Ten questions for allied professionals

Clinical considerations for allied professionals on research ethics—Vulnerable research participant populations: Ensuring ethical recruitment and enrolment

“Vulnerable” in research generally means that a potential participant is possibly open to some form of coercive or undue influence in considering whether or not to participate.¹

Those unable to give their own informed consent, like Maya at the moment, could be vulnerable if they have a substitute or surrogate decision maker (SDM). SDMs must aim to decide according to the known or likely wishes of the incapable person. If these are not knowable, then they must consider the person's best interests. This is not always straightforward. Other vulnerable groups include those who may be capable but have special needs in understanding the relevant information, such as people with limited proficiency in the language(s) in which the study is conducted, or those with certain mental health challenges or developmental disabilities. Information documents, standardized questionnaires, and ratings scales are often only available in English and only in text-based formats.

In addition, people who are in significant pain, those who are terminally or very ill, those in emergency situations, or those whose illness has no effective treatment are all potentially vulnerable when weighing the risks and benefits of the study—their hope for benefit might obscure these considerations and the possible alternatives.

Women who are or may become pregnant and men who may sire children during a study may be considered potentially vulnerable, mainly by virtue of the as-yet-unknown teratogenic potential of trial drugs. Family dynamics can have a coercive effect, especially if there are children not yet of legal adult age.

Maya is presently unable to protect her own interests. In the scenario, the onus would fall on the health care team to consider whether or not to continue, given her distress and their capacity to manage it, as well as the details of the study protocol and its standard operating procedures.

A practitioner's relationship to a research participant is arguably different than that to a patient.

The first difference relates to the departure from the currently accepted standard of care. By its nature, any procedure, drug, or device under research is not yet proven. A second difference is the anticipated benefit. There is none in many studies, at least not for the participants. The same study, however, is likely to offer benefits to the researcher, such as payment, publication, and prestige. In other studies, there may be benefits to participants such as payment, or some form of treatment where no other has been effective. With the latter, the important point is that the treatment benefits are not yet proven. It is important that all parties, both participants and researchers, are clear about this. A well-constructed protocol, coupled with the integrity of the professionals who subsequently implement it, offers one of the only ways for research ethics review bodies (research ethics board [REB], research ethics committee [REC], or institutional review board [IRB]) to review the process before it begins.

In Maya's case, her confusion would suggest that she should not be enrolled because valid consent must always be ongoing. If the standard operating procedures allow for including those not capable of giving consent, then her enrolment may still be possible. For the team, Maya's distress should indicate the need for further deliberation about her participation, including discussion with her husband or other appropriate SDM.

The concern about the vulnerability of research participants stretches back to cases of egregious misconduct. Among these are the Nazi experimentation during World War II,² the American experimentation on conscientious objectors during the same period,³ and the infamous syphilis studies,⁴ to name a few. Rhodes⁵ offers both a review of some of this history and a critique of the regulatory framework that grew out of it.

More recent instances of research misconduct have emerged, including the Alder Hey study, which removed organs from deceased children without consent,⁶ and the Olivieri/Apotex case of suppression of early study results.⁷ Consequently, frameworks for the governance of research continue to evolve.⁸ Concerns for safety and dignity must be balanced against the risk of paternalistically limiting an individual's choice to take an informed risk, as well as the anticipated risks and benefits of the research itself. This seldom-simple balance is at the heart of ethical review.

Regulations in various jurisdictions use differing definitions of vulnerability, often a list of categories.⁹ In addition, different ethics review bodies within the same jurisdiction can have differing opinions on vulnerabilities. The evolution of research regulation and review practice should reduce these over time, but they cause frustration and confusion presently.

In the first instance, ethics reviewers would likely be aiming to ensure that the potential participants are approached and recruited in a manner that seeks to avoid potential influences wherever possible. At the same time, studies should avoid “pre-emptive exclusion” of certain groups.¹⁰ The reviewers will consider the reasons for such exclusion; it is often warranted, but not always.

In the broadest sense, the REB/REC/IRB will expect that participant information documents give adequate detail about the study, its likely risks and benefits, and the burden involved in participating. This must be conveyed in a format—language and/or visuals—that are accessible to the relevant populations. There must also be time allowed for people to consider the information; this is study specific, but should always be as ample as possible.

Concerns arise among reviewers when segments of the actual protocol are copied into the information for participants, using style and content that is more suited to professionals. Equally, the reviewers will be alarmed when there does not appear to be a precise outline of the methods, process, and timeframe for identifying, approaching, and recruiting potential participants.

At the very least, the ethics reviewers will expect that the research team is aware that there may well be individuals and populations who are in a vulnerable position as potential participants in the study, and that consideration has been given to managing these vulnerabilities.

Membership in an ethnic minority is another possible category of those who might be vulnerable.¹¹ This can stem from the marginalization or devaluing of minorities in some contexts, as well as from the communication challenges in working across cultures.¹² Part of the challenge may be the beliefs or values of a culture; there may be more likelihood of deference to those in positions of authority, or there may be a stronger belief in health care traditions beyond conventional Western practice.

Families withholding distressing information from the patient is commonplace in many cultures, and health care practitioners within those cultures often follow this practice, even when the patient is fully capable. Investigators would need to consider whether their study protocol can be followed in such a situation. Context plays an important role. Where an awareness of diversity and an inclusive approach are well embedded in practice, the risk of this vulnerability may be lower.

Quality consent or refusal lies in the informing process. Efforts can be made both to convey the information in a manner that is understandable and also to verify that the information has been understood and has appropriate meaning.

One form of vulnerability to which both patients and researchers are open is the “therapeutic misconception,” in which the presumption is made that the trial intervention is better than the standard of care.¹³ A patient/participant who is not benefitting from standard treatment might minimize the trial's risks and burdens, hoping that the intervention will solve their health problem. The researchers themselves can also be too convinced of the study's merits. The usual standard here is the principle of equipoise—there must be genuine uncertainty about the advantage of the trial intervention over the standard of care.¹⁴

Maya's situation also speaks to another possible vulnerability, that of “pre-emptive exclusion.” Many groups are regularly excluded because of potential vulnerabilities that might be but are not accommodated. The review body may have had a paternalistic approach and expected the exclusion of anyone unable to give consent. This would have been justified with the aim of preventing the very distress currently felt by Maya. With dementia, however, Maya may soon forget her distress—does this make it acceptable to carry on?15, 16 These uncertainties may distress the team itself.

The same paternalistic approach may not so readily apply to other groups, such as women of childbearing age or someone needing support with the language used in the study. Some groups may be included without due attention to their specific vulnerabilities, such as staff and students. Research in the workplace or classroom can exert possibly coercive influences.¹⁷

Like capacity or competence, vulnerability can change over time and in response to changes in context. This is why consent is framed as voluntary, informed, and ongoing. Participants are sometimes “re-consented” when an element of the study changes or it progresses to a new phase. In emergent situations, consent may be given on limited information, owing to the urgency. A participant may subsequently consider withdrawing when given the fuller information and plenty of time to consider it. Equally, a participant's own sense of having invested in the study might leave them feeling they should continue, despite increasingly onerous demands of the study. It may also be that the original vulnerabilities become more acute: the hopes of successful treatment may be failing, an incapable participant may regain their capacity to make decisions for themselves, or vice versa.

The full context of the individual participant has been identified as the more appropriate frame for considering vulnerability rather than the simplistic list of categories.18, 19 That fuller context is easily seen as something that might change over time, either increasing or decreasing potential vulnerabilities.

Maya's confused state has introduced a greater vulnerability to having her decision about participation possibly overruled. On balance, the recruitment and consenting procedures should aim to offer the most protection to the widest range of potential participants, while avoiding unnecessary fettering of capable choice.

Consent in and of itself is not sufficient to make a research study ethical.²⁰ We should not agree to someone being subjected to immense risk or burden simply because they say yes to it. The context of their consent might hold factors that introduce a high level of coercion. Imagine a parent willing to subject their child to an onerous trial intervention because it is the only option for obtaining funds to feed that child or others, or medical care itself.²¹ Sears²² asserts that one can be autonomously consenting, but still be “exquisitely vulnerable to contextual influences.”.

Although informed consent is one important element, other requirements of ethical research include its value and scientific validity, a fair process for selecting participants, an acceptable harm–risk ratio, a thorough independent review, and evident respect for potential and enrolled subjects.²³ Even the highest regard for obtaining informed consent does little to serve the interests of those vulnerable to being left out of research.

In practice, straightforward categories of those who might be vulnerable often guide ethical review. As described earlier, any group in a particular relationship to power is potentially at risk. Prisoners are another example, but some writers suggest that power dynamics exist in any researcher–participant relationship.²⁴

Strategies for managing vulnerabilities start with considering what can be foreseen, avoided, and minimized. This includes defensible inclusion and exclusion criteria, an appropriate period of time to consider participation, an initial approach to participants undertaken by someone not involved in their care where appropriate, or an explanation why this may not be so.

Well-crafted information documents are essential. Complex concepts and complicated intervention schedules can be conveyed using accessible language supplemented with visual or graphic representations. Pediatric research makes frequent use of such strategies, but they can be equally useful to most adults.

Timing is also pivotal. It would likely be considered best practice to refrain from mentioning any specific trials until full information can be shared. Alerting a patient who is a potential participant to an upcoming trial in advance of full information could well plant seeds of that therapeutic misconception in fertile ground. On the other hand, general nonspecific notices that “we do research here” are a useful primer for future approaches about specific trials. These tactics are outside the purview of any REB/REC/IRB, and rely on the ethical judgment and integrity of each researcher.

All parties to a research project should be protecting the potentially vulnerable at different points and places in the endeavor. The research team is the first to consider the participants' interests—in the design and methods of any study, from inception to completion. The team also will be dealing with any unforeseen situations in the approach, selection, recruitment, and ongoing involvement of each participant.

The reviewing bodies have a clear role in providing a final oversight to the proposal before it commences enrolment locally. The review body or its chair is also often specified as the place to which a participant can take any concerns. Where possible, the ethics reviewers should act as a resource to the researchers. Many members are willing to offer input early on in the development of a protocol.

Ethicists also play their role, debating and challenging conventional thinking about the ethics of research and participation in it. The evolution of the thinking behind the processes continues. Over time, the multiple layers of regulation and the review process should evolve to better serve the interests of all parties.