Incidental findings in research subjects — which can be completely benign or herald significant health problems — raise thorny issues for IRBs that are best addressed through informed consent and a detailed contingency plan, says Matthias H. Schmidt, MD, associate professor of radiology at Dalhousie Medical School in Halifax, Nova Scotia.

“Ethics boards have to choose a risk assessment that they are comfortable with, but researchers could do a lot to decrease the risk if they have a good management plan in place that allows for an expeditious workup and a second opinion,” he tells IRB Advisor. “If they have a good connection with their research subjects then incidental findings won’t strike like a bolt out of the blue. They can do a lot to decrease risk of harm coming to subjects and hopefully push this to the ‘minimal’ side of the fence.”

Incidental findings can be life-saving or life-haunting events, prompting a critical intervention or discovering some condition of possible future risk that the patient must then continue to follow for years. Examples include finding a growth or spot on a CT or MRI, and discovering a previously unknown serious medical or psychiatric condition that you have or appear to be predisposed to in the future.

Research subjects’ reactions to the idea of incidental findings will certainly vary, and some bioethicists have argued that patients should have the right to say they do not want to know about anything beyond the scope of the study they have joined.

“We make a lot of assumptions about the risk and benefit of these things,” Schmidt says. “[Do your research subjects] tend to feel that knowledge is power or ignorance is bliss? How will people receive incidental findings? I think a dialogue is very important and research ethics boards really need to be aware of incidental findings as a significant potential outcome for research subjects. They really need to satisfy themselves that there is a good plan in place.”

Agreeing to a stipulation of IF silence, for example, could put researchers and IRBs in an untenable position if serious incidental findings are uncovered.

“Consider the special situation where a study participant says I don’t want to know anything, ever — nothing,” he says. “That’s a very difficult scenario because then if you discover what you think is a real threat [and there are] potential interventions and treatment — you are in a real ethical dilemma. I personally feel that could be an exclusion criteria for research.”

If so, the process of consent should include language that clearly states that research subjects will be informed of incidental findings.

IFs may lead to more IFs

As Schmidt and colleagues observe in a new study1 on IFs in neuroimaging, you can find yourself going down the rabbit hole pursuing IFs. “The discovery of IFs may lead to medical investigations, each with its own associated risks, one of which is the discovery of additional IFs,” the authors note. “In this sense, IFs must be considered among the risks of research participation.”

Therefore, incidental findings must be emphasized in the informed consent process from the outset.

“That’s got to be the cornerstone of management,” Schmidt says. “You have sit down with your research subject before you begin and make them aware that incidental findings occur and that they can be trivial and meaningless or they can be life-changing. Maybe give some examples and then explore with them how would they feel about some of these things and what sorts of things would they want to know about. Because once you have made the finding, you’re stuck with it.”

Unfortunately, it is not always clear at the outset whether an IF reflects a real threat to a research participant or a normal variant, a benign lesion or an imaging artifact, the authors note. Given that, researchers must try to cover the range of possible outcomes during the informed consent discussion, allowing people considering research study participation to weigh the potential benefits and harms from their perspective.

“Assuming the subject wants to know about significant findings then I would feel ethically bound to follow up if I didn’t know what [an IF] was,” Schmidt says. “As a radiologist I would probably propose some further imaging to clarify. If I was a researcher without a diagnostics imaging background I will seek a radiologist’s [opinion] and ultimately one would have to contact the person’s physician and [discuss] a plan for medical follow-up as appropriate.”

Best case, worst case

IRBs in both the U.S. and Canada operate under federal regulations that include a “minimal risk” standard, which determines the degree of scrutiny research proposals receive during the review process. Though subject to change in the recently issued Notice of Proposed Rulemaking (NPRM), currently the minimal risk standard is also used to determine whether participant consent requirements can be waived or altered. Schmitt and colleagues used the minimal risk standard to try to find an appropriate benchmark for the nature and magnitude of risk associated with IFs. They also reviewed the limited published information on IFs in healthy children who have participated in MR neuroimaging research to determine the spectrum and frequency of reported incidental findings. In the study, they categorized IFs broadly according to their implications for participant health and then asked whether IFs can meet the minimal-risk standard under a roughly determined “best-case” and “worst-case” scenario.

“The reason we looked at that was because there really isn’t enough information available to us to know what actually happen to participants,” he says. “We don’t really know what the outcomes are. We know what sorts of individual findings exist and we have some sense of the frequency with which they occur. But there’s really no information about what happens after that. In the studies that have been reported on incidental findings, there is very little information given on outcomes. It is certainly not enough to be quantitative.”

Thus, the decision to create scenarios, with the best case meaning all incidental findings that could be beneficial are beneficial and all findings that could be neutral are found to be neutral. “So what is the risk — what remaining findings could be harmful?” Schmidt says. “And we pegged that risk at about 2%.”

For the purposes of the analysis, the researchers considered IFs to meet the minimal-risk standard by comparing them to a routine examination or an everyday event in the life of a child that is capable of producing similar harm. They chose the well-child examination performed periodically by family physicians and pediatricians as a comparator.

“Then we thought, well, what is the worst thing that could happen — if every one of these findings that could cause undue concern or unnecessary further investigations and so forth actually did? And that got us to a number of about 8%,” Schmidt says. “These are very rough approximations because of the limited amount of information in the literature, but we noted that between 2% and 8% [of IFs] fall right on the borderline between meeting and not meeting the minimal risk standard based on our comparator for everyday life.”

They also reviewed five studies that specifically describe the spectrum and frequency of IFs encountered in healthy children in the developed world who have participated in MR neuroimaging research. They combined IFs into two broad categories that dictate management, including disclosure, as follows:

IFs without implications for participant health. Extracranial IFs reflecting mucosal inflammation of the sinuses and middle ear may reasonably be considered to reflect everyday occurrences in the lives of children, meeting the minimal risk standard by definition. Disclosure optional.

IFs with implications for participant health. Knowledge of some IFs can have benefits for participant health. For example, the fortuitous identification of syringomyelia in a child participating in one reviewed study led to appropriate further diagnostic workup and neurosurgical care. Disclosure mandatory.

The gray zone

Overall, Schmitt and colleagues concluded that IFs in pediatric MR neuroimaging research can meet the minimal-risk standard in the best-case scenario, but not in the worst-case scenario. The true risk likely lies somewhere between these two extremes, with IFs in the “gray zone” distributing themselves among the categories of benefit, minor harm, and major harm in as-yet-unknown proportions, the authors conclude. Large-scale studies using clear, a priori criteria are needed to determine the true frequency of significant IFs in healthy children at various ages. At the same time, more information is needed on the actual outcomes of IFs identified in the course of pediatric neuroimaging research before this kind of research can definitely be said to meet the minimal-risk standard. In the meantime, IRBs should view IFs as potentially exceeding minimal risk, in order to protect research participants and to challenge researchers to consider this problem carefully, Schmidt notes.

“We need more data on the true prevalence of these findings so we can give people a sense of the degree of risk,” Schmidt says. “And to get at that I think we really need to standardize our definitions. There are some incidental findings that are very differently described in different papers and for which different criteria may exist for diagnosis. We also need to have some data on the actual impact of incidental findings because it is really a vacuum. Do certain incidental findings really end up being followed up, being worked up or leading to treatment? And is there variability from center to center in terms of how these things are managed? Because that will allow you to determine what you can tell a subject might happen if a certain finding were to be discovered.”

REFERENCE

  1. Hadskis MR, Downie J, Marshall J. Incidental findings and the minimal risk standard in pediatric neuroimaging research. IRB: Ethics & Human Research 2015;37(5):11-19.