When clinical research turns up the unexpected
When clinical research turns up the unexpected
Anticipate incidental findings in every study
Researchers using magnetic resonance imaging (MRI) in a cognitive psychology study note a suspicious mass in the brain of a supposedly healthy volunteer.
A geneticist investigating the prevalence of a disease in a family discovers that one of the siblings being studied has a different father than the others — a fact the sibling is not aware of.
A researcher using archived genomic data discovers a potentially important clinical finding about a subject in a long-ago research project. The data were made anonymous, but the original researcher still has identifying information.
With the advent of revolutionary technologies designed to collect and analyze data, more researchers are being faced with problems such as these — so-called "incidental findings," or data generated about research subjects that go beyond the original aims of the study.
"It's really a product of the power of the technologies being used for research," says Susan M. Wolf, JD, a professor of law, medicine and public policy at the Center for Bioethics, University of Minnesota, Minneapolis. "Not only the technologies that generate the raw data — things like new imaging technologies — but also the increasingly sophisticated technologies we use to analyze those data: bioinformatics capabilities in genomics, for example, or new computer analysis techniques used to do fine-grained analysis of images.
"As we do more and more of that, it's really inevitable that we'll be faced with more and more extra data."
How to handle that extra data — determining what's important and what isn't, and whether and how to inform participants — has become an issue of growing concern to researchers and IRBs.
Most recently, Wolf was the principal investigator for a National Institutes of Health-funded project about incidental findings that resulted in a 17-article symposium published this summer in the Journal of Law, Medicine & Ethics.1
Wolf says that when she and her colleagues began looking at how IRBs handle incidental findings, they found little guidance for investigators and boards. In examining the top 100 NIH-funded universities, she says most IRB web sites didn't even mention the possibility of incidental findings. Among those that did, there was little consistency about how they should be managed.
In part that may be due to the varied types of findings that can occur in different research settings. Genetic and genomic research can reveal information about a person's possible susceptibility to disease, or can uncover family secrets such as misattributed paternity or undisclosed adoptions. Imaging research can uncover physical abnormalities, ranging from unimportant to life-threatening. Routine eligibility screening could uncover drug use or pregnancy.
In each case, the plan needed to manage the findings would be different, as each would raise different ethical and practical considerations. But Wolf says there always needs to be a plan.
"IRBs should be asking the incidental findings question about every study," she says. "What planning do they see in the protocol for handling incidental findings? Is the plan adequate? What are the plans for the consent process? Who, if anyone, is available to act as a clinical consultant on incidental findings? What are they going to do with this information?"
Different from research results: While incidental findings raise some of the same IRB issues as the return of research results to participants, Wolf says there is a difference.
In the case of research results, the investigator is likely the most knowledgeable person to inform participants about findings. But researchers who turn up incidental findings usually aren't studying the condition that's been uncovered and may know little about it. In those cases, a referral to an expert — a clinical geneticist, a neuroradiologist — may be necessary to know for sure if the finding is significant.
Even the technology used may not be optimized for diagnosing an unexpected finding. MRIs may not be of clinical grade, so a suspicious finding may require a second scan — potentially at the subject's expense.
While there are many elements to a good incidental findings management plan, IRBs should keep several important points in mind, say Wolf and others who study the issue:
• Additional risks. In addition to the risks of the procedure itself, the potential for incidental findings adds other risks for participants, says Michael Hadskis, LLM, assistant professor of law at Dalhousie University, Halifax, Nova Scotia, who has studied review boards' handling of incidental findings in MRI research.
Those can include the physical risks of the follow-up procedures required, the psychological risks of stress as the participant waits to find out if the finding is real and significant, and the financial costs of procedures as well as the potential impact on insurance.
"These are real risks, and they're not minor risks," Hadskis says.
• Therapeutic misconception. In the case of research involving MRI, for example, a participant could mistakenly believe that all scans are being reviewed by an expert in diagnosing abnormalities, or that the technology is optimal for diagnosing problems when it is not.
"The research subject might think, 'If there were something there, it would have been seen. I'm not told anything is there, therefore I'm healthy. And therefore, I'll ignore my headache,'" Hadskis says.
Wolf says a review of consent forms regarding incidental findings turned up a range of approaches to dealing with this problem.
"Some say, 'This is not clinical care — if you think there's something wrong with you, go to the doctor.' Others say, 'If we see something anomalous or something of concern, we are going to share it, with your permission, with a clinician and we'll tell you,'" she says.
Deciding when to tell subjects: Wolf says not all incidental findings necessitate giving information to subjects. A closer study of an initial finding may reveal that it's unimportant.
In genetic testing, results that indicate a non life-threatening condition that the subject can't do anything to address might not be revealed. Wolf says discoveries of misattributed paternity sometimes aren't told to subjects unless it's critically important.
One debate over incidental findings that continues is how to handle subjects who don't wish to be told about them. In some areas, such as genetic testing, a subject may feel that there is little he can do about the result and doesn't want the additional worry.
Complying with such a request is "absolutely recommended, in keeping with the long history in genetics and genomics of offering but not forcing information on people," Wolf says.
But in imaging research, where a scan could reveal an aneurysm about to burst or an aggressive but treatable brain tumor, there is more opposition to giving a subject the choice to "opt-out."
"I feel that that puts an investigator into a tremendously delicate situation, if a subject has signed off that they do not wish to be told, and an investigator by rare chance finds a medical problem that is treatable," says Judy Illes, PhD, an imaging neuroscientist and Canada Research Chair in Neuroethics for the National Core for Neuroethics at the University of British Columbia in Vancouver.
In fact, Illes says, she recently heard a suggestion that investigators use a subject's preference not to receive incidental findings as a part of the exclusion criteria for participating in a study. "I think it was a good idea, in fact."
Hadskis suggests IRBs evaluate each situation to determine whether an opt-out provision would be appropriate.
Archived data: If a researcher is using data from a previous study and analyzing them in a different way, then any individual results would, by definition, be incidental findings, Wolf says. In many cases, the data have been made anonymous and the subject is unreachable, but that's not always the case, she says.
"What if you find a really important incidental finding and the data are anonymous in the public databank on the web, but the original researchers could re-identify? Are there circumstances where you'd want to do that?"
She says that in any study where the results will be archived for later use, consent forms should address the potential for incidental findings well into the future.
Wolf says addressing the potential of incidental findings could add cost to some types of research, particularly when researchers would need to call in a consultant to review findings.
"The money has to be built into research budgets — we argue that that much is part of doing research responsibly," she says.
Illes says she doesn't agree with the concern of some that giving more IRB attention to incidental findings will result in studies being moved higher in risk, necessitating more lengthy reviews.
"What about recognizing the possibility of an incidental finding and expressing a management plan moves the risk position of a study? I don't think it does at all."
Hadskis says IRBs need to prepare for dealing with the issue by ensuring there's a member — or at least an ad-hoc member or consultant — who's familiar with the type of research being discussed, and the potential for incidental findings.
He says that as IRBs become more familiar with the issue, and best practice guidelines emerge, the process should become easier.
"I don't think you're going to have any sort of one-size-fits-all best practice guidelines," Hadskis says. "But I think well-crafted best practice guidelines are going to cover many situations. Some of these things won't be as big an issue as they are right now."
Reference
- Wolf SM, Lawrenz FB, Nelson CA, et al. Managing incidental findings in human subjects research: Analysis and recommendations. J Law Med Ethics 2008;36:219-248.
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