Although many patients want their genetic information, some experts caution that assigning participants access rights to research that is not validated could be putting the cart before the horse. [© 4designersart - Fotolia.com]
Since biobanks were established in the 1990s, researchers, patient advocates, and others have debated what if any duty investigators had to return incidental findings (IFs) and individual research results (IRRs) generated in genomic research back to the patients from which they were generated.
Four years after developing consensus recommendations to address responsibilities of researchers and institutional review boards (IRBs) when investigators discover IFs of potential health or reproductive importance to research participants, a group of researchers have joined on a follow-up project. The latest consensus paper, published earlier this year in Genetics in Medicine, built on the prior study by considering how to identify and manage IRRs and IFs in large-scale research involving biobanks.
Among core questions posed by the research team, led by Susan M. Wolf, J.D., of the University of Minnesota: What information, if any, about IFs and IRRs should be offered back to individuals whose genetic data and samples are stored in biobanks and archived datasets? Who has the responsibility of offering genetic/genomic research results to those individuals? What policies should govern the research practices of existing and new biobanks?
Assessing Need for Disclosure
The consensus paper mostly prescribes a 10-step process by which individual biobanks can develop their own answers. Within those 10 steps are some key answers to the questions posed. More importantly, researchers “should offer” to return IFs and IRRs that meet all of five criteria:
- findings are analytically valid
- return of findings comports with CLIA and other applicable laws
- patients have consented to receiving them
- findings are clinically actionable, allowing patients or their clinicians to “take action with significant potential to prevent or alter the course of the condition or to alter its treatment”
- findings reveal an “established and substantial risk of a serious health condition”
Researchers, the paper continues, “may return” IFs and IRRs that meet all except the “clinically actionable” standard. “Established and substantial risk of a serious health condition” is not defined in the consensus paper, however, answers are emerging from researchers and patients. In the same issue of Genetics in Medicine as the consensus paper, a team led by Robert C. Green, M.D., of Partners HealthCare Center for Personalized Genetic Medicine found that at least 80% of researchers favored disclosure to patients of 64 conditions or genes, 21 of which generated 100% agreement on disclosure.
And in a study published online March 8 by the American College of Medical Genetics, nearly all of 89 people in 10 focus groups in three U.S. cities (Washington, D.C., Philadelphia, and Denver) said they would want at least some individual research results returned. Priority was placed on results that are well understood. Interestingly, the magnitude of the risk conferred and actionability of the result were less important to participants.
Results like these suggest a rising tide favoring increasing disclosure of IFs and IRRs, even as the consensus paper urges more caution. The consensus authors are not alone: Publication of the consensus paper generated a letter from Mats G. Hansson, M.D., Ph.D., of the Centre for Research Ethics & Bioethics at Sweden’s Uppsala University, expressing a concern of many researchers toward full disclosure of IFs and IRRs.
“Assigning participants access rights to research that is not validated could be putting the cart before the horse,” Dr. Hansson wrote. “Incidental findings about an individual’s gene variants need to be verified analytically before being returned to the DNA donor. Even if a variant is accurately defined, further evidence of both clinical validity and utility are needed if its discovery is to be meaningful.”
Similarly, the consensus paper recommended against returning IFs and IRRs that offer “unlikely net benefit” for patients, “including findings whose likely health or reproductive importance or personal utility cannot be ascertained."
Who Shoulders the Responsibility?
Dr. Wolf told GEN that while the issue is far from settled, there is at least consensus that researchers and biobanks have a responsibility to address the issue. “If you look across the literature, I would say there is an emerging consensus that investigators do have a responsibility to address IFs and IRRs in advance of conducting a study, to figure out what they’re going to do with them, and to be clear with human subjects what the answer to that question is.” Dr. Wolf also acknowledged agreement among researchers that some IFs and IRRs include urgent findings that warrant at least consideration for return.
The consensus paper, not surprisingly, envisions a consensus between primary researchers, secondary researchers, and their biobanks in managing IFs and IRRs. The paper’s first recommendation designates a primary researcher and his or her institution as responsible for managing IFs and IRRs in their research. Biobanks, however, “should strive to ensure” development of explicit policy on returns of IFs and IRRs in the design of biobank research systems, then analyze whether a finding qualifies as a returnable IF or IRR.
The paper states that biobanks “should strive to engage actively” with patients and potential patients on their preferences for IF and IRR return, including methods of return. Researchers face arguably a much greater challenge: The paper recommends they communicate aggregate results not only via journals but also via “accessible media such as newsletters, email, and other means of communication appropriate for the population.” That’s a risky recommendation: Popular media, aimed mostly at a lay audience, requires simplification that can distort the nuances of often varied findings.
Also risky is the consensus paper’s recommendation that funders and regulators “have a crucial role to play in making sure that research and biobank budgets adequately support responsible management of IFs and IRRs.” The challenge here will be to deter overreach by funders and regulators into using budgets as a weapon of policy.
The consensus paper merits close study by the Presidential Commission for the Study of Bioethical Issues. As part of its study on whole-genome sequencing data privacy, the commission has explored the challenges biobanks face in securing informed consent from enrollees. At a meeting on February 2, Jane Kaye, D.Phil., director of the Centre for Law, Health and Emerging Technologies (HeLEX) at Oxford University, cited three concerns:
- Authority for biobanks is nationally based and often specific to their overseeing research ethics committees and institutional research boards, posing a problem for global networks seeking to share samples and data.
- Biobanks are limited in their ability to anonymize given the uniqueness of DNA data, the ability to replicate it, and the sharing of data and linking to other datasets globally.
- While medical research ethics calls for participants being able to withdraw from studies at any time, withdrawal cannot be promised when data and samples are shared widely.
“Computer datasets containing personal information must be continually archived, and it’s difficult to claw back minute segments of sequence spread over a global network and data used in multiple research projects,” Dr. Kaye told the commission.
The solution, Dr. Kaye said, requires more rigorous accountability of researchers for how genetic data is used, by articulating a right to privacy in genetic information. As she noted, a model for that right could be S and Marper v. United Kingdom, in which the European Court of Human Rights in 2008 maintained that authorities were violating the privacy rights of the continent’s citizens when they held samples of individuals who were arrested but later acquitted.
Along similar lines, Oxford Radcliffe Biobank and Ensuring Consent and Revocation (EnCoRe) have developed a dynamic consent interface allowing patients and research participants to decide how their data is used, how it is shared with other organizations, for how long, and where.
The interface and the consensus paper offer helpful models for engaging patients, researchers, and biobanks with each other. Yet another key challenge looms: deciding how expansive patient consent for returns should be. Should they be as broad as EnCoRe or along the lines of the consensus paper? One possible answer worthy of serious discussion is varying IF and IRR policies to the purpose of research, the same answer pondered by the presidential commission about patient consent for data access.