 |
Previous Section | This Issue- Table of Contents | Next Section |  |
|---|
 |
Molecular Cytogenetics (FISH) Vol. 13: Spring, 1996 |
With the ongoing success of the Human Genome Project in mapping and identifying disease causing genes, the proliferation of new genetic tests is proceeding very rapidly. Nowhere is this phenomenon more apparent than in the development of sequence-specific and chromosome-specific DNA probes which bind to their complementary DNA sequences in metaphase and interphase cytogenetic preparations.
As these molecular cytogenetic tests become more widely requested and relied upon, the gulf between the evolving "standard of care" and the existing regulatory structures for ensuring efficacy and safety is widening, often stranding genetics service providers somewhere in between. This article provides a brief overview of the content and limitations of current regulatory schemes.
The regulation of a diagnostic laboratory test can focus on the materials used to perform the test, the procedures by which the test in conducted, and the qualifications of the personnel carrying out the procedures. The materials used are regulated at the federal level by the Food and Drug Administration (FDA). The procedures and personnel fall under other federal and certain state sets of rules. Most applicable at this time to the growing diagnostic use of FISH probes is the regulation of test materials by the FDA; and this aspect of the overall regulatory system will be the primary focus of this article.
Medical technology in general is governed by FDA rules which apply to medical devices. Molecular cytogenetics FISH probes are considered by the FDA to be medical devices subject to regulation under the following portion of the medical device definition: "...an in vitro reagent...which is...intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease in man or other animals."
The FDA exercises jurisdiction over the regulation of medical devices under its constitutionally enumerated power to regulate interstate commerce. The scope of the stream of interstate commerce has been so broadly construed that federal jurisdiction can reach any medical device which has had any contact whatsoever with the US mail, or an individual or a device component from another state.
The "home brew" exclusion from jurisdiction for devices which are made and used within one location may not provide comfort to laboratories who make their own FISH probes for use in their own labs. The FDA's opinion is that they could legally reach "home brew" FISH probes used for clinical diagnoses, but they have thus far declined to do so. According to Steven Gutman, M.D., Director of the Division of Clinical Laboratory Devices at the FDA's Center for Devices and Radiological Health, the agency does believe that it might have a role to play in home brews; but it would likely choose not to exercise that role because laboratories are currently regulated under CLIA '88 by the Health Care Financing Administration, and because of the resources required to take such actions.
The producer or sponsor of a medical device is required to obtain FDA approval of that device if it is intended for clinical use. Depending upon the FDA's evaluation of the complexity of the device, the sponsor will face either the pre-market notification process which seeks to establish that the new device is as safe and effective as a similar approved "predicate" device (so called '510-K approval'); or the sponsor will embark upon the more stringent pre-market approval process with clinical trials (PMA), which is designed to establish the intrinsic safety and efficacy of the new device. Either route can be extremely costly and time consuming. A sponsor who knowingly distributes a non-approved device to recipients who use the device for clinical diagnostic purposes can be subject to FDA fines and/or injunctions against further distribution.
The regulatory status of a medical device is indicated by product labeling; and the status of commercially available cytogenetic FISH probes is usually stated on the package insert. The regulatory categories for medical devices are: "For Research Only"; "For Investigational Use Only;" and "For In Vitro Diagnostic Use."
The "research only" status means that the sponsor is making no claim for the product's clinical utility or performance; that the results of tests utilizing the product are not intended to be reported or used clinically; and that the test results cannot be used by the sponsor to establish the performance characteristics of the test itself.
The "investigational use" category means that the sponsor is preparing to submit the product to the FDA for approval and has obtained FDA permission to organize clinical trials. Clearly defined protocols are required for such trials; and the clinical investigators using the product as part of a clinical trial are expected to obtain IRB approval of its particular protocol, to obtain informed consent for clinically diagnostic tests, and to supply the sponsor with test data to support the sponsor's approval submission.
"For In Vitro Diagnostic Use" means that the product has received either 510-K pre-market clearance or pre-market approval, and results may be reported and used for the device's intended use.
As of this time, the FDA has not yet promulgated guidelines by which FISH probes will be evaluated. Many individuals within the genetics community have submitted suggested guidelines to the FDA in response to an earlier request, and the FDA has indicated that these suggestions have been incorporated into draft guidelines which are not yet final. It is possible that future regulatory guidelines may require the less strict "pre-market clearance" (510-K) for metaphase FISH probes used as an adjunctive study with standard cytogenetics, and the full "pre-market approval" (PMA) for probes designed for interphase FISH studies which are not adjunctive studies to standard cytogenetics. The regulatory requirements for metaphase FISH probes designed to be used in studies such as micro-deletion assessment and marker chromosome identification, for which standard cytogenetic confirmation is not possible, remain in a "grey" area.
Mandatory regulations for clinical diagnostic laboratories are set forth under the Clinical Laboratory Improvements Act (CLIA) of 1967 and the Act's 1988 amendments. These rules have not yet addressed molecular genetics, although work is underway to draft FISH and other molecular genetic guidelines for inclusion.
Various voluntary proficiency
testing programs and laboratory guidelines have been developed by groups such as CORN,
regions within CORN such as PSRGN, PacNoRGG, and CAP (the CAP Survey). In general,
federal regulation preempts any state action in this area, unless a state enacts a
regulatory scheme that is accepted by the federal agency HCFA as equal to or more
strict than the federal rules. New York is leading the way in this regard, having been
approved as a CLIA exempt state. California is in the process of seeking CLIA exemption.
While the clinical use of molecular cytogenetics FISH probes is not the only area in which technological advancements have out-paced regulatory action, the current situation nonetheless leaves the providers of genetic services in a difficult position. Continued attempts to provide input to the FDA for use in designing guidelines by which FISH probes will be evaluated are probably worthwhile.
Adherence to laboratory standards and quality assurance practices is essential during this time; and excellent laboratory practice guidelines are being formulated by the American College of Medical Genetics (ACMG). Other considerations include obtaining IRB approval of protocols for FISH studies in situations where this is possible; obtaining informed consent for FISH studies whenever possible; and carefully wording cytogenetics reports to include a description of the investigational nature of the FISH studies.
Also important is the understanding that the term "investigational" as used by various professional groups such as the ACMG may have a meaning different from the FDA language used to designate a medical device "for investigational use only." Finally, careful review of the billing regulations under federal, state and private insurance programs with respect to the regulatory status of billable services seems advisable.
Contributed by Lynda M. Fox, J.D. (CO)
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Table Of Contents: Molecular Cytogenetics (FISH)
Introduction & Basic Techniques
Applications of FISH Technology
FISH Applications in Cancer Cytogenetics
FISH in Microdeletion Syndromes
FISHing in Unknown Waters
Regulatory Issues and FISH
 MoSt GeNe Home |
 Services Directory |
 Genetic Drift TOC |
 MoSt GeNe Publications |
 Search Internet |
|---|