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Regulating Genetic Information

David Korn

Dangerous Intersections

New proposals to protect genetic privacy may collide with the public interest in fostering medical research

Over the past two years, several prominent working groups and expert committees have circulated or published position papers attempting to address widespread public anxiety over the potential uses and abuses of genetic information. A number of proposals put forth in these papers--particularly those focusing on the role of informed consent in guiding genetic testing and research--have provoked deep concern among scientists who work with human tissue samples. These researchers are imaginatively employing the new and powerful tools of molecular biology to gain unique insights into human diseases. They fear, however, that the restrictions called for in these proposals would severely burden, if not fatally encumber, this entire class of promising research.

Our nation's hospitals, especially the academic medical centers, collectively contain an enormous archive of human tissue samples. Originally removed for medical reasons and preserved for future reference and study, these specimens have long provided a rich resource for clinical investigation. Using conventional methods of histopathologic analysis, scientists have gained a wealth of insights into the nature and course of human diseases. Because of the limits of those research methodologies, however, the results of these studies have usually had little relevance for the individual patients (known as "sources") from whom the tissues had been obtained. Accordingly, the practice and standard of informed consent for this vast body of research have been quite minimal.

Most studies involving human subjects require case-by-case review and approval by local institutional review boards (IRBs) as well as the observance of stringent protocols for obtaining patients' informed consent. Studies using archival human tissue specimens, however, have historically been reviewed under more relaxed requirements. Thus, the consent forms routinely used for hospital admissions or operative procedures usually contain only a line or two stating that any removed tissue not required for diagnostic purposes may be used for teaching and research. Local IRBs have approved this type of informed consent, which I shall call minimal informed consent, on the grounds that such research poses "minimal risk" to patient sources and does not "adversely affect [their] rights and welfare" and that the research "could not practicably be carried out" if the full consent protocol were observed.

All that promises to change dramatically with the introduction of powerful new research techniques, such as the use of monoclonal antibodies or the polymerase chain reaction. Pathologists can apply these methods to preserved tissue specimens to identify specific abnormalities of gene structure and expression. For instance, they may be able to determine whether specific genetic abnormalities in individual cancers, for example, breast or prostate, correlate with different degrees of aggressiveness or responsiveness to therapy. Such unprecedented insights would help clinicians diagnose cancers or other medical conditions far more precisely and tailor their treatments accordingly, and may lead to new advances in therapy or even prevention.

The advent of these new genetic research techniques, however, has changed the calculus of risk. In the course of their studies, researchers may discover information that could profoundly affect the lives of the tissue sources and even their relatives. For instance, they may discover that a genetic change found in certain tissue samples is a germline mutation (one that is heritable), rather than a somatic mutation (a spontaneous, localized genetic change). Research results that detect the presence of germline mutations may have predictive value not only for individual patients but for their close relatives as well. Moreover, the inappropriate use of genetic information obtained in the course of research could have dire consequences for individuals and families, affecting critical personal matters such as employment, insurance coverage, and the decision whether to have children. The sensitivity and fears of potential abuse of this information have given rise to the present public concern with issues of informed consent.

Already, the Office for Protection from Research Risks, which oversees the federal regulation of research involving human subjects, has issued guidelines emphasizing that because genetic research protocols involve psychosocial rather than physical risk, such protocols--even those involving archival tissue samples--should no longer automatically be considered of "minimal risk" and therefore eligible for expedited IRB review. In addition, a number of private organizations have set out to take a fresh look at the protection of autonomy and privacy in research and the requirements for informed consent in genetic testing and research with human tissue specimens.

The most influential entity studying this issue is likely to be the Ethical, Legal and Social Implications (ELSI) Program of the National Center for Human Genome Research, sponsors of the Human Genome Project, which has established a working group to examine these matters.. Although the working group has not yet expressed an official opinion or issued a formal statement, ELSI has supported efforts by a number of other organizations, including the drafting of a document called the Genetic Privacy Act, which proposes sweeping model legislation and has been widely circulated to the Congress and state legislatures. Many of its provisions have already been embedded in legislation enacted in 1995 in Oregon, and some have found their way into proposed legislation introduced last summer by Senator Pete Domenici. In addition, a number of other organizations, including the American College of Medical Genetics, the American Society for Human Genetics (ASHG), a committee working under the auspices of the National Action Plan for Breast Cancer, the Task Force on Genetic Testing of the National Institutes of Health-Department of Energy Working Group, and, of particular importance, a working group convened jointly by the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention, have published position papers.

Given the current climate of anxiety about genetic privacy and the privacy of medical information more broadly, there is likely to be escalating public pressure to resolve these issues legislatively or through the hasty enactment of guidelines and regulations. Yet, proposals such as these may frame the terms of the debate over genetic privacy for years to come and lead to unintended consequences of profound import. It is disappointing, therefore, that each of these proposals is directed more at circumscribing the feasibility and scope of genetic inquiry than at creating more effective protections against the inappropriate use of clinical and research data derived from this vital area of research.

Stringent standards

There seems to be broad agreement among the various documents that the dramatically enhanced power of the new research methodologies demands that informed consent procedures for genetic research on tissue samples be significantly strengthened. Different proposals, however, suggest different criteria for determining how stringent those standards should be. Two of the most widely circulated documents--the Genetic Privacy Act and the Consensus Statement from the NIH-CDC Working Group--have stirred serious discontent among scientists who work with human tissue samples.

The Genetic Privacy Act, the most extreme of the documents, reflects an important school of bioethical and legal thought in stressing that genetic information is qualitatively different from other types of personal information and so requires special protection. Thus, the Act sets forth elaborate consent mechanisms for information derived from DNA analysis. Each person who collects a DNA sample for the purpose of performing genetic analysis must, among other things, provide a notice of rights and assurances prior to the collection of the sample, obtain written authorization, and restrict access to DNA samples to persons authorized by the sample source. The authorization includes a description of all approved uses of the DNA sample and notes whether or not the sample may be stored in an identifiable form, whether or not the sample may be used for research under any circumstances, and if so, what kinds of research are allowed or prohibited. The Act further states that an individually identifiable DNA sample is the property of the sample source, who thereby retains the right to order its destruction at any time. In any event, the sample must be destroyed upon the completion of the specifically authorized genetic analysis or analyses unless retention has been explicitly authorized or all identifying information is destroyed.

The Consensus Report from the NIH-CDC Working Group also adopts a stringent position on most of these issues. It interprets narrowly the existing regulations that govern research involving human subjects and states that all research with human tissue samples should require IRB review, whether the tissue samples are anonymous, anonymized (originally identifiable but stripped irreversibly of all identifiers and impossible to link to sources), identifiable (linkable to sources through the use of a code), or identified. The report also calls for full informed consent for tissue samples that are obtained in the course of clinical care as well as for any existing tissue samples that can be linked to sources. Its stringent standard of informed consent includes many of the provisions contained in the Genetic Privacy Act: for example, giving the subject authority to determine whether or not samples may be anonymized for research, whether they will share in the profits of any commercial products that might arise from the research, whether they are willing to have their samples shared with other investigators, and whether they wish their specimens to be used only in the study of certain disorders.

The national tissue archive has always been and should remain a public resource not a depository of private property.

Other proposals seek to vary standards for informed consent based on whether studies are retrospective or prospective--that is, whether they use pre-existing samples or samples being drawn for future use--and whether the samples to be used are anonymous or not. For example, the report of the Rapid Action Task Force of the ASHG states that all human genetic research protocols must undergo IRB review and that stringent informed consent is necessary for all prospective studies. Moreover, it would not allow researchers to ask subjects to grant blanket consent for future genetic research projects if the tissue specimens will be identifiable. In retrospective studies with identifiable samples, investigators are required to recontact sources and obtain their full informed consent, although the IRB may waive this requirement. Full consent is not required for retrospective studies with anonymous or anonymized samples.

The need for definitions

It is noteworthy that the terms "genetic information," "genetic research," and "genetic testing" are often used in the various documents without further definition. Where they are defined, however, the definitions are very broad: for example, the analysis of DNA, RNA, chromosomes, proteins, or other gene products to detect diseaase-related genotypes, phenotypes, or karyotypes for clinical purposes. Among all of the documents produced to date, only the report of the NIH-DOE Task Force on GeneticTesting circumscribes the definition of genetic testing by stating that the authors do not intend to include in their definition tests conducted purely for research, and that they are most concerned about the predictive uses for genetic tests. The Task Force report also seeks to exclude "tests for somatic cell mutations, unless such tests are capable of detecting germline mutations."

Even with this exclusion, however, the definition would encompass much of what comprises the routine surgical pathology work-up of patient specimens, as well as almost all molecular research with human tissue samples. In most cases, tissue from lesions is juxtaposed with normal residual tissue on microscopic slides, so that any test for a putatively somatic genetic alteration in the lesion could readily detect the presence or absence of change in the neighboring tissue, indicating the presence of a germline mutation. Indeed, researchers often do not know at the outset of their research whether or not they will stumble onto a germline mutation, so the distinction between the two types of testing--although important in theory--is difficult to draw in practice.

In the context of contemporary molecular biology, the terms "genetic research," "genetic test," or "genetic sample" are exceedingly broad. As used in the various proposals, the terms are so inclusive and imprecise that it is inadvisable--and indeed impractical--to use them as the basis for new research guidelines or regulations. By defining a genetic sample as any human specimen that contains DNA and a genetic test as any test applied to that specimen that can reveal genetic information (a definition that includes not only direct analyses of DNA but also tests of RNA expression or protein products), these proposals would apply new and stringent consent requirements to many highly informative diagnostic tests that are used routinely in pathology laboratories to work up tissue specimens, as well as procedures that are essential for the conduct of research. As a result, their recommendations would not only contradict the goals of sound medical practice, patient management, and even law, but could wipe out a broad swath of vital research.

For instance, it is commonplace in pathology practice that the initial examination of a specimen may indicate the need for additional diagnostic tests. These tests--often by definition "genetic" tests--are typically carried out in an ordered sequence, where each is dictated by the results of the preceding. Under requirements such as those of the Genetic Privacy Act, the pathologist would have to return to the patient to obtain specific informed consent before performing each of the tests in the diagnostic sequence.

To permit patients to require that tissue samples be destroyed not only contradicts sound medical practice but is actually illegal. The authors of these reports may not be aware that state laws as well as medical accreditation bodies require health care providers to maintain tissue archives for purposes of patient management for up to twenty years. The reason is straightforward: archival tissue samples are part of the medical record. For example, if a patient has a cancer excised and a tumorous lesion later recurs, it is essential for diagnosis and management that the earlier tissue specimen be retrievable for pathologic review to determine whether the new growth is a metastasis or an entirely new tumor. Patients simply cannot be allowed to mandate the destruction of clinical specimens as soon as particular "authorized" tests are completed.

More seriously, by failing to distinguish between diagnostic or predictive testing and tests conducted for purposes of research, these proposals would impose a tremendous burden on laboratory researchers using genetic techniques. For example, scientists may use genetic analyses on human tissue specimens to try to discover whether a genetic marker is associated with a particular disease or determine whether certain kinds or patterns of mutations are correlated with particularly aggressive or therapeutically unresponsive cancers. These research studies would be subject to the same stringent consent requirements as tests used for clinical or diagnostic purposes.

It is probably true, as the NIH-CDC Working Group points out, that the current language in routine operative and hospital consent forms about the use of tissue samples in research is inadequate and that IRBs should establish a higher threshold for "impracticality" as a criterion for waiving a more stringent consent protocol. Nonetheless, the practicality of some of the complex informed consent procedures that have been proposed is highly dubious. The requirement that researchers seek new consent from former patients or their next of kin for research with archival materials is particularly burdensome. In an era in which the demand for biomedical research funding chronically outruns the supply of funds, such consent requirements would impose new administrative, logistical, and financial burdens of enormous magnitude.

The proposals for obtaining prospective consent for human tissue specimens are also problematic. The draft consent forms that have been circulated are lengthy and complex. They might conceivably be workable in protocols involving studies of healthy populations. However, introducing lengthy and complex speculations about the hypothetical future uses of samples in genetic research would likely be confusing and intimidating to anxious patients awaiting surgery whose primary concern is their own health and might well encourage them to forbid any research at all on their specimens--a reaction well known in the epidemiology community that researchers have dubbed "uninformed denial."

Equally inadvisable would be a consent procedure that offered patients multiple opportunities to limit or prohibit the kinds of research that could be done with individual specimens. To construct tissue archives with detailed instructions and proscriptions attached to each specimen would be a logistical nightmare. More important, it is impossible to foresee the kinds of research questions that might arise in future years, and to cramp future research opportunity in such blanket fashion would be tragically unwise.

In theory, researchers could solve this dilemma by relying only on fully anonymous or anonymized tissue samples. Most proposals would continue to require only minimal consent for the use of these specimens. However, this solution proves unrealistic in practice. The national archive of human tissue specimens, which has historically been the predominant source of tissue samples for research, is overwhelmingly comprised of specimens that were removed for medical reasons and must remain identifiable for future access on behalf of the patient, in the same way that the patient's medical record must remain identifiable. Furthermore, researchers often need to obtain follow-up clinical information in order to determine whether their findings are in fact significant in diagnosing or predicting the course of a disease. Given the impossibility of creating a totally anonymous tissue archive, the imposition of stringent consent requirements would burden the vast majority of research involving archival tissue specimens.

The terms used in these proposals are so inclusive and imprecise that it is inadvisable--and indeed impractical-- to use them as the basis for new research guidelines or regulations.

Redressing the balance

The proposals reviewed here reflect the heavy input of bioethical opinion and perspective, but they are insufficiently attentive to the requirements of medical and biomedical research practices. Put simply, they come down too heavily on the side of private interest at the expense of public benefit and thereby distort the delicate equipoise that must always be respected in research involving human subjects.

To help to redress that perceived imbalance, I offer the following principles:

It has been too readily accepted that genetic information is unique and different in kind from other information contained in a patient's medical record. To the contrary, I would argue that the issue is one not of qualitative difference but of degree; and the distinction is important in devising appropriate and workable mechanisms for protecting confidentiality. Although it is true that genetic information is intensely private and can be sensitive as well as predictive, the same is true for much of the information that may be in the medical record; nor is it the case that only genetic information is susceptible to misuse for discriminatory purposes by insurers, employers or others.

It is interesting to note, for instance, that the authors of the Genetic Privacy Act define "private genetic information" so as to exclude genetic information derived from a family history or from routine biochemical tests, on the grounds that the broader definition would make virtually all medical records subject to the provisions of the Act and so would require the overhaul of well established medical procedures and practices. Instead, they define it as information derived from "an analysis of the DNA of an individual or of a related person."

This discussion is intriguing, for it indicates that the authors at least glimpsed the artificiality of the distinctions they were creating and recognized the impracticality of trying to embrace all genetic information within their definition. Unfortunately, they seemed unaware of the entirely analogous impracticalities that arise from attempting to apply these strictures to contemporary diagnostic pathology and biomedical research practices.

The protection of sensitive, stigmatizing, and even predictive information is not a new issue for medicine, nor is the compelling need to strengthen the legal framework of protection against inappropriate or forced disclosure or discrimination limited exclusively to genetic information.

Much more careful attention should be paid to the definition of terms. In particular, the definition of a genetic test should be narrowed to focus on the purpose of the study, not on the particular research methods used. The term "genetic test" should be applied only to tests that are carried out on healthy, or presymptomatic, subjects prospectively for the explicit purpose of determining the presence of heritable risk factors whose predictive significance is well established. This definition would include tests performed on a population sample to determine the distribution of such factors for epidemiologic purposes. Appropriately defined, genetic testing should certainly meet a high standard of informed consent, for it entails potentially significant social, psychological, and financial risks.

By contrast, research studies on human tissue specimens, even if they involve tests to examine gene structure and function, ordinarily should not be defined as "genetic tests." (IRBs would always have the prerogative to decide for cause that particular research protocols warranted exception from the general rule.) They should not be considered diagnostic and should not be entered into the patient record or communicated directly to the tissue source. Genetic data resulting from research are nascent, in the sense that they cannot be fully interpreted until they have been replicated, validated analytically and clinically, and demonstrated to have clinical utility. Only then can the medical community determine whether the results provide the basis of a useful genetic test that should be introduced into clinical practice. In addition, research results are obtained under experimental conditions that ordinarily do not meet the accreditation standards for diagnostic laboratories.

In the event that research yields information that the investigators believe could be of significant consequence to particular individuals, the investigators should bring the matter before the local IRB for determination of whether, how, and to whom to communicate the results.

There appears to be general agreement that the degree of informed consent required for the use of human tissue samples in research depends largely on whether or not the samples can be linked to specific individuals. The problem is that so few samples are anonymous or anonymized. To facilitate tissue-based research, it is essential that research with coded samples continue to be eligible for IRB approval under a minimum informed consent procedure. At the same time, research institutions should take whatever steps are necessary to limit investigators' access to information about the sources' identities. The crafting of credible protective mechanisms will not be a simple task and demands thoughtful consideration.

When samples for research are accumulated in a central repository, a feasible approach is for the hospitals or clinics where the samples originate to code them before depositing them in the registry. The coded samples could then be distributed to investigators. If an investigator requires follow-up information pertaining to specific samples, the request would have to be routed back through the registry and then to the originating hospital or clinic. Identifying information would thus remain restricted to points remote from both the investigator and the registry.

This solution, however, would not apply in academic medical centers, where the central tissue repository typically resides within the pathology department and individual clinicians may compile their own collections of tissue samples from known patients. In such cases, plausible fail-safe coding mechanisms are much more difficult to design. Nonetheless, if the creation of such mechanisms becomes an absolute requirement for permitting research on human tissue specimens to continue under a minimum informed consent procedure, it would certainly be worth the effort to protect patient privacy and assuage public anxiety.

Any modified consent procedures proposed for tissue samples obtained in the clinical setting must be clear and simple. They should be crafted on the premise that the national tissue archive has always been and should remain a public resource and not, like a savings bank, a depository of private property. The blanket imposition of stringent and complex consent requirements offering multiple options to limit or prohibit research, in settings of high patient anxiety, would have a stifling effect on archival tissue research that could only be justified if it served a compelling public interest. In my judgment, such a criterion has not been met.

Federal and state governments should continue their efforts to protect the confidentiality of sensitive medical information resulting from genetic testing and broaden them to include the results of genetic research. Very recently, a number of states have enacted legislation to prohibit employment or insurance discrimination on the basis of genetic testing or information. Similar bills have been entered into both Houses of the Congress, and both the House (H.R. 3103) and Senate (S. 1028) versions of health insurance reform legislation contain provisions that would prevent health insurers from discriminating on the basis of genetic information. Moreover, the U.S. Equal Employment Opportunity Commission recently extended protection from discrimination in employment under the Americans with Disabilities Act to discrimination on the basis of genetic predisposition. These are important first steps in allaying public anxieties about genetic privacy.

Similar concerted energy should be devoted to strengthening protection of the information obtained in genetic research. One valuable mechanism might be the statutorily authorized Certificate of Confidentiality, issued on a discretionary, project by project basis by the Public Health Service (PHS), to protect the identities of research subjects in specific types of research studies. Among the categories of information deemed sensitive are "information that if released could reasonably be damaging to an individual's financial standing, employability, or reputation within the community," and "information that normally would be recorded in a patient's medical record, and the disclosure of which could reasonably lead to social stigmatization or discrimination." It is striking how closely these criteria mirror those applied to the potential misuse of genetic information.

I suggest that the reach of the Certificate of Confidentiality be broadened to include, as a class, all genetic information created in research. This could probably be accomplished through regulation under the existing statute and might be implemented through an assurance mechanism whereby protection would be extended to research institutions that had put into force an institutional confidentiality policy that met federally specified requirements. For this purpose, I would exploit the imprecision of current definitions of "genetic information" and cast the protective net as widely as possible in the hope of providing maximum alleviation of public anxiety.

Most urgently, we need to establish an effective process to guide the public debate and assure that its resolution strikes the proper balance between the conflicting interests of individual privacy and the public benefits of genetic research. To date, these issues have been discussed extensively by geneticists, ethicists, lawyers, and patient representatives, with a nearly exclusive focus on ethical issues. There has been inadequate participation by the larger biomedical research community, especially those who are engaged in genetic research on human diseases. Many of the flaws and oversights of the proposals reviewed here (particularly those involving clinical diagnosis) almost surely are the inadvertent result of inadequate input into the process.

One approach that could bring order and direction to this debate and increase the odds of a constructive outcome would be for the director of the NIH to convene a committee of experts representing an appropriate range of disciplines to review this problem and propose recommendations through the Director's Advisory Committee. Although not foolproof, this process is time-honored and has been used successfully in the past to develop positions of broad agreement on controversial or complex issues, such as fetal tissue research or the NIH intramural research program. By soliciting input from a variety of constituencies, such a committee could ensure an orderly and balanced discussion and help frame a debate that is presently rudderless and susceptible to premature political intercession. The committee's recommendations could set the parameters in an important area of emerging science policy and provide a credible basis for whatever statutory, regulatory, or less formal mechanisms may be deemed necessary.

As biomedical science continues to progress, it will continue to raise new and challenging issues of genetic privacy, informed consent, and the ownership and custodianship of patient data. We will continue to be vexed by troubling questions that lie at the boundary between our society's commitment to individual autonomy and its compelling interest in the benefits that flow from its generous investment in biomedical research. It is important that the policies that emerge from the current debate respect patients' rights to privacy and to informed consent; at the same time, however, they must not unduly encumber researchers' access to the nation's treasury of tissue samples nor inhibit its future growth. The thoughtful resolution of these issues can set an important precedent that will inform future decisions in this difficult arena.

Recommended reading

George J. Annas et al. The Genetic Privacy Act and Commentary. Health Law Department, Boston University School of Public Health, Boston, MA. 1995.

Ellen Wright Clayton et al. "Informed Consent for Genetic Research on Stored Tissue Samples". JAMA 274: 1786-1792, 1995.

C.L. Early and L.C. Strong. "Certificates of Confidentiality." American Journal of Human Genetics 57: 727-731, l995.

Task Force on Genetic Testing of the NIH-DOE Working Group on Ethical, Legal and Social Implications of Human Genome Research, Interim Principles. Washington, D.C.: Office of Communications, National Center for Human Genome Research.

B.M. Knoppers and C.M. Laberge, "Research and Stored Tissues. Persons as Sources, Samples as Persons?" JAMA 274: 1806-1807, l995.

E.R.B. McCabe et al. "American Society of Human Genetics Rapid Action Task Force Report on Informed Consent for Genetic Research." American Journal of Human Genetics, forthcoming.

National Academy of Sciences/Institute of Medicine. Assessing Genetic Risk: Implications for Health and Social Policy. Washington, DC. National Academy Press, 1994.

Office for Protection from Research Risks, "Human Genetic Research" in Protecting Human Research Subjects, Institutional Review Board Guidebook, National Institutes of Health, 1993.

J.A. Phillips et al. "American College of Medical Gentics Statement. Policy Statement on Storage and Use of Genetic Materials." American Journal of Human Genetics 57: 1499-1500, 1995.


David Korn is Distinguished Scholar in Residence at the Association of American Medical Colleges, Senior Scholar in Health Science Policy and Administration at the Association of Academic Health Centers, and professor of pathology at the Stanford University School of Medicine.