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As technology in genetic and genomic research expands, most if not all IRBs will face the issue of incidental findings, including how to manage them, and whether researchers have a duty to report them to study participants, experts say.
"Given the fact that these new technologies — some new and some standard — are now in widespread use in clinical and research settings, sometimes researchers will be looking for one thing and find others," says Lisa M. Lee, PhD, MS, executive director of the Presidential Commission for the Study of Bioethical Issues in Washington, DC. "What to do with the findings is the key question."
Incidental findings (IFs) are findings that arise secondary to the stated goals of the research protocols. In addition to fulfilling regulatory requirements to protect human subjects, many IRBs are faced with creating plans to manage and disclose IFs to research subjects. There is no regulatory guidance for managing IFs, leading to IRB judgment calls on the issue — and debate among researchers and ethicists.
One of the biggest areas of IFs is in whether to return results to subjects in genomic and genetic research. Whole genome sequencing, for example, has opened the door to new discoveries in genetics research — and a new host of IFs. "In thinking about genomics sequencing, there’s a huge debate going on in the genetics field about how to handle IFs," says Michelle Huckaby Lewis, MD, JD, research scholar at the Johns Hopkins Berman Institute of Bioethics and the Genetics and Public Policy Center in Washington, DC. "If you sequence the whole genome, you may get information you weren’t looking for. There is an ongoing debate in the field about whether to return those findings."
A major issue of IFs in genetics research, Lewis says, is whether the researcher has a duty to "look at everything." In whole genome sequencing, she says, the machine can be set to look only at the information a researcher needs, and not necessarily at anything else. "Is that any different from reading an X-ray?" Lewis asks. "Even if they [technicians] are only looking for a broken bone, the way a chest X-ray is read is methodical. If they notice a suspicious spot that could be indicative of lung cancer, that would be reported. There’s a question of whether incidental findings are the same kind of thing in other studies."
So far there is no consensus in the research field about reporting IFs, Lewis says. There is not a standard of care as far as what is returned. "Actionability is the key factor," Lewis says. "Think about actionability of return — is there something that can be done about it [the finding]? Can we prevent the disease from developing, or lessen the symptoms?"
IRBs must consider many different ethical issues when deciding how to manage IFs within a specific protocol. There is no regulation or law that addresses the return of IFs to subjects. Every research protocol has different goals, and disclosure of IFs to research subjects may not work in the context. Subjects in imaging studies may believe that a diagnostics expert will be reviewing the scans in a timely fashion, even if informed consent states otherwise. The IF may not have any clinical relevance, and disclosure could lead to great anxiety and emotional harm for patients.
Two years ago, Janet K. Williams and colleagues at the University of Iowa conducted a study to gather IRB chair and researcher perspectives on IFs.
"The idea of the study came when newer forms of testing could yield results you weren’t anticipating and not necessarily answer your research question," says Williams, PhD, RN, FAAN, professor of nursing and chair of the Behavioral and Social Science Research IRB at the University of Iowa in Iowa City. "Testing was changing, and newer forms for testing could yield answers not anticipated."
For example, she says, a researcher may be investigating what gene variants occur in children with autism and discover a variant for inherited cancer. "Several ethical questions come up as to how you would handle that," she says.
The 2012 study involved structured interviews with 53 participants that included IRB chairs and genomic researchers. The participants were asked questions about what comes to mind when they hear the term "incidental finding;" whether and how they have encountered IFs; if the topic of genetic or genomic IFs had been discussed at IRB meetings; how researchers feel about giving subjects a way to opt out of receiving findings; and what information chairs think should be included in informed consent documents. At the time, Williams says, neither group had much experience with IFs.
"The IRB chairs looked at the matter from an ethical perspective, but had very little experience with it; either they hadn’t encountered it at all, or there was very little guidance for when they did encounter it. Others wanted to be prepared for it." Overall, the IRB chairs followed ethical principles when considering genetic IFs: They endorsed the need to develop a management plan prior to protocol approval, for returning the IFs to subjects for clinically significant, actionable issues, and informing subjects of the possibility at the informed consent stage. Others did not have a policy due to a lack of literature and guidance on the issue.1
Researchers also had little experience with IFs but gave general reasons for not disclosing them: the belief that research is for general knowledge and not individual results; risks associated with disclosure or over-disclosure; and labs not being CLIA (Clinical Laboratory Improvement Amendments)-approved. But some researchers who did encounter IFs felt compelled to disclose and went to the IRBs for guidance.1
"The changes since this study are that the research community is more engaged in trying to determine how to proceed and inform research participants of possible incidental findings," Williams says. "It is now a very common topic."
Although it has been two years since the study was released, many of the issues involved are the same, Williams says. "There are practical issues that come up with informed consent: What kind of information should be disclosed or returned? There are issues with variants that may have uncertain implications for health risks. There are also issues with how the information should be returned; some researchers say they are not qualified to discuss this, as they are not genetic counselors. The types of situations have changed, but the basic questions and issues are still very relevant — it’s just a bigger field," she says.
When IRBs are reviewing protocols, it is important for them to identify studies that could result in IFs and create adequate plans for managing and reporting them, Lewis says. "The researchers and IRBs should be doing this in the right way to protect patients," she says. "It’s important to make sure there is a plan in the protocols to handle the findings. It may be that the researcher goes back to the IRB or goes before a committee, but there must be some sort of plan. Research participants must also know the plan upfront in the informed consent documents."
Some experts have proposed the idea of determining IF disclosure by dividing IFs into three groups. The categories were proposed in a report by Susan M. Wolf and colleagues2:
• Findings that offer strong net benefit. These findings reveal conditions that are potentially grave or life-threatening, and can be treated. One example is the discovery of an operable brain tumor in an unrelated MRI imaging study.2
• Findings that offer possible net benefit. Researchers may wish to disclose these findings that a research subject may deem important, even if the potential condition cannot be avoided.2 One example is the discovery in a woman of the BRCA gene mutation that could lead to breast or ovarian cancer. While developing either condition cannot be avoided, the subject could then choose to have annual cancer screenings based on the findings. The finding could also have reproductive significance, as the gene may be passed down to children. An indication of susceptibility to Alzheimer’s disease also falls in this category. Researchers can consult with IRBs when determining whether to reveal these findings.
• Findings that have unlikely net benefit. The report recommends that these findings generally not be returned to subjects, as they could offer greater burden than benefit. These could reveal conditions that have no clinical significance and would not lead to a life-threatening condition or reproductive significance. Some of these IFs may have undetermined clinical actionability and reproductive significance, and would only cause distress for the subject. Examples of this include misattributed paternity, or the discovery of a very small nodule in the lung of a nonsmoker.2
There is also debate as to whether IFs should be reported to research subjects at all. "When you get sequenced in a clinical context, a physician ordered it and is there to help you interpret the results," says Robert Green, MD, MPH, associate professor of medicine in the Division of Genetics at Brigham and Women’s Hospital and Harvard Medical School, Associate Director for Research at the Partners HealthCare Center for Personalized Genetic Medicine, Boston. "Who is the intermediary if you get sequenced in a biobank? In the clinical context, the chain of custody for the sample and analysis is in a CLIA-approved, standard pipeline. The patient says, Please perform this test to help me with my health.’ Biobank donations in a research context don’t have the same fiduciary contract with the researcher." The amount of time elapsed between the collection of the sample and the discovery of the incidental finding, and whose responsibility it is to contact the individual with the result, can complicate disclosure. This creates a "parallel clinical system" with the research study just to deliver the care, Green says. "Some find that acceptable and some don’t," he continues. "I think this is a great issue, and I certainly don’t have the answer."