This piece first appeared in Health Affairs and has been cross-posted here with permission.
The emergence of the novel coronavirus has magnified the importance of clinical trials for finding safe and effective treatments for patients. At the same time, COVID-19 has shone a bright light on health disparities in the United States. Groups disproportionately affected by the virus include older adults, racial and ethnic minorities, and people with underlying health conditions. Some groups may be vulnerable based on prevalence of clinical risk factors, as well as for logistical and structural reasons. For example, individuals living in nursing homes often have comorbidities or other concurrent illnesses and experience frequent personal contact when assisted with bathing or toileting. Moreover, the close proximity characteristic of most nursing home housing, particularly where patients share rooms, could promote the spread of a highly infectious disease. While disparities in who is most vulnerable to COVID-19 is concerning at a base level, this concentration of risk is even more alarming given that it is occurring in those same groups that have been historically underrepresented in clinical trials.
Avoiding Exploitation And Overprotection In Clinical Trials: Finding The Balance
Ethical and legal protections are in place to ensure that vulnerable groups are not exploited in clinical trials. Here, we use the term “vulnerable” to broadly include populations historically considered at risk for being misused in clinical research or for whom a truly voluntary decision may be compromised from a regulatory perspective (for example, prisoners, the decisionally impaired, children); as well as groups historically and currently prone to poorer health outcomes, less access to health care, or unfair treatment in research (for example, racial and ethnic minorities). These protections are important and necessary, especially given historical abuses carried out in the name of research.
While protections for clinical trial participants remain critical, it is important that these protections do not create unintended consequences, such as systematic exclusion of vulnerable groups from COVID-19 clinical trials. In other words, in the name of “protecting” vulnerable populations, researchers may end up harming them. By deciding that certain groups should be excluded from studies to protect them from the risks inherent in clinical research, investigators take away patients’ (or their caregivers’) right to decide if clinical trial participation is desirable. Such actions also foreclose the possible medical benefit that a clinical trial may offer participants, such as first access to a beneficial therapeutic. This is particularly important in the context of COVID-19, a potentially fatal disease with no cure and only one proven treatment that is provisionally approved, via an Emergency Use Authorization.
It is a serious matter to exclude a group from research eligibility, and this must be done only when no less restrictive option is sufficient to ensure protection from undue risk, including from exploitation. For example, conducting research on prisoners raises concerns about the possibility of voluntary consent, but rather than forbidding such studies, we permit this population to be enrolled into certain types of studies, so long as there is oversight, including by a representative charged with representing the interests of the incarcerated. Not only is it inappropriate to unnecessarily bar vulnerable populations from participating in research, there are instances in which it would be appropriate to have a trial that consists solely of members of vulnerable populations: For example, to learn how to treat COVID-19 and the related multisystem inflammatory syndrome in children, it would be reasonable to have a trial consisting solely of pediatric patients. As children are physiologically and developmentally different from adults, a COVID-19 trial that limits inclusion to patients ages 0–17 would likely be scientifically appropriate and ethical.
Key Ethical Principles
It is ethically problematic, on the grounds of justice, to overly limit who may participate in research, even when dealing with groups deemed in need of special protections, and such limitations are even more concerning when the excluded groups are disproportionally at risk from the condition of interest. Furthermore, researchers jeopardize the scientific value of research if they fail to study those who are most at risk. COVID-19 trials face twin facts: Certain groups may be wary of participating in research due to historic wrongs, mentioned above, and researchers may be reluctant to include traditionally vulnerable populations in studies, as this entails additional compliance requirements. To address this conundrum, we advise researchers to pay due diligence to the following considerations.
Social and clinical value: A research question should contribute to the scientific understanding of health or improve ways of preventing, treating, or caring for people with a given condition such as COVID-19. For the use of humans to be morally justified, studies must be scientifically valid and capable of answering the selected research question. Research questions that deal with specific vulnerable populations, for example, children or the elderly, must involve the study of those groups themselves rather than the extrapolation of data from other groups (such as non-elderly adults) unless a neutral body, such as an institutional review board (IRB), deems this untenable in a specific situation.
Fair subject selection: Risks and benefits of clinical research should be shared; those who shoulder the risks of participation should be able to enjoy any resulting benefit, while those who may benefit should share some of the risks and burdens.
Informed consent: Individuals deemed legally competent to make their own decisions about research involvement should be permitted to do so. In the case of children or adults rendered decisionally incompetent by conditions such as dementia, unconsciousness, or severe developmental delay, rather than declaring such populations off-limits for study participation, decisions about inclusion should typically rest with the patient’s legal authorized representative.
Four Strategies For Enhancing Inclusion Of “Vulnerable” Groups In COVID-19 Trials
First, give careful thought to a trial’s inclusion and exclusion criteria, so as to avoid systematically reducing the pool of potential participants. Common comorbid conditions such as hypertension, diabetes, and obesity should not constitute exclusion factors unless there is a safety risk. Research compliance officers and IRB members must understand that part of their job is to protect research participants from harm and injustice.
Second, make sure people are aware of and invited to participate in trials when eligible. In some cases, a health care provider may offer trial participation to a patient directly. Alternatively, direct-to-consumer methods of recruitment may provide greater equity in awareness of research opportunities. For example, some health systems send notice of research opportunities through the patient portals of their electronic health record systems. Advertise in places where the target population is most likely to see or hear it. Work collaboratively with institutional administrators and communications and marketing professionals to ensure compliance with relevant policies.
Third, ensure that those eligible to participate have access to studies where they live or get their care. This may require academic medical centers to partner with community hospitals, federally qualified health centers, prisons, or solo medical practices.
Fourth, minimize participation burden, both to enroll in a trial and to remain compliant with it. Individuals who missed work due to illness, particularly those who do not have sick leave or flexible hours, are unlikely to be able to take time off for trial-related follow-up visits, and children’s availability will be limited by that of their parents or guardians. Offering flexible appointments times (for example, evenings and weekends) and virtual visits may expand who can participate. Given social-distancing policies, it may be difficult or risky for patients to travel for outpatient appointments; try to use phone or video tools or wearables instead, to enable data collection from the research participant’s location. Consider offering participants reimbursement for parking or a taxi, or using a visiting nurse-type service to take the follow-up visits to them. If they must travel and be on site, frail or debilitated participants will most likely require able-bodied companions’ assistance; these companions’ travel expenses should likewise be reimbursed.
COVID-19 has hallenged every aspect of research in the United States: its scale, its speed, and its conduct. Researchers must use this opportunity to also challenge the status quo of who is afforded the opportunity to participate in research. While viruses are immune to considerations of race or class, COVID-19’s impact has been greatest upon certain vulnerable groups. In the context of clinical trials, vulnerability has often been seen as a reason to exclude groups from research; however, such protectively intended measures can, in some cases, result in injustice, both in who is permitted to participate in studies and in who benefits from the resultant knowledge. Researchers cannot allow the populations most at risk of harm from COVID-19 to be shut out from the clinical trials related to the disease, as that would only further exacerbate the inequality that the virus is exploiting.
Aisha Langford, MPH, PhD, and Alison Bateman-House, MPH, PhD, are assistant professors in the Department of Population Health at NYU Grossman School of Medicine.