Navigating Ethical Challenges: Research with Adults Lacking Capacity to Consent

Introduction

The inclusion of adults lacking capacity to consent to participation in research is critical to ensuring equitable representation and access to developing medical interventions, but it requires careful examination by stakeholders involved in the research. Considerations should include both the ethical component of the inclusion, as well as the scientific necessity. Research stakeholders include regulatory agencies, clinical research sponsors, the institutional review board (IRB), the research team directly interacting with participants, the participants, and participant caregivers. Here we provide the IRB’s perspective, including the ethical and regulatory framework for the inclusion of adults lacking capacity to consent in clinical research, and highlight solutions for common issues WCG’s IRB has found when reviewing protocols that include adults lacking capacity to consent.

Regulatory Framework

The concept that some populations require additional consideration is established by the Respect for Persons principle of the Belmont Report. This principle incorporates at least two ethical convictions. First, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.¹ The Belmont Report provides further explanation of diminished capacity as individuals who have lost “capacity wholly or in part because of illness, mental disability.” While the term “diminished capacity” does not appear in Food and Drug Administration (FDA) or Office for Human Research Protections (OHRP) regulations, the rules provide protections for this population.

The FDA regulations 21 CR 56.111 and 45 CRF 46.111 set forth the criteria for IRB approval of research, including a requirement that the selection of subjects is equitable. With this requirement, the IRB is expected to “be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons.”^2,3 Furthermore, FDA regulations stipulate that “when some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence additional safeguards have been included in the study to protect the rights and welfare of these subjects.”³ Notably, the Revised Common Rule does not include pregnant women as vulnerable subjects.

While regulations provide specific criteria that the IRB must consider for the inclusion of some vulnerable populations, such as children and prisoners, there is not a comparable regulatory framework for individuals lacking capacity to consent. Therefore, the IRB must rely on guidance provided by OHRP and the FDA, as well as the IRB’s own policies and procedures. OHRP guidance requires that the IRB (and investigators) “be knowledgeable about the condition and any level of impairment that is likely to be present in the subject population.”⁴

A 2023 FDA guidance included recognition that impaired capacity to consent may involve partial or complete impairment and may vary over time.⁵ This guidance also recommends the consideration of safeguards, such as independent assessment of capacity to consent, tools for an enhanced consenting process, re-assessment of capacity, and utilization of an assenting process. However, before the IRB can apply this guidance, the IRB must first determine if the research will include, and is ethically appropriate for, adults lacking capacity to consent.

IRB Considerations for Including Adults Lacking Capacity to Consent

The IRB uses the applicable regulatory framework, i.e., the FDA and/or OHRP and their corresponding regulations and guidance, along with the IRB’s own policies and procedures, to make the determinations. As regulations do not provide specific criteria that must be met for the inclusion of adults lacking capacity to consent, IRBs rely on internal policies and procedures to guide their deliberations.

Eligibility Criteria

WCG’s IRB relies on the eligibility criteria in the written protocol to determine if vulnerable populations, including adults lacking capacity to consent, will be selected for the research. The inclusion and exclusion criteria should clearly dictate a requirement for informed consent, which can include a criterion requiring that the participant is “able and willing to provide informed consent.” This language would allow the IRB to determine that adults lacking capacity to consent are not the intended population for this research. Alternatively, a statement such as “the participant or their legally authorized representative provides informed consent” would be interpreted by the IRB to mean that adults lacking capacity to consent will be recruited for the study. For protocols which provide a straightforward position on the inclusion of adults lacking capacity to consent, the IRB proceeds with ethical considerations.

Risk Assessment and Ethical Considerations

As with all research, the IRB considers the risk of the research and categorizes the research as minimal risk or greater than minimal risk. For most minimal risk research, the inclusion of adults lacking capacity to consent is not problematic. For research determined to be greater than minimal risk, IRB considerations include the potential benefit of the research and the necessity to conduct the research in a cognitively impaired population.

If there is potential of direct benefit, the IRB will evaluate whether it is equitable to include individuals lacking capacity to consent, either by scientific necessity or by the potential benefit being at least equal to the benefit offered by other therapies and the prevalence of adults with diminished capacity in the overall population being studied and the importance of the knowledge gained. For example, an investigational treatment may offer benefit to people with cancer who have failed or did not tolerate first- or second-line treatments, as these individuals may be facing a decision between no treatment or other anticancer therapies that have not been shown to have efficacy in that population.

If there is no potential of direct benefit, the IRB will evaluate if the research can be conducted without including this population or if the condition being studied is specific to a population in which most or all individuals may be lacking capacity to consent. The IRB will also assess the level of foreseeable risk and whether there are safeguards to protect the participant’s well-being.

If the research does not offer the potential for direct benefit to the participant, such as in healthy volunteer or human challenge studies, and the objectives can be achieved without including adults lacking capacity to consent, it is generally not acceptable to enroll this population.

If the research must initially enroll individuals with diminished capacity to consent, the IRB may consider if the population includes different levels of impairment and how it relates to the objective of the research and the potential benefit of the research. This combination of information helps assess criteria for approval and for the most appropriate population. For example, a study of an investigational drug for the treatment of Alzheimer’s disease may reasonably require the enrollment of individuals with cognitive impairment ranging from mild to severe with several considerations. Enrollment of people with moderate to severe cognitive impairment, with adequate provisions for soliciting the permission of their legally authorized representative, may reasonably be considered scientifically necessary and provide participants with direct benefit. However, individuals with mild cognitive impairment, capable of providing their own consent, should have their autonomy honored regardless of whether a caregiver may need to assist with study assessments such as quality of life questionnaires.

Evaluating Benefits

When considering potential benefit, the IRB can also consider if the potential benefit offered by the research is only available via the research. A common example of this is a compassionate use or expanded access protocol. Benefit is also not strictly related to increasing overall survival, as an investigation of an oral version of a treatment may have benefit in quality-of-life areas compared to an intravenous version of a treatment.

These considerations for the inclusion of adults lacking capacity to consent comprise the policy followed by WCG’S IRB and are described in greater detail in “Adult Lacking Capacity to Give Consent,” authored by WCG’S IRB leadership.⁶

Assent Process

Once it is established that the research will include adults lacking capacity to consent, an adult who lacks capacity to consent may be capable of participating in the consenting process and consideration of this is an important aspect of respecting autonomy. The FDA guidance recognizes that the participant may “be able to provide some form of oral agreement at the outset of the study and, as appropriate, throughout the course of the research.” This type of agreement is often referred to as assent and can incorporate a variety of indicators of agreement, including non-verbal communications, such as a head nod or a thumbs up.⁷

Although not required by regulation, if the IRB determines that assent should be obtained, a best practice is to document the assent process. Some IRBs, including WCG’s IRB , will include instructions on the consent form with the IRB’s expectations for documenting the discussion. The IRB’s determination for assent documentation should reflect an understanding that participants may have different levels of capacity to provide assent as well as varying physical abilities to document assent. While the IRB will provide direction on when assent should be attempted, it is the responsibility of the research staff who are directly interacting with the individual to determine the individual’s capacity to provide assent. The IRB’s decision should recognize that the research staff interacting with potential participants will need to make an independent decision for each individual. A frequently used option is to include a signature section on the consent form which allows the research staff member who conducted the assent discussion to document the process. This method respects the autonomy of participants, while providing flexibility for the researcher to document what level of assent the individual was able to provide. Documentation of assent can also occur by the participant signing the consent or assent form as an indication of their agreement to take part in the study. When the participant is asked to sign their agreement, it is preferable to use the consent form with a separate assent signature section as the sole documentation source for the research. However, this decision is nuanced and study-specific, and there may be studies for which documentation of assent on the assent form is the logical decision. The assent process and documentation instructions are the IRB’s minimum requirements for assent. Should the sponsor describe measures beyond that in the protocol, they will have also been reviewed by the IRB.

Providing Justification for Including Adults Lacking Capacity to Consent

Although the IRB is open to including individuals who lack capacity to consent in clinical trials, there are several scenarios in which the IRB does not have enough information to make ethical considerations.

When protocols are submitted for IRB review without adequate sponsor rationale, the board must ask for additional justification for the necessity or appropriateness of including adults lacking capacity to consent. These issues and potential strategies are described in Table 1.

Table 1. IRB Concerns and Recommendations for Research Involving Participants Lacking Capacity to Consent

IRB Concern	Example	IRB Concern Example Information to Include for IRB Consideration
Protocol with vague eligibility criteria.	Eligibility criteria written as “informed consent must be obtained” does not state who provides the informed consent.	Clearly define from whom informed consent will be obtained because the IRB considers the eligibility criteria to be the final determinate of the intended study population.
Eligibility criteria that are inconsistent with other information in the protocol.	Eligibility criteria require informed consent given by the participant, but other sections of the protocol reference legally authorized representatives.	Align language in all sections of the protocol with the requirements in the eligibility criteria.
Research procedures or requirements that increase the participant’s burden of care or impact ability to complete the protocol.	Research procedures include additional exploratory imaging or tests, especially if the research is determined to be greater than minimal risk. Participants are required to complete research-specific questionnaires.	Provide a rationale for the necessity of additional procedures or visits and any allowances for which procedures may be optional. Consider the use of proxy questionnaires. Assess understanding of research procedures during the assent process.
First-in-human research.	This includes Phase I or dose-finding studies.	Provide a strong justification stating why inclusion would be medically or scientifically necessary (e.g., rare disease, limited effective treatment options). Justify the potential benefit compared to available alternatives and how any research procedure risks are outweighed by this potential benefit.
Existing treatments for the condition being studied.	Research for conditions with existing symptom maintenance products or enrollment of treatment-naïve participants.	Provide a strong justification stating why inclusion would be medically or scientifically necessary. Compare the new product and anticipated benefits and risks to those of the existing, approved product or product with a similar mechanism of action. Include any risk mitigation that has been established to minimize risk to participants. Compare expected benefits of study treatment to alternatives (e.g., expected to have fewer side effects or have qu ality-of-life benefits related to administration route).
Anticipated benefits compared to anticipated risks do not appear to be favorable.	The study design involves a placebo-controlled arm.	Create an open label extension phase where participants who were in the placebo arm have an opportunity to receive the study treatment. Allow participants to continue their background maintenance or supportive medications. Describe a proactive rescue medication plan. Include only a study population that has exhausted or did not tolerate standard methods of treatment.

Conclusion

Respect for persons requires protection of individuals with diminished autonomy, including adults who lack capacity to consent. However, excluding adults who lack capacity to consent from a research population where they would otherwise be able to receive potential benefits or contribute valuable knowledge may also pose a justice issue. The IRB is responsible for assessing the risks and benefits specific to individuals who lack capacity to consent when determining whether it is appropriate for them to participate in the research. From an IRB perspective, the most common barriers to allowing individuals who lack capacity to consent to participate in research can be resolved by providing more background information and emphasizing aspects of study design that minimize risk.

Do you have additional IRB questions for WCG’s experts? Our team is at the ready to provide you the guidance to advance your study. Connect with us today by completing the form below.

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References

1. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979). The Belmont Report: Ethical principles and guidelines for the protection of human subjects of research. Washington, DC: U.S. Government Printing Office.
2. Code of Federal regulations Title 21 56.111 https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-56/subpart-C/section-56.111.
3. Code of Federal regulations Title 45 46.114 https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46/subpart-A/section-46.111.
4. Informed Consent FAQs- https://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/informed-consent/index.html.
5. Informed Consent – Guidance for IRBs, Clinical Investigators, and Sponsors, August 2023 https://www.fda.gov/media/88915/download.
6. Forster DG, Borasky DA Jr. Adults Lacking Capacity to Give Consent: When Is It Acceptable to Include Them in Research? Ther Innov Regul Sci. 2018 May;52(3):275–9. doi: 10.1177/2168479018770658. Epub 2018 May 3. PMCID: PMC5944077. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944077/.
7. What Is Assent, When Provided by an Adult Participant Lacking Capacity? And What Are WCG’s Expectations and the Investigator’s Responsibilities? | WCG.