Should participants have access to study results?
Some research should include access protocols
As genetics research yields more and more information about individuals’ predispositions to disease and illness, researchers are beginning to question whether study participants should have access to the genetic information obtained about them. And should such access be granted to subjects in other types of research?
"It’s an evolving issue," says Rebecca Pentz, PhD, professor of hematology and oncology in research ethics at The Winship Cancer Institute at Emory University in Atlanta. "It used to be that we never returned research results or information obtained about the person back to that person. It just wasn’t considered necessary, and no one thought about it."
But as we know more about genetic influences on disease risk and disease processes, early intervention or monitoring could mean the difference between life and death for these people, Pentz notes.
As an ethical matter, researchers and former research participants are questioning the traditional view that information obtained in human studies should be under the sole control of the research entity. Studies have shown that people considering participation in research trials are interested in knowing the information that is gathered about them and its relevance to the purpose of the research, she adds.
"We are just becoming more sensitive to these people and their needs," says Pentz, who frequently works with the parents of children who are participating in oncology studies or who have done so in the past. "Patient advocates have played a huge role in that. They are beginning to say, We want to know.’ And researchers are saying, Well, of course, yes, you should know, but there are a lot of challenges that we face if we are going to provide that information to you.’"
Granting research subjects access to information obtained about them is not as simple as it sounds.
First, research participants are not going to have enough background knowledge to be able to understand the raw results or to be able to put them in context so that the information is relevant to them, say researchers and ethicists. If investigators plan on granting access, they must build education and counseling into the study protocol.
"If they have decided that information is to be provided, the IRB should be sure that the investigator has a plan for how much information will be given, what kind of information will be revealed, how it will be revealed, and whether there will be any substantive counseling available or whether the subjects will be referred to counseling, etc." says Anna Illtis, PhD, assistant professor in the Center for Health Care Ethics at St. Louis University. "All of those sorts of structures have to be in place at the outset."
And not all information may be suitable for dissemination. Researchers and members of the review board have the responsibility to consider what types of information participants can derive some benefit from and what, in fact, may be damaging.
"I think it’s important to distinguish between knowledge and information because in some research, you don’t necessarily have — at various points in the trial or even at the end — information that is actually going to help the person," notes Mary Anderlik, JD, PhD, associate professor in the Institute for Bioethics, Health Policy and the Law at the University of Louisville (KY).
If asked up front, participants may say they want to know any information obtained about them but not have a real context about what that might mean.
"If you participate in a study of genetic factors and heart disease and the end finding is that if you have a child, that child is at risk for some genetic disorder," she says, "that is not the kind of information you expected from the study. The same would be true of a finding of nonpaternity."
In genetic trials, there also are complex issues of privacy and confidentiality that can be raised, adds Illtis. "With genetic information, that is not just information about you, the participant," she emphasizes. "It is often also information about other family members that could be revealed to you, especially genetics trials that involve families. If one person chooses to know information and others don’t want that information revealed, and you reveal to the one person, you have essentially revealed genetic information about an entire family to that one person."
Participants also may not be able to comprehend the true implications such knowledge might have for their future, says Pentz. "Once you have the information, you have it. And with a lot of information about genetic predispositions, even researchers are not really sure what that means. Even if the information is not included in your medical record, if you are filling out an insurance form and it asks whether you have any information that you might be at higher risk for a certain type of disease, you have to decide: Am I going to tell the truth, or am I going to lie about this information? It is difficult situation to be in."
Most genetic trials now require genetic counseling for participants to be built into the overall study protocol. Researchers at Washington University in St. Louis who are studying genetic factors and Alzheimer’s disease are requiring that participants go to three sessions with a genetic counselor before the consent process begins, says Gerard Magill, PhD, director of the St. Louis University’s Center for Health Care Ethics.
"The purpose of these sessions is to inform the individual that he or she is in a family environment and to understand the significance of the information obtained both for themselves and their family, " he explains. "And it is designed to help people understand what the risk-ratios mean. What does a 13% increased risk mean? Or even a 40% increased risk?"
Even with such protections, however, it’s still a duty of investigators and IRBs to determine whether access to study results even should be offered. IRBs should be guided by the core ethical principles outlined in the Belmont Report — respect for persons and beneficence — as well as recent guidance published in the Health Information Portability and Accessibility Act (HIPAA)1 and findings issued by the National Institutes of Health, Department of Education (NIH-DOE) Task Force on Genetic Testing2 and the National Action Plan on Breast Cancer,3 Anderlik says.
"It’s important to make the distinction between therapeutic and nontherapeutic research and also between the findings you expect to generate vs. accidental findings," she continues.
Study protocols should stipulate what types of information the researchers intend to offer participants and how it should be offered.
"Researchers should anticipate and address these issues in their protocols: how they will handle findings related to the purpose of the study and what criteria they will use to determine this (i.e., validity of results)," Anderlik explains. "And they should indicate what they will do with accidental findings, such as a finding of nonpaternity in a medical study or finding of a chromosomal abnormality that may affect reproductive decision making in a study of genetic risk factors for heart disease."
In addition, she notes, if the study involves therapeutic research, HIPAA stipulates that participants have a right of access to any information in their medical record at the conclusion of a clinical trial, subject to certain exceptions.
For example, most research laboratory testing is performed in labs that are not certified under federal Clinical Laboratory Improvement Amendments (CLIA). Labs without such certification cannot give results suitable for clinical diagnosis or use. If testing is performed in this manner and investigators want to offer access to test results, they must have a protocol in place for contacting the participants at the conclusion of a trial and asking if they want to have testing repeated in a CLIA-certified lab.
How beneficial is info to the participant?
IRBs mainly should be involved in evaluating how beneficial the information will be to the participant, Anderlik says. In an article for an IRB ethics journal, Philip Reilly and colleagues advise review boards to consider three factors:4
- the magnitude of the threat posed to the participant that the information reveals;
- the accuracy with which data predict that the threat will be realized;
- the possibility that action can be taken to ameliorate the potential injury.
The NIH-DOE Task Force on Genetic Testing suggested standards for the use of genetic test results in clinical practice, Anderlik adds. These might be useful criteria for judging whether genetic test results performed as part of a research trial might be useful and relevant for the participants.
Those criteria are as follows:
- Scientific validity. Findings independently replicated and subject to peer review.
- Analytical validity. Reliably detects analytes (e.g., particular sequence) when they are present in specimens and does not detect analytes when they are absent.
- Clinical validity.
Data are available related to clinical sensitivity, specificity and predictive
"Clinical validation," she notes, "involves establishing several measures of clinical performance including: (1) the probability that the test will be positive in people with the disease [clinical sensitivity]; (2) the probability that the test will be negative in people without the disease [clinical specificity]; (3) the probability that people with positive test results will get the disease [positive predictive value (PPV)] and that people with negative results will not get the disease [negative predictive value].
"Parameters of clinical validity will depend in part on the group or population in which the test will be used," she notes. "For instance, the frequency of disease-related alleles might differ between ethnic groups, making it difficult if not impossible to extrapolate test sensitivity from one group to another."
- Clinical utility. Data permit evaluation of the benefits and risks that accrue from both positive and negative results.
Some experts have argued in favor of giving potential study subjects the option of requesting individual results even if nontherapeutic research, as part of the informed consent process, but others argue that there is not clear benefit to the participants and giving individual results runs the risk of making the results seem more accurate than they really are, she notes.
When access is impossible
Of course, information in some research trials is completely "anonymized." The information is stripped of all information linking it to a particular person, making sharing of research results with individual participants an impossibility, note Illtis and Anderlik.
Even in these cases — and in situations where investigators and IRBs determine that no useful information is available — participants should be informed that they will not have access during the informed consent process.
"You should always tell potential participants about the intentions of the investigators concerning the communication of results and inform them if provisions of information will not be possible," Anderlik says. "You might consider a newsletter or some other means of communicating aggregate results to participants."
Obviously, some trials take years, or decades, to complete and contacting participants once relevant information is known would be very difficult, if not impossible, notes Pentz.
However, in some cases, researchers have concluded that the information obtained was so important that they had a duty to contact the people involved, she says. "I worked with Louise Strong at MD Anderson [The University of Texas MD Anderson Cancer Center in Houston] in studies of families with the p53 gene mutation," Pentz says. "When she first started, 20-30 years ago, they didn’t know it was the p53 gene [that predisposed people to colon cancer]."
Over time, as the research revealed the genetic link, the researchers were left with a large pool of people that they knew had this mutation. In addition, there is significant benefit to people who know they have this mutation: They can get colonoscopies more frequently, and if detected early, the cancer can be treated.
Researchers worked out a system to contact people who had participated in the study and ask if they wanted to get re-tested at a CLIA-certified lab, she notes."
"These days, if you have something like the HMPCCC gene, we are not going to do a research study on that within a family and not have provisions within the protocol for genetic counseling and then offering of test results," she notes. "We are evolving toward feeling responsible, at least when there is a medical intervention available, to let people know and build that access into the protocol." A newer debate in the field of research ethics is whether participants have a right to request their personal information, whether or not investigators feel that it provides useful information, Pentz adds.
Researchers with the Children’s Oncology Group — researchers at different institutions who collaborate on pediatric oncology studies — are exploring ways to build in participant access to information into their protocols.
"Ethically, we believe that if people take the trouble to join a research trial, they are partners in the research; and if they are partners, then we owe them the results," she says. "It is a complicated issue, particularly in oncology, when the results may be seven to nine years later."
The group is currently preparing a study that will involve building information access into the protocols of a few studies on a pilot-testing basis. Some researchers have balked at the idea of disclosing individual information after the fact, both because of the added costs and the potentially painful information that may be revealed to the parents of children who participate, she notes.
"What if their child was in the arm of the study that proved to be the less-effective treatment?" she asks. "That’s going to be true of half the people involved. And maybe their child died."
Some parents may not want to know what role their child played in the research, but some parents will, she says.
"The Patient Advocacy Committee of the Children’s Oncology Group is providing feedback to the researchers — these are parents of children who had cancer and who have died," she explains. "They are saying, Look, parents aren’t as crazy as you make them out to be; we know these things. Some people won’t want to know, but you need to have a nonthreatening mechanism for saying: The paper is now ready to be published. You were partners in the research; we will offer you a conversation with your doctor who will explain everything to you.’"
Such an approach also will help the researchers obtain information about long-term effects of some of the treatment regimens, she adds.
"We are getting better at curing cancer, but we now have these long-term effects of aggressive cancer therapy," she says. "So we also need to be able to bring people back in years later and share the new knowledge with them."
1. HIPAA Privacy Rule. 45 CFR 164.524.
2. Holtzman MA, Watson MS, eds. Promoting Safe and Effective Genetic Testing in the United States: Final Report. Baltimore: Johns Hopkins University Press; 1998.
3. Cancer Diagnosis Program. National Cancer Institute. National Action Plan on Breast Cancer; Model Consent Form for Use of Tissue for Research. Web site: www.cdp.ims.nci.nih.gov/infcondocs991.html.
4. Reilly P. When should an investigator share raw data with the subjects? IRB: Ethics & Human Research (formerly IRB: A Review of Human Subject Research); 1980; 2(9):4-5,12.