Genetic research issues defy easy answers

The three Rs — reconsent, reidentification and returning results — beleaguer IRBs, researchers

While IRBs and researchers seem to agree on the most vexing issues in IRB review of genetic research, consensus still is elusive.

Even among researchers or within IRB circles, for example, there's not agreement on all aspects of when subjects must give fresh consent for a new use of their data or samples.

As stakeholders work through these questions, IRBs reviewing genetic research protocols will have to navigate their own way through the thorny ethical and practical questions.

Consent/Reconsent issues

When a person gives a sample for research of one kind and a scientist seeks to deidentify it and make it available for other research, does the subject need to give consent again? In surveys of IRBs and genetic researchers, the best consensus appears to be "sometimes."

"They were pretty much in agreement in certain scenarios, where you have subjects who only gave a sample for one specific thing and not to be put into a biobank," says Karen L. Edwards, PhD, MS, professor of epidemiology at the University of Washington and director of the university's Center for Genomics and Public Health in Seattle.

"But there are grayer areas — what if they did consent to do a genetic study but now you want to look at a different gene for maybe a related disease? Some people would interpret that as being within the spirit of the original consent and others don't."

P. Pearl O'Rourke, MD, director of human research affairs at Partners Healthcare Systems in Boston, MA, says the secondary use of samples raises ethical issues about respecting the subject.

"Let's say I gave my blood to study diabetes," she says. "Maybe I am suspect of physicians and the scientific community, but let's say people in my family have diabetes and I gave my blood solely to study diabetes. The idea that someone can take my blood, which I went out of my way to give, deidentify it and use it for schizophrenia research feels wrong."

She says institutions take a variety of approaches to handling this problem. Some word their consent very broadly, noting that science is moving quickly, that it's impossible to know now all the potential uses of a subject's sample and so their specimen may be deidentified and used for other research.

Others use a tiered consent process, saying specific uses are allowed — some provide a checklist — but others would require reconsent. Still others advocate having a person give consent to have a sample stored, then requiring that they be contacted for further consent to approve any further use of it.

"While on one level, reconsent for every use shows respect for persons, the logistics are chilling," O'Rourke says.

Edwards says wording of consent forms is one area where researchers look for guidance to IRBs.

"Not just for the study today, but anticipating what we can do a year from now, or five years from now, because the technology is moving so quickly. That would be an area to focus on for both groups."

She says development of best practices, based on areas where researchers and IRBs can find agreement, also would be helpful.

"That would seem to cut down on some of the back and forth," Edwards says. "If you're in this situation, you do, or you don't need reconsent and just be done with it."


Information technology has rendered even common demographic information to be highly identifiable. At the same time, O'Rourke says, whole genome sequencing and exome sequencing is challenging the definition of 'identifiable.'

"One of the huge issues is what is identifiable anymore?" she says. "There are so many reference sets — my DNA does not identify me, but it is unique to me. So if, somewhere, you have a reference set and it says 'this is Pearl O'Rourke's DNA,' it's like having my fingerprints on file."

O'Rourke says many investigators tell her that as technology improves, it will be practically impossible to create a truly deidentified tissue bank. She notes that IRB review as codified in the Common Rule is very dependent on the identifiability of the data or specimen.

"Remember that the definition of human subject includes 1) a person with whom you have an interaction for the purposes of research and 2) data or tissue that is personally identifiable," she says.

"In reality, we have a bar graph with black on one end, meaning identifiable, white on the other, meaning not identifiable, with a huge section of gray in the middle," she says. "The rather dichotomous Common Rule definition of a human subject as it relates to identifiability makes it difficult to address the gray sections.

"And what we're hearing from the public in a number of different studies is that they don't care if it's identifiable or not. They just say, 'If you're using my stuff, I'd like to know what you're using it for.'

Edwards says the potential for reidentification can be an area of tension between IRBs and researchers. In the GRRIP surveys, 34 percent of IRB professionals believed that reidentification was a likely outcome, and the same percentage thought that harm was likely to result from it. Seventy percent of researchers thought reidentification was unlikely, and 76 percent thought it unlikely for a participant to be harmed as a result of reidentification.

"Researchers say, okay, it might be possible, but it seems really unlikely, and even if it did happen, it's hard to imagine what the harms would be," she says. "But for IRBs, part of their function is to think about this, and say, well, if it's possible, then maybe you need to deal with it."

Return of research results

The return of results from research to subjects has become an issue in a variety of types of research. Genetics adds a layer of complexity, based on the sheer volume of data that can be generated from a sample, O'Rourke says.

She says IRBs and researchers need to distinguish between research findings — those expected to be generated by the research — and incidental findings, which although not part of the research hypothesis are generated in the process of research.

The return of research results is very dependent on the study's context, O'Rourke says. "For example, justification for return of research results is very different for a study focusing on a small family with a known disease, versus a study involving 20,000 'control' persons who are part of a large tissue bank. IRBs must consider return of results on a case-by-case basis. Many have a default of not returning results unless there is robust justification."

Return of research results raises a number of issues that should be considered: Was the sample taken and processed properly? Who is in the best position to interpret the results and relay them to subjects? What does an abnormal genetic result really mean? Is it possible that it will mean something different five years from now? Are we placing an unnecessary burden on subjects, knowing something that they can't do anything about?

While a majority of both IRB professionals and researchers in the GRRIP survey thought results should be returned to participants if their health or health care was affected, a majority of researchers (66 percent) believed the logistical challenges of returning results from large-scale studies made it "practically impossible for most researchers."

"I would say researchers are a little more hesitant to do it," Edwards says. "I think planning for how this should be done will be important. As a researcher myself, I do not feel qualified to be doing that. And so I think it needs to be discussed and some sort of mechanism figured out."