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Statement on "Genetics Testing in the New Millennium: Advances, Standards and Implications" by William F. Raub, Ph.D.
Deputy Assistant Secretary of Science Policy
Office of the Assistant Secretary for Planning and Evaluation
Office of the Secretary
U.S. Department of Health and Human Services

Good morning, Madam Chairwoman and members of the Subcommittee. My colleagues and I at the Department of Health and Human Services (DHHS) appreciate your interest in genetic testing. Thank you for the opportunity to describe our major activities that bear on the validity and utility of this emerging technology.

The Promise of Genetic Testing

The ongoing explosion of new knowledge about the structures and functions of human genes and new laboratory technology for analysis of genetic material is yielding a wealth of new tests for genetic traits. These tests offer more than improved capability for diagnosing existing disease. They also offer unprecedented means to estimate future disease risks for a currently healthy individual and for his/her offspring and, where an effective preventive intervention is available, to initiate medical or behavioral steps to reduce that risk.

Hundreds of genetic tests already are in routine use for diagnosis of disease. Most of them are in the form of clinical laboratory services - some of which are marketed directly to the public. Many more genetic tests are under development, and their number and variety are expected to grow rapidly within the next decade.

These advances stem in large part from research conducted and funded by agencies of the DHHS, especially the National Institutes of Health (NIH). In particular, the Human Genome Project - a joint venture of the NIH, the Department of Energy, and collaborators in the United Kingdom and elsewhere around the world - promises vast new insights in human biology and, thus, extraordinary advances in medicine and public health. Dr. Collins' testimony discusses the current status of this history-making endeavor.

Potential Harms from Genetic Tests

Yet, for all its promise, genetic testing can result in considerable harm. A test may be flawed and measure something other than that which it is purported to measure - thereby producing erroneous information. A test's result, though accurate, may be poorly or incorrectly characterized with respect to its clinical meaning - thereby giving health care providers and/or patients a false sense of confidence in the finding, whether positive or negative. Information about a genetic test may be communicated inaccurately or incompletely from laboratorians to health care providers and/or from providers to patients. Health care providers may employ a genetic test inappropriately - for example, employ a test that has little or no likelihood of benefitting the patient. Such shortcomings, individually or in combination, could compromise the quality of care or mislead patients with respect to their health status.

Even when a test is highly accurate and the clinical significance of the result is well understood, the outcome may do more to create anxiety for the patient than to provide reassurance. This can occur when an apparently healthy individual tests positive for a genetic marker associated with a disease that may or may not develop at some future time - perhaps for many years - and for which no validated preventative intervention is available. For example, a positive result from a test for one of the genes associated with breast cancer does not predict with certainty that the disease ever will emerge - much less when. Nor does a negative result mean that the disease never will emerge. Both provider and patient need to consider the pros and cons of performing genetic tests in the absence of clinical symptoms and make their decision on a case-by-case basis.

Last, but far from the least, the potential harms associated with genetic testing are not limited to the clinical milieu. Health care providers, employers, insurance companies, or others may handle information about genetic tests without adequate attention to privacy and confidentiality. As a consequence, individuals may be denied needed and deserved insurance coverage, or be discriminated against by current or prospective employers, or suffer psychosocial harms such as increased anxiety and altered family relationships.

The opportunities and challenges associated with genetic testing are discussed thoroughly in the report entitled "Promoting Safe and Effective Genetic Testing in the United States " - the principal product of the Task Force on Genetic Testing, which was commissioned jointly by the National Institutes of Health and the Department of Energy. The Task Force report is an invaluable resource for government, academia, and industry. The report outlines a set of overarching principles to guide the development and use of genetic tests and provides thoughtful recommendations in several areas: ensuring the safety and effectiveness of new genetic tests, ensuring the quality of laboratories performing genetic tests, improving providers' understandings of genetic testing, and ensuring the availability of effective genetic tests for rare inherited disorders.

DHHS Oversight of Genetic Testing

The findings and recommendations of the Task Force are highly relevant to DHHS' responsibilities for overseeing genetic tests. Three distinct statutory authorities are involved: the Medical Devices Amendments of 1976 to the Food, Drug and Cosmetic Act, the Clinical Laboratory Improvement Amendments (CLIA) of 1988 to the Public Health Service (PHS) Act, and those provisions of the PHS Act that govern the protection of human subjects of research. I will summarize each of these three authorities as they relate to issues raised the Task Force.

First, genetic tests are in vitro diagnostic devices and, thus, are subject to regulation by the Food and Drug Administration (FDA) as medical devices. To date, FDA has required pre-market review and approval for genetic tests packaged and sold as kits but has not actively regulated commercial, laboratory-based genetic testing services - which sometimes are referred to as "home brews".

Second, the CLIA statute, enacted by Congress to ensure the quality of laboratory testing in the U.S., regulates all sites at which testing is performed on specimens derived from the human body for health purposes. The requirements such laboratories must meet are based on test complexity; the more complex the procedure, the more stringent the requirements. Although a few CLIA requirements specifically address genetic tests, such tests generally are covered under the major CLIA standards for quality control, quality assurance, personnel qualifications, proficiency testing, and patient-test management. Thus, CLIA provides for regulation of the personnel, the procedures, and the environments in which genetic tests are performed. CLIA does not, however, provide for regulation of individual tests. In particular, laboratories that perform genetic tests on human specimens and provide test results to either the person tested or his/her health care provider are subject to regulation under CLIA by the Health Care Financing Administration (HCFA) and the Centers for Disease Control and Prevention.

Third, DHHS regulations for the protection of human research subjects may be applicable to human clinical trials of new or improved genetic tests. DHHS oversight comes into play if the trial is funded in whole or in part by a DHHS agency and/or if the trial is conducted with the intent to develop the test for commercial use. The Office of Protection from Research Risks, NIH, oversees the protection of human research subjects in DHHS-funded research. FDA oversees the protection of human research subjects in trials of investigational devices, drugs, or biologics being developed for commercial use. Laboratories, however, are not required to comply with these provisions since they provide a service and are not considered to be performing research.

Recent Relevant Actions by DHHS Agencies

Since the publication of the Task Force report in September, 1997, DHHS agencies - individually or collectively - have taken several important steps to foster the development and appropriate use of high-quality genetic tests. I will discuss each one briefly.

Secretary's Advisory Committee on Genetic Testing. In June, 1998, Secretary Shalala chartered this new advisory body in accord with the terms of the Federal Advisory Committee Act and assigned to the NIH the responsibility for providing staff services to the Committee. The costs of this secretariat are to be shared among the pertinent DHHS agencies. Formation of such a Committee was the primary recommendation of the Task Force on Genetic Testing.

The following excerpts from the Charter summarize its background and function:

Toward ensuring appropriate coordination of genetic testing activities and policies among pertinent DHHS advisory bodies, the Secretary's Committee is to include among its appointed members at least one current member of the Clinical Laboratory Improvement Advisory Committee and at least one current member of the Medical Devices Advisory Committee.

During the latter part of 1998, through a notice in the Federal Register, DHHS solicited nominations for membership on the Secretary's Committee. The solicitation produced 173 nominations. A DHHS interagency staff group assessed the qualifications of the nominees in relation to the requirements of the Committee charter and prepared alternative slates for consideration by the Assistant Secretary for Health and the Secretary. The Secretary intends to announce the first set of appointments to the Committee in the near future. FDA is also in the process of chartering a panel under the Medical Device Advisory Committee to assess tests in kits for human genes.

Quality of Active Ingredients Used in Laboratory-Based Genetic Tests. In November, 1998, the FDA promulgated a final rule -- "Medical Devices; Classification/ Reclassification; Restricted Devices; Analyte Specific Reagents"-- which introduced minimal FDA regulatory oversight of commercial, laboratory-based testing services. This rule specifies general controls for the active ingredients - also known as analyte specific reagents(ASRs) - of "home brew" assays. The controls cover registration and listing, quality systems requirements, and post-market reporting requirements. The rule also establishes labeling requirements for both ASRs and the "home brew" tests developed using them. It further restricts use of ASRs to facilities registered under CLIA as high complexity laboratories. With only a few exceptions, ASRs are exempt from premarket review. Currently, FDA applies its ASR requirements uniformly to all "home brew" tests, including genetic tests. However, FDA has preserved its flexibility to reassess this decision in the light of its further consideration of the recommendations of the Task Force on Genetic Testing and advice from the Medical Devices Advisory Committee and the Secretary's Advisory Committee on Genetic Testing.

Potential Refinements to CLIA Regulations. Late last year, the Clinical Laboratory Improvement Advisory Committee offered a wide-ranging set of recommendations for refining CLIA regulations in areas applicable to genetic testing. Among the topics addressed are definitions of genetic tests, informed consent, re-use of tested specimens, confidentiality of information about genetic tests, clinical information needed to establish the appropriateness of genetic testing, qualifications and responsibilities of laboratory personnel, quality control, specimen integrity, proficiency testing, validation of genetic tests, reporting requirements, and record retention. HCFA and CDC will assess these recommendations in the context of the continuing development of the overall DHHS regulatory framework for genetic tests and genetic testing.

Development and Dissemination of Information on Genetic Tests. As the number and variety of genetic tests increase, so will the need for data on their validity and utility. The Task Force on Genetic Testing recognized this emerging need and offered several recommendations for addressing it.

Late in 1998, the CDC and several collaborating organizations took an important step in this direction by launching the Human Genome Epidemiology Network (HuGE Net). The goals of the Network, as reported last year in the American Journal of Epidemiology, are three: to promote global collaboration in the development and dissemination of peer-reviewed epidemiologic information on human genes; to develop an updated and accessible knowledge base on the World Wide Web; and to promote the use of this knowledge base by health care providers, researchers, industry, government, and the public for making decisions involving the use of genetic tests and services for disease prevention and health promotion.

In a related effort during the past year, an interagency DHHS staff group has been assessing possible ways to achieve systematic national data collection on the validity and utility of genetic tests. This effort is driven by the realization that a comprehensive understanding of many, perhaps most, genetic tests may not be possible until the test has been used for a considerable period of time, in different population groups, and in a wide variety of clinical contexts. In the coming months, the DHHS group intends to expand its discussions to include representatives from other government agencies as well as academia, industry, health care providers, genetic counselors, and patient advocates. The objective of these broader discussions will be to identify promising approaches to national data base development - especially pilot projects that lend themselves to voluntary public/private partnership.

Considerations regarding Privacy/Confidentiality and Professional/Public Education. As indicated in Dr. Collins' statement, the National Human Genome Research Institute (NHGRI), NIH has continued its longstanding distinguished leadership in addressing ethical, legal, and social issues associated with the Genome Project in particular and the burgeoning field of genomics research in general. Through sponsorship of studies and workshops and through participation in other public fora, NHGRI has been at the forefront of efforts to raise public awareness regarding actual and potential instances of genetic discrimination by health insurers and employers. NHGRI also has been a prominent contributor to efforts to enhance the genetics-related components of primary and continuing education for health care providers and genetic counselors.

Conclusion