When the federal Office for Protection from Research Risks (OPRR) ordered Virginia Commonwealth University (VCU) to halt all human subject research in January, it was another punitive measure in that agency's 14-month-long series of actions that sent a clear message to the research community: Researchers spending federal tax dollars should diligently consider ethics in their work.
This particular case, however, especially troubled genetics researchers. It involved the father of a research participant who complained to federal officials that a VCU genetics study asking his daughter questions about her family history was an invasion of his family's privacy. Following an investigation of the university's institutional review board (IRB), OPRR and the Food and Drug Administration (FDA) suspended VCU's human subject research, citing administrative reasons.
The suspension didn't last long--the university's studies were reinstated by the end of the month. But the issue has raised hairs on the necks of uneasy genetics researchers about meeting federally mandated informed consent procedures in studies involving surveys about family medical history. It concerned the American Society for Human Genetics (ASHG) so much that on March 28 the society sent out a "membership alert" urging its 6,700 members to take notice.
Ethical WrinkleBecause research into the genetics of health and psychology climbs through a subject's family tree and across its branches to living family members, the situation adds another ethical wrinkle for scientists trying to ensure privacy of information. As private citizens question the intrusiveness of research studies into lives beyond that of the person scribbling a signature on an informed consent form, IRBs at universities and medical centers may be forced to reevaluate how they secure informed consent.
The central question for genetics researchers: If family members of research subjects are asked for medical history information, are the family members considered "human subjects" and should they have to sign consent forms?
The problem at VCU started with a project involving twins, a popular kind of genetics research study because of the siblings' similar genetic structures. A survey intercepted by the twins' parents asked questions the father thought were too personal. When he appealed to the university and then to the federal authorities, OPRR investigated.
In December the FDA suspended 1,000 research studies at VCU. Then in early January, OPRR suspended another 100 and revoked VCU's multiple projects assurance (MPA), the formal agreement between universities and the federal government promising compliance with federal research standards. Without an MPA, researchers cannot perform human experiments with federal funds.
VCU said in a press release that the OPRR suspended research because of a lack of documentation from IRB meeting minutes about continuing review of research protocol, and because IRB procedures for continuing review didn't comply with OPRR requirements. The university said it was a fundamental training issue, both of its IRB and of university researchers who needed to be more cognizant of federal regulations.
On January 31, OPRR lifted the suspension on the condition that the university, with a revised MPA, contract the independent Western Institutional Review Board as its IRB of record and begin immediate review of research project protocols.
The case raised the eyebrows of the American Society of Human Genetics in the fall after Linda Corey, professor of human genetics at VCU, contacted the ASHG Social Issues Committee about the case, says Uta Francke, a professor of genetics at Stanford University and past president of the ASHG. Francke says this kind of administrative procedure might lead to the problem of balancing potential harm of a study with undue regulatory burden on the researchers. "We are worried that human genetics research could be severely inhibited if this is enforced on a regular basis," Francke says.
So Francke led the ASHG drive to issue the March 28 membership alert, warning that if consent from so many people becomes necessary, collecting family histories "will be enormously cumbersome and prohibitive, and will seriously impede medical research."
The issue worries others in medical genetics. Louis Elsas, director of Emory University's Division of Medical Genetics and president of the Association of Professors of Human or Medical Genetics, says that the use of a medical history is part of general medical care. "To take the stand that all members of a family in which a pedigree is to be assessed must give informed consent is to limit benefits of health care to our citizens," he says.
But Francke says she clearly sees the other side of the debate. "The father also has a point," she says. If researchers are studying genetic linkages, they should consider whether family members about whom they collect medical history should be categorized as "human subjects."
Some research ethicists agree with her. "No one should obtain information for research purposes about an identifiable person without their express consent," says Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania. "If that hinders genetic research then so be it. The principle of consent by identifiable person is one I would argue cannot and should not be breached with respect to research."
Minimal RiskThe ASHG alert stated that "geneticists, both researchers and clinicians, need to work with their IRBs to help them understand the issues involved and the importance of family history to genetic research." One point the ASHG considers crucial is the use of waivers. An IRB may give waivers in cases where there is minimal risk to subjects--in this case the family members--from the research, and where the research does not interfere with any of the subjects' rights. "If the IRBs can show that the issue of human subjects was discussed at meetings, and that there is minimal risk, then it should be acceptable to issue waivers," Francke says.
The alert goes on to say that because there is no federal rule on gaining informed consent from family members, the IRBs at the local level must be vigilant in determining whether research protocols violate a person's privacy.
The bottom line at OPRR is that IRBs are responsible for considering all effects of their institutions' research protocols. Michelle Russell-Einhorn, OPRR director of regulatory affairs, says that the definition of human subjects is flexible. If a research protocol includes collecting information from people through a survey, then the researchers must consider whether those people are also research subjects, she says.
Russell-Einhorn says that for the VCU twin study, the IRB should have considered whether using a questionnaire to survey family members actually made those family members research subjects. "Practice may vary between IRBs, but they each have to determine their research protocols." Because 17 federal agencies are involved in signing off on the common rules that make up the federal regulations, "changes to regulations are very difficult to promulgate, and we have not considered changes related to genetics and family histories," she adds.
But Francke says the regulations were created before the boom in research genetics. The fact that genetic information, by definition, reveals facts about other persons, says Caplan, is a problem unique to genetics.
Francke says that the federal government may need to reevaluate the regulations so that there are clear guidelines for IRBs. She says that the ASHG plans to explore the issue in a summer workshop--organized by VCU's Corey--that will bring together representatives from patient advocacy groups, regulatory agencies, and professional societies. Concerned about the implications for her own genetics research, Francke says she hopes that discussion will lead to improved regulations to better serve both patients and researchers. "We want to help the IRBs deal with all of the issues."
Regardless, Caplan says, IRBs should insist that individual researchers develop broad consent forms and that they acquire consent for information that is linked or traceable to any living persons before it is accumulated and stored. He adds that research participants should "point out that any harm or adverse events suffered by them that is traceable to the disclosure or use of information collected by researchers would create a compensable harm that the researchers would be responsible for."
More to ComeThe question may be coming up for researchers at Rush Presbyterian-St. Luke's Medical Center in Chicago--an institution that has previously felt the wrath of the OPRR and that is now gearing up for a large national study on the genetics of depression. Funded by the National Institute of Mental Health, Rush and six other medical centers across the country will pursue what they say is the largest psychiatric genetics study to track how depression is passed through families.
On April 7, Rush issued a press release advertising for subjects to participate and saying that the study will include taking medical histories. They guarantee confidentiality, even between family members. However, the recent case at VCU and the issues it raised may mean a more extensive informed consent procedure.
Within the Department of Health and Social Services, the issue was brought up intramurally by Francis Collins, director of National Institutes of Health's National Human Genome Research Institute, at the Feb. 25 meeting of the HHS Secretary's Advisory Committee on Genetic Testing (SACGT). Committee chairman Edward McCabe, a professor of pediatrics at the University of California, Los Angeles, says his committee will look into the matter.
McCabe says that although the SACGT is primarily focused on clinical genetic testing--it was created in 1998 to gather public opinion and determine guidelines about risks and benefits of testing--the case brings up possible concerns for clinicians. Interpretation of genetic testing often relies on information outside of the test, he says. Using methods such as Bayesian analysis to interpret the results of genetic tests for a disease such as breast cancer requires knowledge about prior probabilities of the disease occurring in a family. "If a policy is established in research, then it will quickly move to the clinical arena," McCabe says.
He put the issue on the agenda for the next SACGT meeting, June 5-7 in Washington, D.C., where he says both OPRR director Gary Ellis and Richard Curtin, the father in the VCU case, will speak.
McCabe says he understands the concerns about private information and is keeping an open mind about his constantly changing field. "As geneticists, we will learn to adjust," he says. But he is quick to raise another concern that he says has not been part of current discussions: privacy for the research subjects themselves. People who enroll in research studies (e.g., for depression) may not be inclined to have family members know about their participation, he says. "The privacy of the subject, as well, has not been addressed so far."
Dave Amber (firstname.lastname@example.org) is a freelance science writer in Bryan, Texas.