Screening Tests to Determine Study Eligibility Are Not Foolproof
Clinical trial administrators rely on screening tests to determine which participants should be included or excluded, but no screening tests are foolproof. All produce false-positives and false-negatives. This inevitably means some eligible participants are excluded, and some ineligible participants are included.
“In research ethics, when writing regulations or guidelines, there is a gap or discrepancy between what seems ideal and what is practically possible,” says David Wendler, MA, PhD, head of the section of research ethics at NIH Clinical Center, who authored a paper on this topic.1
In 2004, Wendler studied the same gap with respect to informed consent guidelines, which state people have to understand the risks and potential benefits.2 “The problem is, when you start doing this in reality and enrolling people in clinical trials, it’s hard — and sometimes impossible — to know whether they truly understand these things,” Wendler laments.
The same issue arises regarding eligibility criteria. “If you look at regulations for research, they will say things like, ‘Only eligible people should be enrolled,’” Wendler says. “When people read studies in the literature, they assume that all the people enrolled were actually eligible.”
Studies offering payment (or access to experimental treatments) incentivize prospective participants to want to meet the criteria. “At a minimum, investigators or IRBs should be cognizant of that and realize that people may not always accurately characterize themselves or their history,” Wendler offers.
In addition, transparency on eligibility criteria is regarded as ethically critical. “However, the problem with that is you just gave the person the information they need to know what to say to be in the study,” Wendler says.
In some cases, it might be better not to let people know the criteria in advance. “Obviously, there are ethical worries about that. What IRBs need to do is figure out how to balance these things,” Wendler says.
Statisticians may be able to find a way to take into account the fact that some percentage of people in a given clinical trial were not actually eligible. “Even when it’s all objective tests, and there are not really a lot of incentives to enroll, there’s still this possibility that some ineligible people are going to get in and some will be excluded,” Wendler says.
IRBs and investigators need to be comfortable with some degree of uncertainty. The trick is to figure out how much evidence is enough to accept someone met eligibility criteria. “That’s going to depend on what’s at stake,” Wendler notes.
If an ineligible person is accepted into a study and develops a mild rash, that might not be a serious issue. If a heart attack is a possibility, that is far more serious. “Even then, you can’t be certain. You have to realize there’s going to be a risk,” Wendler says.
Inclusion of ineligible participants also affects scientific results. To what extent depends on the particulars of the study. For a large randomized trial with thousands of participants, “it maybe washes out. But a smaller trial with only five people showing a treatment didn’t work, you have to consider whether those people were really eligible,” Wendler says. “Did they really have the disease? Did they have comorbidities that made them ineligible?”
The issue of uncertainty raises numerous concerns for IRBs. “But it’s little discussed. It’s something that’s flown under the radar,” Wendler says. “To a certain extent, investigators are aware of it. But whether or not the awareness feeds back into the design of the study and screening measures, I don’t know.”
“Screening tests can be an important part of ascertaining whether an individual meets inclusion or exclusion criteria for a particular trial. These criteria may reflect scientific considerations or safety considerations,” says Emily A. Largent, JD, PhD, RN, assistant professor of medical ethics and health policy at the University of Pennsylvania Perelman School of Medicine.
It may be desirable to exclude participants who are taking certain prescription drugs for safety reasons. It makes sense for investigators to screen for those drugs before enrolling individuals.
Screening tests can be especially helpful when subjective self-reporting will not suffice. For instance, investigators may need evidence indicating an individual is not pregnant at the time of enrollment. “For any screening test, you’ll have the chance of a false-positive or false-negative conclusion,” Largent notes.
Bias is another concern if screening tools are used to exclude people from trials. “Screening tools may seem neutral, but in practice they can work to systematically exclude certain groups of people and reduce the representativeness of research samples,” Largent reports.
Recruitment barriers become an ethical concern if some groups are systematically excluded. “For example, many dementia clinical trials have eligibility criteria that disproportionately exclude African American or Hispanic individuals,” Largent says.3
Generally, this practice limits the generalizability of those studies; specifically, it is a particular concern if excluded groups carry a disproportionate disease burden. “It can reduce the value of research, result in unfairness in subject selection, and potentially alter the risk/benefit radio,” Largent cautions.
IRBs and researchers should expand eligibility criteria to diversify representation, remove extraneous inclusion/exclusion criteria, and eliminate some screening tests if they are not strictly necessary (particularly tests that produce many of false-negative or false-positive results). “If these tests cannot be entirely removed, it’s worth exploring whether there is an alternative screening test,” Largent says.
- Wendler D. The inevitability and ethics of inaccurate screening in clinical trials: A call for research and guidance. Ethics Hum Res 2021;43:37-44.
- Wendler D. Can we ensure that all research subjects give valid consent? Arch Intern Med 2004;164:2201-2204.
- Massett HA, Mitchell AK, Alley L, et al. Facilitators, challenges, and messaging strategies for Hispanic/Latino populations participating in Alzheimer’s disease and related dementias clinical research: A literature review. J Alzheimers Dis 2021;82:107-127.
IRBs and researchers should expand eligibility criteria to diversify representation, remove extraneous inclusion/exclusion criteria, and eliminate some screening tests if they are not strictly necessary, particularly tests that produce many false-negative or false-positive results.
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