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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What Does E-consent Mean to the IRB?

Electronic consent can refer to the process by which a participant’s signature is obtained and documented electronically, and it can also refer to other aspects of the informed consent process. E-consent can describe the exact representation of the IRB-approved document on an electronic device as well as refer to a consent process using electronic devices and audio-visual aids. The Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) and the Food and Drug Administration (FDA) have issued a joint guidance titled Use of Electronic Informed Consent in Clinical Investigations – Questions and Answers.

Is an E-signature Different from E-consent?

Yes, but often the terms are used interchangeably which can lead to confusion. E-signature is specific to the documentation of consent while e-consent refers to the process of consent which includes technology and can support or replace a face-to-face, wet-ink signature process. In the draft guidance, “Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations Questions and Answers,” the FDA defines e-signature as “a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.” FDA does not define e-consent.

Is E-consent Different from Remote Consent?

E-consent can be used as part of a remote consent process, but remote consent does not necessitate that e-consent is utilized. For example, informed consent obtained via a telephone conversation with a paper copy of the signed consent mailed to the research site would be an example of remote consent that is not e-consent.

Does E-consent or Remote Consent Require IRB Review and Approval?

Yes. The consent process and any modification to the prior approved consent process must be submitted to the IRB for review and approval. Additionally, the IRB must review and approve the e-consent materials (including consent language) and any modifications to the e-consent materials that the participant will view or receive. The IRB must also review any e-consenting tools used in conjunction with a paper or e-consent, such as questions or methods used to gauge participant comprehension of key study elements. If an approved static consent form will not be altered, but will be uploaded to an electronic platform, the document does not need to be submitted as an e-consent. However, if additional technology is used to obtain consent when a static consent form is used, the process is considered e-consent, and how e-consent will be utilized in this scenario must be reviewed by the IRB.

WCG IRB’s specific requirements for review of e-consent can be found on page 24 of the WCG IRB Guide for Researchers. When WCG IRB approves a remote or e-consent process that is not part of a protocol or a separately submitted document, it is documented on Certificate of Action as “Alternative Consent Process approved.”

Does the IRB Consider Compliance with 21 CFR 11 (part 11)?

If the research is FDA-regulated and the submission indicates that the consent signature will be obtained and documented electronically, the IRB will ask the submitter to confirm that the system used to generate electronic signatures is compliant with 21 CFR Part 11. Part 11 does not apply to wet ink signatures that are uploaded to an electronic system. Part 11 compliance is also not required if a wet-ink signature is scanned and uploaded by the participant and transmitted via email or fax to the investigative site.

Do All Consent Requirements Still Apply?

Yes, all elements of consent required by 21 CFR 50.25 and 45 CFR 46.116 must be present in e-consent forms. When implementing an e-consent process that is remote or asynchronous, special consideration should be paid to the availability of the research team for questions. Additionally, the process should ensure that the participant receives a copy of the consent document. FDA guidance recommends that the consent form provided to the participant is a signed copy which includes the date of the signature.

What About E-consent for Non-FDA Regulated Research?

The consent process and any modification to the consent process must be submitted to the IRB for review and approval. If the research is not subject to FDA regulation, the Part 11 requirements do not apply to the e-signature. In addition, for research that meets the requirements, a waiver of documentation of consent by the IRB would make signatures not required. Furthermore, in “Use of Electronic Informed Consent Questions and Answers,” the HHS has provided the following guidance:

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As decentralized clinical trials (DCTs) become more common, what are the IRB’s requirements for submitting research locations?
– Director, Regulatory Affairs, CRO

Answer:

If the protocol is designed as a decentralized clinical trial or a hybrid decentralized clinical trial, some or all research activities may occur at locations that are not traditional clinical trial sites. For example, a local healthcare provider clinic, a mobile unit, or the participant’s house may serve as the location for some research activities.  

The FDA draft guidance, Decentralized Clinical Trials for Drugs, Biological Products, and Devices -Guidance for Industry, Investigators and Other Stakeholders – (May 2023), references the FDA Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs Frequently Asked Questions – Statement of Investigator  (Form FDA 1572) (2010). That guidance notes the definition of sub investigators to be individuals who make a direct and significant contribution to the study data. Locations of sub investigators activities would be expected to be submitted.

Moreover, WCG’s IRB applies the Common Rule for this consideration to all research regardless of funding and requires a location to be submitted to the IRB if the location is “engaged in research”. Determining if a location is engaged in research can be complex and is specific to the individual study.

Utilizing OHRP’s Guidance, “Engagement of Institutions in Human Subjects Research,” WCG’s IRB considers locations with personnel conducting the following activities to be considered engaged in research. However, please be aware that there are several exceptions to this list, and these exceptions are listed in the next paragraph.

• Intervention for research purposes with any human subjects of the research by performing invasive or noninvasive procedures.
• Intervention for research purposes with any human subject of the research by manipulating the environment.
• Interaction for research purposes with any human subject of the research.
• Obtaining informed consent of human subjects for the research.
• Obtaining, for research purposes, identifiable private information or identifiable biological samples.

Exceptions

When looking at the engagement of a location, there are exceptions to the above, including consideration of activities that may be included in routine monitoring of an individual’s healthcare. Noted exceptions in which a location would not be considered engaged in research include:

• Personnel perform only commercial or other services that are normally performed for non-research purposes; they do not merit professional recognition or publication privileges; and they do not administer the study intervention being evaluated.
• Personnel provide clinical trial-related medical services that are dictated by the protocol and would typically be performed as part of routine clinical monitoring and/or follow-up of subjects. Examples of these activities include medical history, physical examination, assessment of adverse events, blood test, chest X-ray, or CT scan. Where the:
  • Personnel at the location do not administer the study interventions being tested or evaluated under the protocol.
• • Clinical trial-related medical services are typically provided by the location for clinical purposes.
  • Personnel do not enroll participants or obtain the informed consent of any subject for participation in the research.
• Personnel administer study interventions on a one-time or short-term basis in the participant’s best interest; they do not obtain consent; another institution maintains oversight; and the IRB is informed.
• Personnel just inform potential participants about the research and permission to contact them and do not obtain consent.
• The institution only allows use of their facility by personnel from another institution.
• Personnel only release information to another institution.
• Personnel who author a paper, journal article or presentation describing a human subjects research study.

There are several additional exceptions which are related to the use of identifiable information and coded information. Please refer to the above referenced OHRP guidance for the specific requirements of those exceptions.

If the location is not engaged in research, WCG’s IRB does not require the location to be submitted as a research site.

If telehealth visits will be conducted or other digital health technologies will be used, the address of the healthcare clinic or office used by the research staff when conducting the research activities should be submitted as the research location. The address of the participant’s home does not need to be submitted to the IRB.

If mobile units will be used, the address of the affiliated engaged research location can be submitted as the research location. The location where the mobile unit is temporarily located would not be a research location.

Refer to the FDA draft guidance for Decentralized Clinical Trials for Drugs, Biological Products, and Devices -Guidance for Industry, Investigators and Other Stakeholders – (May 2023) and the FDA Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs Frequently Asked Questions – Statement of Investigator (Form FDA 1572) (2010) for more information.

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The earliest phases of research often require the participation of healthy individuals, and this population can be difficult to reach. Additionally, some studies require more targeted patients due to the nature of the study population and this can make it difficult to identify and reach appropriate individuals who may qualify for the research. Often, the best person to encourage others to participate in research studies is someone who has had a positive experience as a research participant them self. Therefore, one of the recruitment strategies frequently employed to overcome recruitment hurdles is called patient-to-patient referral.

Patient-to-Patient Referral Programs

“Patient-to-patient” referral programs – which often refer to healthy volunteers rather than patients with a disease or condition – are generally designed to motivate someone who has had experience with being a research participant to reach out to their friends, family members, and other personal contacts. The experienced participant encourages others to either consider enrolling in a specific clinical study, or to consider research participation in general. To persuade them toward this outreach effort, researchers or research facilities provide a monetary reward to the referring person, usually for each contact who contacts the site about participation in a study. Many referral programs, especially for healthy volunteer research, are not for specific studies, but rather encourage others to join a database from which future studies can be recruited.

One specific type of patient-to-patient referral program is ”snowball sampling”, which is a non-probability sampling method in which a participant in the research study is asked to help recruit other participants by relaying information about the study to peers they know who are in the group being studied; for example, other people who are community leaders, other people living with long-term HIV, or other families where someone has a specific rare disease. Snowball sampling is frequently used in qualitative research, when the researchers are seeking a group with very specific characteristics, and when people within that group are likely to know others within the group. Study populations obtained through snowball sampling techniques cannot be considered a random or representative sample of the population, so it is not appropriate for certain types of research and researchers must be aware of the potential for selection bias and the possible impact that may have on study conclusions. Snowball sampling would not be used for clinical trials for this reason, but may be used in observational biomedical research, such as when doing surveys of patients.

IRB Oversight of Patient-to-Patient Referral Programs

Any recruitment plans including potential participant referral programs must be submitted to the Institutional Review Board (IRB) in advance of beginning them, whether they are initiated at the start of the study or added later after the study has already begun. Any written materials, such as brochures prepared for current participants to distribute to others, content for them to share or post online, or scripts for them to use, must also be submitted to and approved by the IRB.

Benefits of Patient-to-Patient Referral Programs

Patient-to-patient recruitment can be particularly effective for harder to reach populations, or to reach a population with uncommon characteristics.

The potential recruitment benefits of the strategy include:

• Participants are generally more apt to trust close, personal peers rather than individuals they do not know. The referring party can provide direct, trusted knowledge to the potential participant. The referring party can describe their experience and expand on information not directly discussed during the consent process. This may include realistic expectations regarding the necessary time commitment and experiences related to the specific research. Examples of this include commuting time, parking availability, and office wait times.
• One participant may have relationships with several qualified individuals. For example, if the research involves a rare disease, a person involved with an advocacy group can provide information to the entire group via one social media post or discussion at an annual meeting.
• Participants can outreach to individuals who may not have the same access to information. Individuals frequently have access to different information compared to other people in their network, based on their socio-economic status, hobbies and interests, as well as access to healthcare providers. Patient referrals provide an opportunity to reach potential participants who may be missed by traditional recruitment campaigns.

Concerns

While patient referral methods can create new recruitment opportunities and the methods are not inherently problematic, they do raise some potential issues that need to be considered prior to setting up the program.

• Patient referrals may create a bias in the research due to having more similar participants than may naturally occur otherwise. Personal networks tend to be more analogous to the individual in terms of race, socioeconomic status, geographic location, etc., and patient referrals could bias the research by oversampling a particular group. Most research studies will have a limit to how many participants will be enrolled, and the use of patient referrals may lead to a situation where more similar participants are enrolled than may be the case without patient referrals. Even if this doesn’t bias the study, it could distort the results and/or limit the applicability as there is not a more representative cross section of the population being enrolled into the research. Of course, if the goal of the referral program is specifically to enrich the study population for a certain type of participant, this may not be a concern.
• Research sites may want to have processes to handle situations where the referring party knowingly refers unqualified participants simply to increase their payment. Programs sometimes try to manage this by paying for referrals only if the referred person is eligible for and agrees to enroll in the study. However, this is not an appropriate control since the referring participant cannot control whether someone else meets all study eligibility. Paying a participant only if their referral agrees to be in the study can cause incentive for the participant to unduly influence the referred party to agree to participate. or to encourage them to lie about their eligibility for the study. It would be acceptable for the research site to put some restrictions on the referral program, which could include a prescreening process to evaluate basic eligibility requirements such as appropriate age and condition, and restrictions on concurrent research participation. The site could also limit the number of referrals provided by each referring party. As many of these programs are used due to low recruitment or to increase pre-screening databases, this may not be an overly burdensome issue.
• Patient referral programs may include the possibility of coercion. Coercion is the act of persuading someone to do something, by threats or influence. For example, relationships between the referring party and the potential participant may include a power imbalance, where the potential participant is more likely to join the study or to stay in a study they would have otherwise withdrawn from simply so that the referring party gets paid.

Setting Up a Patient-to-Patient Recruitment Program

A well-designed patient-to-patient referral program should include:

• Payment to the referring party based on the referral, without requiring the potential participant to meet certain milestones such as randomization, length of participation, or completion of the study.
• Specificity about when the payment will be made. For example, the program may require that the referring party receives payment after the potential participant sets up an appointment, or completes a screening visit, but the payment should not be contingent on actual enrollment or randomization of the potential participant in the study.
• Payment in an amount that is unlikely to provide an incentive for the referring party to pressure the potential participant to enroll in or stay in the research.

Individuals tend to trust the people they know and are more likely to do something if the suggestion comes from a family member, a friend, colleague, or even an acquaintance. Because of this, patient referral practices can be extremely effective. Patient referral programs have the potential to increase enrollment into research studies by allowing trusted individuals to share their knowledge and experiences with their friends and family members. Ideally, these strategies reach individuals who may not otherwise be aware of the research or may be hesitant to participate. When designing these programs, research sites should be aware of the factors that may create the potential for coercion or undue influence, bias the participant pool, or create a drain on staff resources.

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