other applicable law permits and independent monitoring) may be highly advisable in certain circumstances. But treating all individuals who have cognitive deficits as incapable of understanding research is inaccurate and disrespectful of their autonomy. Many individuals, adequately informed, may be willing to undertake certain risks so that they, or others, may benefit in the future. Researchers and IRBs must strive for a balance that maximizes potential benefits and opportunities, recognizes and extends individual autonomy, and minimizes risks associated with scientific inquiry.

ADDENDUM: The National Bioethics Advisory Commission (NBAC) has addressed related issues and published a comprehensive report: Research Involving Persons with Mental Disorders that May Affect Decisionmaking Capacity. The full text of this report can be found on the NBAC web site.

The NIH Points to Consider document is generally consistent with the NBAC report, but is intended to provide practical guidance now for investigators and Institutional Review Boards (IRBs) working in these fields.

1. Legally effective refers to informed consent as specified in 45 CFR Part 46 and to applicable state and local law and regulation.

2. Human Subject Protection Regulations [45 CFR 46.109(b), 46.111(b) and 46.116]

3. When some or all of the subjects are likely to be vulnerable to coercion or undue influence, including those with cognitive limitations, the IRB must be sure that additional safeguards have been included in the study to protect the rights and welfare of these subjects {45 CFR 46.111 (b); 21 CFR56.111 (b)}.

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