Chronic pain is a major public health challenge, and it is linked to another major public health challenge — the opioid crisis. “For many decades, insufficient attention has been given to multimodal and non-pharmacologic treatment options for pain,” says Joseph Ali, JD, associate director for global programs at Johns Hopkins Berman Institute of Bioethics.
One reason is a lack of robust empirical research to inform pain-related healthcare decision-making. Pragmatic clinical trials provide a means to develop the evidence to support non-pharmacologic treatments. “Multiple large pragmatic clinical trial networks have been developed over the past five years to study non-pharmacologic treatments,” notes Ali, member of the Johns Hopkins Bloomberg School of Public Health IRB.
Clinical trials testing the effects of interventions on participants’ pain also measure mental and behavioral health conditions, which can be associated with chronic pain. Clinical researchers are not in the same position as treating clinicians when it comes to addressing the health needs of patients.
“But pragmatic clinical trials sometimes blur the lines between researchers and treating clinicians,” Ali says.
Who is responsible for monitoring potentially large volumes of information, including sensitive behavioral and mental health data? Who is responsible to respond if there are indications someone is possibly suicidal? “Unfortunately, limited guidance exists to help navigate this common but complicated challenge,” Ali laments.
Researchers from the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) program recently set out to address this. For study investigators thinking about how behavioral and mental health data should be handled, PRISM researchers suggest considering the characteristics of the trial and study population to determine the likelihood and magnitude of risks that may emerge. Identify triggers, thresholds, and responsibilities for action in response to risk-signaling data. Also, consider appropriate response mechanisms and capabilities, along with data privacy-related concerns.
For study investigators and IRBs, the central ethical challenge is finding an appropriate balance. The approach must allow for “effective and practical trial implementation, while meeting one’s ethical obligation to ensure actionable risk-signaling information is being addressed in a respectful and desired way,” Ali says.1
Researchers’ ethical obligations to monitor signs of mental health risks are not one-size-fits-all.
“This issue is connected to a larger conversation about how to interpret the general duty of investigators to protect the welfare of research participants,” says Ana S. Iltis, PhD, director of the Center for Bioethics, Health, and Society at Wake Forest University.
Expanding researchers’ duties to encompass proactively monitoring participants for health conditions unrelated to the research could undermine that work. Also, this could further confuse people regarding differences between research participation and clinical care. “For example, simply because researchers are aware that many people in society are experiencing anxiety does not mean all clinical trials must monitor people for anxiety,” Iltis says.
Researchers should monitor for mental health risk if the concern in question could undermine participants’ ability to voluntarily remain in a study. If a person loses decision-making capacity such that he or she could not give voluntary informed consent, then that person cannot choose to voluntarily remain in a study. “That does not necessarily mean that they need to be removed from the study. But it does mean that a surrogate needs to be involved,” Iltis says.
If someone can give consent at the start of a study but loses that ability, the prior consent does not suffice. Participants must be able to exercise their right to withdraw from research. If they have lost decision-making capacity (e.g., they experience delirium or psychosis), then the participant cannot voluntarily exercise this right.
Some mental health conditions leave people unable to make decisions, at least temporarily. “It is important to note that simply having a mental health condition or psychiatric disorder does not necessarily mean someone lacks capacity,” Iltis says.
A trial intervention or procedure could put participants at higher risk for mental health concerns or could exacerbate existing concerns. For example, a medication might increase the risk of depression, or a study might require participants to go through a “washout” period during which they are not taking current medications.
People who develop certain mental health concerns during study participation could compromise the integrity of the trial. Similarly, participants might be known to be at higher risk of developing mental health issues. This could be because of a history of suicidal ideation or because they have a medical condition, such as cancer, that is associated with a higher risk of developing a mental health condition.
As for how researchers should respond to signs of risk, “the context, including the nature and source of the risks, matters here as well,” Iltis says.
Options include notifying participants, referring participants for care, or providing care. “Monitoring can take many forms, from making staff aware of ‘red flags’ to frequent use of standardized instruments to assess participants,” Iltis says.
When determining the right type of monitoring, consider whether research interventions themselves may introduce those risks, whether the participants are expected to be at higher risk for developing mental health concerns because of their current condition, and the types of mental health risks in question. Also consider whether those concerns would make research participation riskier for those participants or whether those mental health concerns would undermine the integrity of the trial.
A good example is someone who has or develops a substance use disorder, and begins using heroin in a study on management of back pain. Perhaps someone is using a substance that interferes with the study medication. Is it appropriate to require researchers to monitor for mental health risks? If so, how will researchers monitor for risks? What will researchers do if they detect mental health risks in participants? Are staff appropriately trained to monitor and respond to risks?
“Monitoring participants known to be at increased risk of mental health concerns often is preferable to categorically excluding them,” Iltis notes.
Researchers found excluding individuals with suicidality from antidepressant trials is common.2 Categorically excluding people at increased risk for developing signs of mental health problems from research undermines the generalizability of results. “Developing plans to monitor participants and intervene as appropriate can be more appropriate than blanket exclusion,” Iltis says.
An overarching concern is the overall problem of “mental health exceptionalism.” The idea is IRBs treat research involving people with mental health conditions or risks that are associated with mental health differently from how they treat medical studies involving a comparable level of risk. IRBs might assume people with mental health conditions are less likely to maintain decisional capacity.3,4
Consider the harms that can result from excluding people at higher risk for mental health concerns, along with whether such restrictions are evidence-based.
“Populations overall can be harmed when knowledge obtained through research is not applicable to them,” Iltis says. “They are left without access to evidence-based treatment.”
REFERENCES
- Ali J, Morain SR, O’Rourke PP, et al. Responding to signals of mental and behavioral health risk in pragmatic clinical trials: Ethical obligations in a healthcare ecosystem. Contemp Clin Trials 2022;113:106651.
- Iltis AS, McCall WV, Deria R. Suicidality, depression, and the FDA: Health inequities and the ethical conduct of research. J Clin Psychiatry 2020;81:19m13050.
- Tait RC, Chibnall JT, Iltis A, et al. Assessment of consent capability in psychiatric and medical studies. J Empir Res Hum Res Ethics 2011;6:39-50.
- Iltis AS, Misra S, Dunn LB, et al. Addressing risks to advance mental health research. JAMA Psychiatry 2013;70:1363-1371.
Consider the characteristics of the trial and study population to determine the likelihood and magnitude of risks that may emerge. Identify triggers, thresholds, and responsibilities for action in response to risk-signaling data. Also, consider appropriate response mechanisms and capabilities, along with data privacy-related concerns.
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