Ethical and Regulatory Issues for Embedded Pragmatic Trials Involving People Living With Dementia

Abstract

Embedded pragmatic clinical trials (ePCTs) present an opportunity to improve care for people living with dementia (PLWD) and their care partners but also generate a complex constellation of ethical and regulatory challenges. These challenges begin with participant identification. Interventions may be delivered in ways that make it difficult to identify who is a human subject and therefore who needs ethical and regulatory protections. The need for informed consent, a core human subjects protection, must be considered but can be in tension with the goals of pragmatic research design. Thus, it is essential to consider whether a waiver or alteration of informed consent is justifiable. If informed consent is needed, there is the question of how it should be obtained, as researchers must acknowledge the vulnerability of PLWD due in part to diminished capacity and also to increased dependence on others. Further, researchers should recognize that many sites where ePCTs are conducted will be unfamiliar with human subjects research regulations and ethics. In this report, the Regulation and Ethics Core of the National Institute on Aging (NIA) Imbedded Pragmatic Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) Clinical Trials (IMPACT) Collaboratory discusses key ethical and regulatory challenges for ePCTs in PLWD. A central thesis is that researchers should strive to anticipate and address these challenges early in the design of their ePCTs, as a means both of ensuring compliance and of advancing science.

Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) affect over 5 million individuals in the United States.¹ People living with dementia (PLWD) commonly experience fragmented, poor quality, and high-cost care that fails to address their needs and those of their care partners. At present, there is a paucity of evidence to support the adoption of effective interventions and services into health care systems that improve the well-being of PLWD and their care partners.

The National Institute on Aging (NIA) Imbedded Pragmatic AD/ADRD Clinical Trials (IMPACT) Collaboratory aims to remedy this evidentiary gap by building the nation’s capacity to conduct embedded pragmatic clinical trials (ePCTs) to benefit PLWD and their care partners in the health care systems that serve them. The Regulation and Ethics Core supports this mission through promulgation of guidance, best practices, and training materials for the research community. In doing this, we are building on work done by others—including the National Institutes of Health Health Care Systems Research Collaboratory—and extending it to PLWD.^2,3 Additionally, our Core provides consultation for IMPACT Collaboratory pilot-grant applicants and recipients as well as for early-stage investigators who receive IMPACT Collaboratory career development awards.

Central to our Core’s guidance, training, and consultation activities is the fact that ePCTs in PLWD generate a complex constellation of ethical and regulatory challenges. These challenges begin with participant identification. Interventions may be delivered in ways that make it difficult to identify who meets the regulatory definition of human subject and therefore needs protections. Because ePCTs seek to evaluate interventions in actual clinical practice, research-related informed consent, a core human subjects protection, can sometimes conflict with a pragmatic study’s goals and conduct. In such cases it is essential to consider whether the ePCT qualifies for a waiver or alteration of informed consent. If it does not and informed consent is required, researchers must then design a consent process that acknowledges the vulnerability of PLWD—due in part to diminished capacity and also to increased dependence on others. Finally, researchers should recognize that many ePCT study sites will be unfamiliar with research regulations and ethics frameworks. By highlighting these considerations, the Regulation and Ethics Core aims to illuminate how the features of an ePCT interdigitate with human subjects protections.

In this report, we discuss ethical and regulatory challenges in ePCTs for AD/ADRD populations (see Table 1). Our overarching thesis is that researchers should anticipate and address these challenges early in the design of their ePCTs. This will ensure that ePCTs for PLWD reflect ethical reasoning and comply with relevant regulations. Moreover, early attention to these challenges can advance the pragmatic nature of a study and make the research more efficient.

Table 1.

IMPACT Collaboratory Regulation and Ethics Core Research Agenda

Topic	Description	Challenge	Our Plan
Research/care distinction	Existing regulatory and ethical frameworks are grounded in a distinction between medical research and medical care.	ePCTs are specifically designed to blur or erase the research/care distinction, making existing frameworks less suitable or inapplicable.	Articulate regulatory and ethical frameworks that are tailored to guide the practice of ePCTs for PLWD.
Subject identification	Appropriate human subject protections require applying regulatory criteria for human subjects.	ePCTs for PLWD will often employ designs (e.g., cluster randomization) that affect many people, and it may not always be clear who meets the regulatory definition of human subject.	Develop guidance to help researchers identify who the human subjects are.
Informed consent	Collecting written informed consent is the primary mechanism of demonstrating respect for all research subjects.	Decision-making capacity of PLWD may be impaired; traditional informed consent can make the study population less representative or can make the conduct of the study logistically impossible, potentially frustrating the aims of ePCTs.	Clarify how the regulatory and ethical conditions for adopting waivers or modification of informed consent should be applied to ePCTs with PLWD.
Conflicts of interest	Minimizing risk and ensuring research integrity demands strict, comprehensive conflict of interest policies.	Researchers may have financial interests in their interventions.	Develop policies to help manage conflicts of interest, without stifling scientific incentives.
Regulatory compliance for new research settings	Multiple laws and complex regulatory frameworks exist to protect the rights and welfare of participants.	ePCTs for PLWD may involve care settings (e.g., nursing homes) that are not accustomed to research and lack dedicated staff/experts to navigate the regulatory environment.	Develop guidance, training, and checklist materials to help study sites that are new to research understand the relevant regulations.

Blurring the research/care distinction

A sharp conceptual distinction between research and care has been central to the development of research ethics and regulations.^4,5 Yet, ePCTs are specifically designed to produce generalizable knowledge from contexts that are as close as possible to the conditions of usual care, and therefore they blur the research/care distinction. The well-recognized Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2) and Readiness Assessment for Pragmatic Trials (RAPT) tools allow researchers and institutional review boards (IRBs) to score the level of pragmatism in a research protocol.^6,7 Features of a trial, such as delivery of the intervention, are “very pragmatic” if they are “identical” to or as “flexible” as usual care. An ePCT with very pragmatic features promises evidence with higher external validity and can therefore be of higher value to health care systems. Unfortunately, there is not yet consensus that existing research ethics frameworks and regulatory structures—particularly with respect to participant identification and informed consent—are sufficiently flexible to appropriately guide the design and conduct of ePCTs.⁸ Attention to this difficulty has recently increased, and ethical and regulatory aspects of pragmatic trial design continue to evolve.^9,10

Participant identification

It is critical, albeit not always straightforward, to identify who is and who is not a participant in an ePCT. This is important because researchers should extend appropriate protections to those who need them and avoid assuming unnecessary ethical and regulatory burdens for those who do not.^11,12

Participant identification involves important regulatory considerations. The Federal Policy for the Protection of Human Subjects (Title 45 Part 46 of the Code of Federal Regulations, known as the “Common Rule”) defines a human subject as “a living individual about whom an investigator … : (i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens” (45 CFR §46.102).¹³ The Common Rule goes on to explain that intervention includes both physical procedures and manipulation of the participant’s environment performed for research purposes, and interaction includes communication or interpersonal contact between the investigator and participant.

Interventions tested in ePCTs with PLWD are typically programmatic or environmental in nature and implemented at the level of the unit of care—such as an entire nursing home or entire adult day program. Random assignment to the intervention or control arm is also typically done at the unit of care or “cluster” level. These design features may complicate the usually straightforward process of identifying participants. For example, imagine that a particular nursing home is randomized to receive a training intervention for the staff and that after the training, the researchers use data from medical records to measure both staff behaviors and patient outcomes. Who are the participants? The patient and staff environments have been manipulated, and the researchers are gathering information. One interpretation is that the participants are not just the PLWD but also the facility staff and possibly other residents coincidentally affected by the intervention.^14,15 A distinct but closely related question, raised below, is whether the facility staff are “engaged in research.”

Waivers and alterations of written informed consent

Informed consent from participants is generally a regulatory and ethical requirement of research.^16,17 Yet, obtaining informed consent can frustrate the pragmatic nature of a trial. A waiver or alteration of informed consent can, under certain conditions, be ethically acceptable.^18,19 The Common Rule also stipulates conditions that, if met, justify a waiver or alteration of consent.

However, in ePCTs that involve PLWD, a waiver or alteration of informed consent presents an ethical dilemma.¹⁸ Individual-level consent is typically obtained by research staff, or in some circumstances by clinical providers, with both approaches potentially undermining the pragmatic nature of a trial. If the ePCT design and informed consent are truly not compatible, the researcher—and ultimately the IRB—must determine if a waiver or alteration is permissible. Investigtaors conducting ePCTs with PLWD have the added responsibility of considering PLWDs’ vulnerability when assessing permissibility, as vulnerability is generally thought to merit more rather than fewer protections. Attention to and understanding of the conditions that justify a waiver or alteration of informed consent from the earliest phases of trial design can facilitate alignment between scientific, practical, ethical, and regulatory considerations in ePCTs with PLWD.

The first step in assessing the need for informed consent is to determine which aspects of the overall study design are research procedures. For example, if the intervention tested in the ePCT is itself considered a part of routine clinical practice and is delivered by usual care providers, it is likely not a research procedure. By contrast, the use of protected health information gathered from medical records to ascertain trial outcomes likely is a research procedure.

The next step to consider is whether some or all of the research procedures may qualify for waivers or alterations of informed consent. The Common Rule lists five criteria that research proposing a waiver or alteration must conform to: (1) the research involves no more than minimal risk to subjects; (2) the research could not practicably be carried out without a waiver or alteration; (3) the research could not practicably be done with de-identified private information; (4) subjects’ rights and welfare will not be adversely affected; and (5) whenever appropriate, the researchers will provide subjects or their legally authorized representatives with information after participation (45 CFR §46.116). All five criteria must be met to waive or alter informed consent. Figure 1 outlines steps to help determine the need for informed consent.

Figure 1:

Logical flowchart for satisfying ethical and regulatory criteria for waivers or alterations of informed consent. These criteria are stipulated in the U.S. Code of Federal Regulations (45 CFR 46 §116(f)). Abbreviations: CFR = Code of Federal Regulations, LAR = legally authorized representative.

Minimal risk

The Common Rule tasks IRBs with reviewing and assessing risks and benefits that may result from research procedures (45 CFR §46.111). “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” (45 CFR §46.102). There has been considerable debate about how to apply this definition in ePCTs.²⁰

It is unclear what the proper comparator is for making a minimal risk assessment. Whose daily life? For PLWD, the concept of “minimal risk” is particularly fraught. Should the risk assessment account for the high morbidity of AD/ADRD and the poor quality of much existing care? If yes, PLWD could be exposed to significant risks that, paradoxically, would not exceed “minimal risk.” A more sensible baseline is to compare the research risks to risks encountered in the daily lives of persons with comparable impairment who live in safe, high-quality care settings. This “real and ideal world standard” grounds the minimal risk standard in the lives of PLWD with an expectation that they receive appropriate care.

Practicability

How to determine whether research could not practicably be carried out without a waiver or alteration of informed consent is unsettled. Waiver or alteration may be appropriate if requiring consent would compromise the scientific validity of a trial or make it logistically impossible to conduct. For instance, waiver or alteration may be appropriate if participants declining to participate would likely result in a substantially less representative study population, introduce bias, and so frustrate the pragmatic goal of a trial. Practicability should not be determined by considerations of the cost, convenience, or speed of obtaining informed consent.²¹

Respecting subjects’ rights and welfare

A concern in all human subjects research is the potential for dignitary harm if participants are treated as mere means to an end.²² Dignitary harms ought to worry us even more when participants are PLWD, people who due to AD/ADRD progressively surrender privacy and self-control to others. In a private setting, such as one’s own home, the terms of this surrender are personal matters, negotiated between the person with dementia and his or her care partners. This negotiation becomes more challenging in spaces, like nursing homes or adult day programs, where the private and public fuse. Introducing research into spaces where the public and private are so intimately connected may carry dignitary risks to PLWD that merit careful consideration.²³ For example, PLWD who reside in nursing homes have a reasonable expectation of privacy in their bedrooms—even if their bedrooms are also sites of care delivery. Thus, there may be heightened risk of dignitary harm from waiving or altering consent if a research intervention will include manipulation of nursing home residents’ bedrooms.

Engagement with PLWD and their care partners will often be essential to a determination that participants’ rights and welfare will not be adversely affected by a waiver or alteration of informed consent. Participant or care partner engagement in research design (and oversight), though potentially difficult, can provide important insights and help ensure that participants’ values and interests are respected.²⁴

Notification

When appropriate, researchers should provide participants with information about their research participation, including the research findings. This is an opportunity for messaging, communications, and community engagement that builds trust in and identification with the research among PLWD and their care partners, as well as among clinicians and staff members. This can occur through mechanisms such as notices posted in common areas of a long term care facility, newsletters, or letters from the health care system administrators and investigators.

Obtaining informed consent

All five of the Common Rule criteria outlined above must be met to waive or alter informed consent. If an ePCT (or any portion thereof) is not eligible for a waiver or alteration, the Common Rule details how researchers should seek informed consent from those identified as human subjects (45 CFR §46.116).

When research is conducted with PLWD, the consent process must account for participants’ broad spectrum of cognitive impairments. Capacity is a task-specific ability to appreciate the situation and its consequences, understand relevant information, reason about options, and communicate a choice.²⁵ It cannot be assumed that everyone diagnosed with dementia lacks capacity to consent to an ePCT.

Because it is essential that researchers seek consent from PLWD if possible, researchers must have a plan for assessing prospective participants’ capacity to consent.²⁵ Researchers should list out key facts participants must understand about their particular ePCT and use a conversation-based approach to disclose information and also to assess a prospective participant’s ability to understand that information. For example, the researcher may ask the prospective participant to paraphrase the meaning of what was disclosed about the purpose of the ePCT, to explain how participation will or will not benefit her, or how participation in the ePCT will affect her daily life. The researcher’s assesment of the answers—inadequate, marginal, or adequate—will inform the final determination that the prospective participant has the ability to provide his or her own informed consent.

Tests that measure overall cognition, such as the Mini Mental Status Exam (MMSE) or the Montreal Cognitive Assessment (MoCA), may be useful to predict the likelihood a person will have impaired decisional abilities, and so warrants a close assessment of ability, but these tests cannot substitute for an assessment of decisional abilities.²⁶ The scores are not sufficiently predictive of decisional ability, and, even if they are, substituting a test of cognition for a conversation about the research is an affront to a person’s dignity. So too is asking staff if a person can provide his or her own informed consent.

As an aside, capacity testing—particularly in longitudinal studies where consent is ongoing and capacity testing is iterative—may offer insights into declining cognition upsetting to PLWD. This potential harm should be factored into the risk/benefit assessment of the ePCT.

PLWD who lack capacity will often have a legally authorized representative (LAR). The most common approach to obtaining consent for research when the PLWD lacks capacity is to seek surrogate consent from the LAR. Some state and local laws distinguish the ability of an LAR to consent to clinical care from the ability of an LAR to consent to research participation on behalf of the PLWD. Therefore, researchers should understand the laws governing surrogate consent at their study sites.

Surrogate consent does not preclude the participation of PLWD in research-related decision-making, and simply forgoing all conversations with PLWD is a dignitary harm. Two important ways to demonstrate respect for PLWD are to seek their assent and respect their dissent.^27,28 Thus, the recommended approach to obtaining consent for research participation when the PLWD lacks decision-making capacity combines surrogate consent with participant assent or (lack of) dissent.

Given the vulnerability of PLWD, other people and institutions often control researchers’ access to PLWD. These “gatekeepers” could include informal caregivers as well as staff and leadership in long-term care settings.²⁹ These individuals are charged with protecting the rights and welfare of PLWD. While it will often be necessary to secure gatekeepers’ permission to conduct an ePCT, their permission is not a substitute for participants’ informed consent or assent.¹²

Additional issues

Conflicts of Interest:

In situations where researchers have a financial interest in the intervention—for example, it was developed with commercial intent—their primary interest in producing generalizable knowledge is at risk of being biased by their secondary, financial interest.³⁰ Such conflicts of interest may bias judgments about ePCT design and interpretation of results. Conflict management can take the form of disclosure and peer review or, in some cases, prohibition of the arrangement or activity.³¹

Unique Institutional Settings:

The Common Rule applies to all research funded by the U.S. Department of Health and Human Services (HHS). Any institution “engaged in research”—generally, when its employees are obtaining: data for research purposes through intervention or interaction with participants, identifiable private information for research purposes, or informed consent—supported by HHS is required to have an approved Federalwide Assurance (FWA) committing to compliance with the Common Rule requirements on file with the Office for Human Research Protections in HHS (45 CFR § 46.103). It is also important to determine which individuals within the institution are “engaged in research,” as they must be listed as study team members and receive human subjects research training.

Often, ePCTs in PLWD are conducted in institutions such as nursing homes or adult day programs that do not typically participate in research and therefore lack familiarity with relevant ethics frameworks and research regulations. Researchers must be attuned to the possibility that, depending on the study design, the institutions may be considered “engaged in research.” Researchers should consider whether the study can be altered to avoid this; if it cannot, they should be willing to assist facilities in obtaining needed FWAs, human subjects training, and IRB oversight.

Protected Health Information:

Researchers conducting ePCTs will often seek to use administrative data such as electronic health records and insurance claims routinely collected by study sites or other health care providers to recruit their cohorts, characterize their participants, and measure outcomes. These data are considered protected health information and are subject to the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule. The data owners (i.e., covered entities such as nursing homes) may be aware of HIPAA requirements surrounding the use of this data for clinical care and billing purposes but less familiar with the requirements surrounding the release of this data for research purposes. Researchers must understand HIPAA authorization requirements for protected health information. They should also be mindful, given the sensitive nature of data regarding cognition and the possibility of re-identification, to prioritize data security and privacy.³²

Beneficiary Inducement:

Medicare and Medicaid serve nearly all PLWD. The federal Anti-Kickback Statute prohibits inducements to beneficiaries of these federal healthcare programs, and many states have similar prohibitions. These prohibitions are intended to prevent overutilization of medical services, which inappropriately increases federal and state healthcare program costs, potentially harms beneficiaries, and improperly influences patients’ treatment decisions. Advisory Opinions from the HHS Office of the Inspector General suggest that these prohibitions potentially apply to a range of clinical research designs and recruitment strategies.³³ If an ePCT intervention is designed in a way that offers participants something of value in return for their research participation—for example, reimbursing expenses, waiving coinsurance or a copayment, or offering a small incentive—then it may implicate these beneficiary inducement prohibitions.

Conclusion

The IMPACT Collaboratory’s Regulation and Ethics Core will work to clarify and advance understanding of the issues discussed herein. As our Core gains additional insights into the particular ethical and regulatory challenges that arise when conducting ePCTs with PLWD—such as through our pilot-grant consultations—our list of research priorities will continue to grow and evolve. Our findings will inform the guidelines, best practices, and training materials we develop and disseminate. Understanding and addressing these ethical and regulatory challenges early in the design of an ePCT is not just a means of ensuring compliance but also a means of advancing the science.