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

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.

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.

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FDA regulations include certain criteria for “exemption” from the IND requirement, including

For marketed (approved) drugs

• The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug.
• If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product

Bioavailability/Bioequivalence Studies

• The drug must not be a new chemical entity
• The drug must not be radioactively labeled or cytotoxic
• The dosing for both the investigational and reference drug must follow the approved drug label for the reference product

Radioactive or Cold Isotopes

• The product is only used for basic research
• The dose studied is not known to cause pharmacological effects in humans

Whether an investigational product qualifies for an IND exemption also takes risk into consideration.  FDA provides the requirements at 21 CFR 312.2(b)(1)(iii) which states:

“The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.”

The risk assessment is based on the known risks from the label indication, route, dose, and timing. The IRB uses the US Package Insert (USPI) as its primary source for determining if the proposed use qualifies for an IND exemption. When assessing whether off-label use (i.e. outside of FDA approved USPI indications) of a drug d constitutes a “significant increase in risk”, the IRB is tasked with answering two questions:

• Does the research use of the drug increase known risks or raise the potential for unknown risks significantly?
• Does the research use of the drug adversely affect the relationship of risks and potential benefits compared to approved uses of the drug such that the risks are less acceptable?

The use of a new route of administration or dosage level may immediately confer unknown risks to a degree that the risks are significant or lessen the acceptability of the risks. Substantially different patient populations from those in the indication may also confer additional, significant known risks or increase the chance for unknown risks significantly.

In order for the IRB to better assess the risks, decreasing the unknown factor is valuable. Providing literature documenting the risks of use or similar information can support a request for IND exemption. Similarly, addressing the differences between the USPI approved population and those to be studied and how the risks and acceptability of the risks are addressed is necessary. Claims based on current standards alone without addressing the risks and acceptability of risks is a reasonable clinical approach but does not address the regulatory requirements.

Therefore, when submitting a proposal for a drug study to the IRB, requesting and exemption from the requirement to obtain an IND, the protocol should provide a clear analysis of risk in the context of FDA regulations:  “The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.”

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Despite common parlance, “minimal risk” has a definition in the regulations. The FDA defines “minimal risk” broadly for us in 21 CFR 50.3(k):

            “Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”

This means that the risks of the research are those that a healthy person could expect to encounter at routine clinical visits. 

Examples of procedures that are generally considered to meet the minimal risk threshold include:

• Blood sampling from a vein or indwelling line (in children, the blood volume must be less than a limit based on total blood volume)
• MRI without contrast and without sedation
•  “Surface” (external only) imaging, without the use of contrast agents
• Placement of a peripheral venous line for less than 24 hours

Examples of procedures that are not considered to be minimal risk include:

• Administration of virtually any investigative drug or biologic, even if the product is approved for the indication being studied or for other indications and is known to have a generally mild safety profile and adverse events are rare. 
• A clinical investigation of a device that involves invasive sampling
• MRI with contrast and/or sedation 

In the IRB review process, the assessment of whether a submission is categorized as “minimal risk” in accordance with the regulatory definition is important because it impacts how the research may be reviewed. Any research that is more than minimal risk or that is minimal risk but does not fall into the expedited categories defined by the federal regulations, must be reviewed by the convened IRB.

However, minimal risk research that does fall into one or more of the expedited categories may be reviewed through a different pathway. The IRB regulations permit, but do not require, an IRB to review certain categories of research through an expedited procedure if the research involves no more than minimal risk and falls into at least one of the expedited categories defined by the federal regulations. The “expedited review pathway” involves review of the research by the IRB chairperson (or by one or more experienced reviewers designated by the chairperson) from among members of the IRB in accordance with the requirements set forth in 45 CFR 46.110.   These reviews often take less time because the review does not need to be conducted at a scheduled IRB meeting. The expedited reviewer can make the decisions to approve or to conditionally approve a submission, but if they have questions that cannot be resolved to get to one of these outcomes, the submission must be escalated to the full board for review at a convened meeting. 

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