Rapid advances in molecular genetics have raised new questions about the use of human cells and tissue in research - questions that have prompted several groups of leading scientists, clinicians, and bioethicists to take a second look at the issues surrounding the research use of stored tissue samples.

Some of the answers that those groups have come up with, most notably in the form of a model "Genetic Privacy Act" and a set of recommendations published in the Journal of the American Medical Association (JAMA), have sparked heated debate in the biomedical research community, and NIH is no exception. To shed light on this complex topic, The NIH Catalyst asked Leslie Biesecker, a medical geneticist at NCHGR, and Mark E. Sobel, a molecular biologist at NCI, to share their perspectives.

Before jumping into the fray, consider this background. A project funded by the Human Genome Project's Ethical, Legal and Social Implications (ELSI) branch kindled the controversy last year with the release of a report that included a proposal for a far-reaching piece of federal legislation called the Genetic Privacy Act. Another group, consisting of participants in a workshop convened by NCHGR and the Centers for Disease Control and Prevention (CDC), sharpened the focus of the debate with its consensus statement, "Informed Consent for Genetic Research on Stored Tissue Samples," in the Dec. 13, 1995, issue of JAMA.

Both supporters and critics of those reports agree that genetic tests can furnish valuable information that can improve the health of an individual. However, casting a pall across these positive aspects are some negative factors. Release of genetic test information may adversely affect patients and their relatives through loss of health insurance, compromised employability, or psychosocial trauma. Therefore, health-care providers and researchers alike support safeguarding the confidentiality of test results. Conflict arises over how to protect the individual without compromising biomedical research that may benefit society as a whole.

Currently, human subjects are protected from invasion of privacy and other potential hazards of research by federal regulations put into place in 1981 by the Department of Health and Human Services' Office for Protection from Research Risks (OPRR). Under OPRR rules, all institutions that receive federal funds must establish Institutional Review Boards (IRBs) to review research involving humans and to stress the obligation to obtain informed consent.

Importantly, OPRR guidelines draw distinctions among anonymous samples, which are never labeled with identification that could link the specimen to a person; anonymized samples, which are rendered anonymous by irreversibly removing identifiers; identifiable samples, also referred to as linked, linkable, or coded samples, which are unidentified for research purposes, but can potentially be linked to the source through use of a code; and identified samples, which are labeled with a specific patient identifier such as a medical record number. IRBs are asked to consider a research proposal's potential risk to human subjects and whether it involves retrospective or prospective samples, and then, based on that information, to stipulate the type of informed consent to be used. Currently, research on retrospective, anonymous samples usually does not require IRB review because it is thought to pose little risk to human subjects. However, prospective research on identified samples must undergo IRB review and requires specific informed consent due to the risk it poses to a subject's privacy. Between these extremes are gray areas - and it is these gray areas that the recent recommendations address.


by Leslie Biesecker, M.D,. NCHGR

The current controversy about genetic research on stored specimens may be partly attributable to a misunderstanding that higher standards are being proposed for genetics research. In fact, what is being suggested is that current practice needs to be brought into line with existing regulations. The informed-consent issues for stored samples are not unique or novel but they do represent new twists on old questions. In addition, the history of research on stored specimens is one of a gradual evolution from clinical care and diagnosis toward exploratory research. This evolution was not always accompanied by a corresponding evolution in protections for human subjects.

My reading of the NCHGR-CDC workshop document is that it applies existing standards to activities that are currently being performed with inadequate or no informed consent. In a study published in IRB: A Review of Human Subjects Research, Robert Weir and Jay Horton of the University of Iowa found that only 23% of a nonrandomly selected group of 103 consent forms explicitly requested permission to bank specimens when such activity is taking place. Although these data do not directly address the use of previously collected specimens for research, they suggest that current practice is not uniform when it comes to consent for molecular genetics research.

Leslie Biesecker

It is fundamental to the ethical conduct of research that people be respected as autonomous agents. It is unacceptable by any reasonable standard to involve people in research without their consent (or the consent of their appropriately designated surrogate) when that research can have adverse effects on them. That this requirement poses formidable challenges for stored specimens is certain. What is also certain is that there are creative mechanisms for acquiring specimens and upholding autonomy. Many studies on allele prevalence can be conducted by stripping samples of identifiers. This stripping separates the sample from its source and insulates the source from adverse events. Other studies that require correlation with clinical characteristics can be performed by linking a small amount of clinical data (insufficient to identify the sample) and then removing the identifiers. This approach requires careful hypothesis generation and statistical analysis to ensure adequate power to address the hypothesis and inadequate power to deduce identities from the clinical data. Granted, this approach is not amenable to small scale "fishing expeditions" that occasionally identify important scientific avenues but such expeditions, in my opinion, are more often fruitless and wasteful.

Another solution is to develop banks of tissue for the express purpose of research. These banks could be prospectively collected with full informed consent for research into a particular area (e.g., breast cancer pathogenesis) and associated with a broad array of clinical data that would be useful for many future studies. The consent process can be streamlined by designing the bank to be used without the return of individual results to the subjects. Establishing research banks would initially be expensive, but this investment would be amortized by repeated use of the specimens and would obviate redundant clinical ascertainment. In addition, it is likely that a highly organized and prospective bank would contain better quality data than would less organized specimen acquisition by individual researchers.

Patients should have ongoing reassurance that all activities surrounding their clinical care are solely directed toward individual benefit. Patients must be informed and given a choice about whether to become research subjects. Just as importantly, research into the molecular etiology of disease must continue because of the enormous benefits to the public good. There is a clear difference between research and patient care despite arguments that blur the issues. Informed consent is crucial for maintaining a wall that separates clinical activities from research activities in order to avoid loss of confidence in clinical providers and to maintain the stature of the research enterprise. Erosion of that separation may lead to short-term gains for some research projects, but it will result in loss of trust in both researchers and clinicians and put our social consensus for biomedical research at risk.


by Mark E. Sobel, M.D., Ph.D., NCI

Although the following views are my own, they have been greatly influenced by my participation in an ad hoc committee of pathologists that was formed to respond to the "Genetic Privacy Act." Our goal is to seek a consensus that, while being respectful of informed consent, would not compromise patient care or unduly encumber research that is relevant to human disease.

Recent proposals to enforce confidentiality policies and to restrict genetic testing and research unless the subject gives specific informed consent for each test have a laudable goal: protecting the privacy and autonomy of human subjects. However, if not worded carefully, such policies might unintentionally conflict with pathologists' provision of diagnostic services, thus impairing patient care. Some proposals define a genetic sample as any tissue or bodily fluid from which DNA can be extracted, including urine and sputum. In addition, a patient's genetic status can be detected by tests that do not directly assess nucleic acid structure, such as protein, immunologic, biochemical, and morphologic tests. Under the broadest interpretation of some proposals, any diagnostic test is potentially a genetic test - creating a liability nightmare for diagnosticians.

Mark E. Sobel

Efforts to strengthen informed-consent guidelines seem to have concentrated on prospective tissue banks in which people volunteer samples exclusively for research use. There is little disagreement that informed consent is necessary and relatively easy to obtain in such a setting. Volunteers can be offered an array of options, including designating use of their samples for specific research studies, keeping samples anonymous, and requesting test results or counseling. However, a large proportion of research is currently performed on residual tissues that were routinely collected with general consent during medical care. Access to these "leftover" tissues has been critical to the advancement of medical knowledge. Nonetheless, some proposed and recently enacted state legislation offers patients the option of having their tissue destroyed after appropriate tests are completed. Other proposals would apply the same informed-consent procedures developed for tissue banks to residual-tissue collection. These complicated procedures may intimidate patients who are awaiting surgery. Even under the best of circumstances, it is impossible to anticipate all future uses of residual tissue. In these cases, general consent should be sufficient with the proviso that all research results remain confidential.

Both the Genetic Privacy Act and the NCHGR-CDC workshop recommendations suggest that IRBs review research proposals before samples are anonymized and also determine whether subjects consented to the research at the time the samples were collected. If not, researchers might be required to recontact patients to get informed consent. Also, IRBs would be asked to determine whether researchers can collect their desired data by using a protocol that allows for informed consent. Currently, federal informed-consent regulations do not apply to tissue samples taken from individuals who have since died. However, the NCHGR-CDC workshop statement recommends that informed consent be obtained from the dead person's heirs and/or legal executors before new research is performed. These added requirements to recontact subjects or families would significantly increase the cost and time of performing research - a heavy blow in an era of shrinking research dollars.

A current advantage of using anonymous samples for genetic research is the exemption from obtaining informed consent. However, the inability to obtain correlative information from the medical record (such as patient outcome) might severely compromise utility of the data. Therefore, many research projects today use so-called identifiable, or linked, samples. Although such samples are not readily identifiable by the casual observer, a code exists that can enable researchers to link the sample to the donor. Under what circumstances might research on identifiable samples be eligible for the minimum informed-consent procedure? We cannot dismiss the possibility that an ethical dilemma can arise when a linkable sample is used in research with only minimal informed consent. For example, while examining tissue for a research study, a pathologist might find a previously undetected cancerous lesion. Isn't there an ethical obligation to contact the patient? One solution being considered by the pathology community would include the following provisions: the code that links the sample to the patient's identity would be physically separated from the research setting, researchers must demonstrate that they enforce confidentiality policies, researchers must provide written acknowledgment that no one involved in the research will attempt to gain access to the patient's identity or any other information in the medical record unless approved by the IRB, and the IRB will determine the best course of action should it agree that patient contact is necessary.

It seems to many pathologists that the fundamental issue concerning stored tissue samples is not the genetic information obtained from such samples, but its use or misuse. Although authors of the Genetic Privacy Act and the NCHGR-CDC workshop statement argue that the consequences of misuse of genetic information are worse than the misuse of other medical information, the operative word to me is "misuse." As long as confidentiality is strictly maintained, the need for specific informed consent for retrospective research on residual, archived tissue does not serve a legitimate purpose and could encumber scientific research.

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