HUM-MOLGEN archive: DIAG, ETHI: genetic lab standards

Here is the complete discussion of the first meeting of the Task Force on Genetic Testing. It will shortly be available on HUM-MOLGEN'S www site. Hans Goerl, ETHI Editor ********************************************************************** TASK FORCE ON GENETIC TESTING of the NIH-DOE Working Group on Ethical, Legal, and Social Implications (ELSI) of the Human Genome Project 550 N. Broadway, Suite 511 Baltimore, Maryland 21205 Summary of Issues Discussed at the First Meeting of the Task Force on Genetic Testing April 13-14. 1995 - Baltimore. MD I. Definition of Genetic Tests. The definition is critical to the scope of the Task Force's work and its recommendations. For now, the Task Force is using the following broad definition: The analysis of human DNA, chromosomes, proteins or other gene products to detect disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes. Such purposes include prediction of disease risks, idernificanon of carriers, monitoring, diagnosis or prognosis, but not do not include tests conducted purely for research. The Task Force has not decided whether acquired as well as inherited mutations fall in its purview. II. Issues in Genetic Test Development. A. Scientific Validation: Of prime concern to the Task Force is the validation of genetic tests. Determining how good a test will be in terms of sensitivity, specificity and predictive value will often require tracking large numbers of people, perhaps for many years. There is often no "gold standard" by which to measure these tests. Validity may differ between high-risk groups and the general population. As a result, manufacturers and the FDA face a significant challenge in assessing the efficacy of many genetic test kits. Through the creation of a Subcommittee on Scientific Validation the Task Force immediately set out to develop validation criteria. Ensuing approaches to meet those criteria include: guidelines developed by the biotechnology industry and/or professional genetics organizations, and FDA regulation. Granting manufacturers provisional pre-market approval so they could market test kits and receive fair return while continuing to collect validation data will also be considered. B. Institutional Review Boards (IRBs). Whenever a device (which includes probes, primers and other key test reagents) that has not been previously approved is used to make a clinical decision or to provide a patient with information, the FDA requires submission of a research protocol to an IRB for approval. Absence of a confirmatory test, as is often the case in genetic testing, requires the laboratory or manufacturer to obtain an investigational Device Exemption from FDA. FDA has not enforced these requirements and the survey of companies and laboratories conducted for the Task Force suggests that they are not always complied with. C. Home Brews. Home brews are probes, primers or other reagents made by laboratories for internal use in the development or provision of testing services. Because such brews are never marketed, they elude review by the FDA. Consequently, the safety and efficacy of the tests developed with home brews are not formally established. CLIA has some potential to regulate the clinical use of home brews through its lab quality standards. HCFA and FDA have discussed the problem but not collaborated to resolve it. D. Off-Label Use. Off-label use of genetic tests occurs when a test kit or other medical device approved by the FDA for one purpose is used in developing and performing tests for other uses. An example is the use of maternal AFP kits, cleared for detecting neural tube defects, in testing for Down Syndrome. The Task Force noted that while manufacturers can only market a device's intended use, clinical laboratories use the tests for other, unapproved applications. Off-label use could grow as more test kits obtain clearance. The Task Force noted the Institute of Medicine's recommendation that the FDA require identification of all possible uses of tests. So far, the FDA has not pursued that course. E. FDA In-Vitro Device Regulations. The FDA is in the process of revamping its 510K "substantial equivalence" and pre-market approval (PMA) criteria in order to streamline the approval process. Manufacturers may be dissuaded from investing in development of test kits because of the time and cost of collecting the required validation data. The regulations are hard-pressed to deal with certain tests, such as that for BRCAl, which can take years to validate. The current regulatory scheme also has shortcomings in dealing with home-brews and off-label use of genetic test kits. While maintaining high standards for clearance of test kits, the FDA is challenged by a relative lack of resources in the face of a potential increase in submissions. III. Issues in Providing Genetic Tests. A. Laboratory Ouality. The Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulate the quality of labs performing tests for clinical use. The Act mandates minimum standards in quality control, personnel, and proficiency testing. However, genetic tests are largely unaddressed by CLIA. Aside from the limited "clinical cytogenetics" subspecialty, there is no direct provision for ensuring the quality of genetic test services and no proficiency testing. CLIA provides for the authorization or "deeming" of professional organizations to serve as aecrediting entities in specialized testing areas, in lieu of CLIA requirements. To date, only the College of American Pathologists (CAP) has been authorized by HCFA to accredit genetics testing labs and oversee proficiency testing programs. Participation in the CAP programs is voluntary. CAP and the American College of Medical Genetics are helping train genetics lab inspectors. CLIA exempts labs licensed under state laws considered eq or more stringent" than CLIA. Some states, such as New York, impose test regulations in areas CLIA leaves unaddressed. Having many different state regulations increases the cost of compliance to the biotechnology industry. To address these issues, the Task Force will consider the advisability of a genetics specialty under CLIA. Having such a specialty may result in more consistent federal standards. CLIA requires that labs performing clinical tests register with HCFA. However, without such registration, HCFA is largely unable to identify labs failing to comply with CLIA mandates. From the survey conducted for the Task Force, there is evidence that some labs performing genetic tests fail to register with HCFA. B. Informed Consent. The Task Force heard a variety of opinions regarding informed consent for genetic testing. Some members felt the potential effects of positive results, such as stigmatization and discriniination, warranted informed consent for any genetic test. Another view held that while informed consent was necessary, it need not require formal documentation and could be obtained through conversation between a physician and patient. Another member felt that routine genetic testing should not require informed consent, which was more appropriate for research protocols than clinical services. Circumstances involving emergency situations, in which informed consent for testing is impractical, and pathological biopsies, in which analysis could reveal genetic disorders, further complicated the issue. The Task Force will address the question in its Subcommittee on Education, Counseling and Delivery of Genetic Tests. C. Education. Counseling and Delivery. Properly educating consumers who are being offered or who receive genetic tests is a concern of the Task Force. This entails fmding ways to indicate the limitations of current technology, including predictive capabilities of tests. Several Task Force members expressed the view that consumers should participate in formulation of policies on test validation, access, delivery and follow-up. A common theme was that interpretation of test results and counseling about their implications are integral parts of the test itself. Great care must be taken in offering tests and communicating test results, especially when there is no intervention of proven efficacy for an identified genetic condition and little or no data on the impact of test results on people being tested. Furthermore, the predictive value of these tests can vary greatly and must be taken into account. Some interpretative services might be provided by laboratories, but may prove costly, intrude on the practice of medicine, and raise liability issues. The Task Force will consider the extent of manufacturer and laboratory responsibility in assuring appropriate test education and post-test interpretation. Given the increasing likelihood that primary care providers will be ordering genetic tests to aid in preventive care, their education in the essentials of this technology is important. Task Force members differed over the extent to which primary caregivers could master the subject. Even if sufficiently educated in genetics, the traditional directiveness of primary care providers in advising patients may be less desirable than the relative impartiality of genetic counselors. Nevertheless, some patients may expect and desire direction in this area. Genetic counselors could assume the responsibility of properly interpreting test results, but there is a shortage of counselors and training programs. For some tests, such as TaySachs, providers are less involved; results are often sent to patients directly. D. Insurance and Reimbursement. Insurers play a critical role in determining the diffusion of genetic tests in the American health care system by whether or not they will reimburse for them in pilot phases as well as after they are marketed. Insurers look to FDA approval or indicators of general acceptance by the medical community, such as recommendations in the literature or by professional groups. Cost-benefit or effectiveness calculations of tests is also considered. The insurance industry is interested in the ability of genetic tests to reveal risk of future disease. At present, insurers are not requesting genetic screening of potential insureds due to the cost and uncertain predictive value of most genetic tests. Moreover, such underwriting practices are not applicable to group coverage when they involve rare diseases, except for small groups. However, insurers are interested in learning who has been tested. They could then charge higher premiums to those with identified genetic conditions, which could preclude their purchase of coverage, or deny them coverage altogether. Issues of insurance discrimination have been considered by another ELSI Task Force. IV. Orphan Diseases. Orphan diseases are rare genetic disorders for which manufacturers have little incentive to develop test kits. Consequently, research laboratories and academic centers often create their own tests for these disorders. The Task Force noted that home brews facilitate orphan disease testing. At the same time it recognized that such tests might never be properly validated. Establishing collaborative arrangements and adhering to FDA's investigational use requirements might assure adequate development of orphan disease technology and validation. One drawback to commercial development is that with investigational use no profit-making is permitted. Because testing for orphan diseases is infrequent, labs performing them only periodically may lack appropriate quality control. The Task Force considered regionalization of orphan disease testing laboratories, to promote the necessary expertise and reduce costs. New York State provides an Orphan Disease Exemption system that enables labs to simply state their compliance with quality control regulations, subject to routine verification. While compliance with CLIA requirements is not onerous on its face, many smaller labs cannot meet the specified standards for tests performed infrequently. Certificate fees are scaled to the volume of testing.