Genetic Testing Report-Appendix 2

National Human Genome Research Institute

National Institutes of Health
U.S. Department of Health and Human Services

Promoting Safe and Effective Genetic Testing in the United States

Appendix 2

Response of the Task Force to the Food and Drug Administration 19s Proposed Rule on Analyte Specific Reagents


In this proposed rule, FDA noted that the "active ingredients" or "analyte specific reagents" (ASR 19s) used by clinical laboratories to develop and prepare their own tests are often purchased from biological or chemical suppliers. By law, these ASR 19s are medical devices, but FDA has done little to regulate them. FDA proposed the following:

"1. The biological or chemical suppliers would have to register with FDA, provide the agency with a list of the ASR 19s they are supplying to laboratories for use in developing tests. These suppliers would be required to follow good manufacturing practices, in accordance with 21 CFR part 820. The suppliers would also have to report to FDA, under 21 CFR part 803, adverse events that may have been due to their ingredients."

"2. These class I devices would be exempt from the premarket notification requirements of section 510(k) of the act. ... "

"3. .... FDA is proposing that use of these active ingredients to produce in-house developed tests be restricted to those clinical laboratories certified under CLIA- 1988 as 'high-complexity laboratories.' ... "

"4. ... no specific analytical or clinical performance claims could be made in the labeling or in promotional material. ... "

"... In addition to the proposed classification of most ASR 19s in class I, FDA is proposing that certain active ingredients used in-house developed tests be classified either in class III subject to premarket approval because of the serious health risks associated with their use or in the class of the test in which the ASR is being used, or regulated under other appropriate mechanisms. ... (T)he agency is seeking public input ... that this group of reserved ASR 19s should also include those active ingredients intended for use in human genetic testing."

Task Force Response

The following letter dated June 11, 1996 summarizes the Task Force 19s response to the proposed rule.

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
Phone: (410) 955-7894
Fax: (410) 955-0241

June 11, 1996

Dockets Management Branch (HFA-305) Food and Drug Administration 12420 Parklawn Dr.

Rm. 1-23

Rockville, MD 20857

RE: Docket #96N-0082-Medical Devices; Classification/Reclassification; Restricted Devices; Analyte Specific Reagents

The attached document was drafted by a subcommittee of the Task Force on Genetic Testing including Neil Holtzman, Michael Watson, Patricia Murphy, Stephen Goodman and Victoria Odesina and represents a majority consensus opinion. The draft prepared by the subcommittee was circulated to the entire Task Force. A majority of voting members supported the document, but approval was not unanimous. Additionally, the document does not necessarily represent the points of view of the organizations represented by those drafting the document nor of the organizations represented by others on the Task Force.

As to substance, a minority opinion was held that the onus should not be on the manufacturer of the product used in "home brew" assays, but rather that alternative or new approaches to assuring that ASR 19s are used appropriately by the laboratories building those tests were required.

The Task Force on Genetic Testing was convened to review genetic testing in the United States and make recommendations to ensure the development of safe and effective genetic tests, their delivery in laboratories of assured quality, and their appropriate use by health care providers and consumers. The Task Force is responding to FDA 19s solicitation of comments on the regulation of analyte specific reagents (ASR 19s) intended for use in human genetic testing. We applaud FDA for establishing labeling requirements for ASR 19s. Despite the greater assurance of product integrity that good manufacturing practice (GMP) oversight and the proposed labeling provides, the Task Force finds it inadequate for genetic tests for three reasons. First, certain intended uses of genetic tests engender questions of safety and effectiveness that require a greater level of control. Second, the proposal omits from regulation clinical testing laboratories that make their ASR 19s "in-house" for "home brew" tests (to use FDA 19s terminology). Third, restricting the sale of ASR 19s to high complexity laboratories as defined under the Clinical Laboratory Improvement Amendments of 1988 (CLIA- 1988), as FDA proposes, does not afford adequate assurance of safety and effectiveness. We will discuss each of these in turn.

Intended uses of genetic tests

Genetic tests can be used clinically to predict disease risks, identify carriers, diagnose disease, monitor progression of disease and response to therapy, and suggest the prognosis. The same genetic test can be used for more than one of these purposes. Some tests provide information about acquired as well as inherited disease. For instance, tests for mutations in the p53 gene can be used to predict and diagnose inherited cancer (Li-Fraumeni syndrome) with high predictability, as well as to assist in staging particular types of acquired tumors, and to identify the category of environmental mutagens responsible for the tumor.

It is predictive uses of tests for inherited disorders that are of great concern to the Task Force. These tests raise complex psychosocial issues. Moreover, their clinical validity may be difficult to establish and their sensitivity and predictive value may not be high. Nor, in some instances, have the benefits they confer been proven. Consequently, test interpretation requires training and experience in human genetics and genetic counseling.

Positive test results for germline mutations in common complex disorders do not often carry as high predictive values as observed in single-gene (Mendelian) disorders like the Li-Fraumeni syndrome. In some instances, frequently occurring "normal" alleles (polymorphisms) have been associated with common diseases, such as insulin-dependent diabetes mellitus (non-asp57 HLA DQ beta alleles) and Alzheimer disease (Apolipoprotein e4 allele), but many, if not most, people with these alleles will not develop the specific diseases.

Predictive testing in the general population (screening) has a greater chance of clinical false positive test results than testing in high risk families. The predictive value of a positive (PVP) test for an inherited susceptibility mutation in the BRCA1 gene in healthy individuals who do not have a family history of breast cancer (i.e., screening) may be considerably lower than the PVP of approximately 85 percent observed in women from high risk families.

Because of allelic diversity, and new mutations in X-linked and dominant disorders, negative test results for single-gene disorders do not always exclude the presence of a disease-related allele. Even when the predictive value of positive and negative test results is high, as in families with the Li-Fraumeni syndrome, psychosocial concerns of those tested can be great.

For many genetic disorders, safe and effective interventions have not been established, so healthy individuals with positive test results face considerable uncertainty about what course of action is best. For instance, the benefits and risks of mammography in asymptomatic young women found to have an inherited BRCA1 susceptibility mutation, or of prophylactic mastectomy, oophorectomy, or chemoprophylaxis are not currently known.

The Task Force is of the opinion that a predictive genetic test should not be available on any but an investigative basis until information on its clinical validity and clinical utility is available or until detailed protocols for gathering this information are in place. This has been accomplished, for instance, in tests for mutations in the RET oncogene that are highly predictive of multiple endocrine neoplasia type 2. Preliminary data in predictive tests for other disorders, such as the Apolipoprotein e4 test for Alzheimer disease, have not been convincing. By limiting regulation of ASR 19s used for predictive genetic tests to the labeling requirements in proposed paragraph (e) of 21 CFR part 809.10, FDA will encourage the use of such tests without collection of the requisite data to ensure their safety and effectiveness.

In regulating in vitro diagnostics, FDA relies heavily on the intended use of the device as stated on the manufacturer 19s proposed label. This should hold true for predictive genetic tests as well. The Task Force is of the opinion that ASR 19s capable of being used for predictive genetic tests, such as human DNA probes or primers, should be excepted from Sec. 864-4020 (b)(1) of the proposed rule and added to the categories listed in SEC 864.4020 (b)(2). Human DNA is not the only category of ASR 19s capable of being used in genetic tests. Assays for enzymes and other proteins, which may employ ASR 19s, can yield predictive information for both carriers and apparently healthy affected individuals. It is also likely that monoclonal antibodies raised against specific proteins will be used to test for genetic diseases. Consequently, it accomplishes little to exclude human nucleic acids from the definition of ASR 19s, as proposed by the Immunology Devices Panel.

Because of the wide range of ASR 19s that could be used for predictive genetic testing, FDA must, in the opinion of the Task Force, develop policies to determine which categories of ASR 19s could be used for predictive genetic testing. To assist it in this task, FDA should convene a Genetic Test Devices Panel under its Medical Devices Advisory Committee. This panel could establish criteria for determining whether an ASR could be used for predictive genetic testing. When such a determination is made, this panel could advise FDA on the classification of the ASR.

An alternative approach, which is less enforceable and, consequently, less desirable in the opinion of the Task Force, is to require manufacturers to label every ASR as "not for use in predictive genetic tests without the approval of FDA." As FDA knows, the labeling of reagents "for research use only" or "for investigative use only" has not precluded their use in routine clinical tests in humans. Similarly, there has been little control over off-label uses of many approved drugs and devices.

In-house testing

In the background to its proposal, FDA states that "at a future date" it may "reevaluate whether additional controls over the in-house tests" are needed. It further acknowledges such controls as "especially relevant. . . as testing for the presence of genes associated with cancer or dementing diseases becomes more widely available." Predictive genetic tests for breast and colon cancer and for Alzheimer disease are already available.

The Task Force is of the opinion that laboratories that use ASR 19s for in-house predictive genetic tests should establish safety and effectiveness of their tests before making them available on any but an investigative basis. The Task Force recognizes that the considerable time and expense that may be needed to determine safety and effectiveness could deter clinical laboratories from developing and providing genetic tests. FDA should consider how it can expedite assessments of safety and effectiveness of predictive genetic tests that are provided in-house. Until additional policies are established, the Task Force agrees with the Immunology Devices Panel 19s recommendation that "laboratories, when reporting results from in-house developed tests using ASR 19s, include a disclaimer ...." However, we would suggest that the disclaimer indicate that "This test has been developed in-house and analytically validated under the requirements of CLIA '88." Unless otherwise noted, the disclaimer should indicate that "the safety and effectiveness of the test have not been established."

Protection afforded under CLIA-'88

CLIA- 1988 provides no authority for assessing either the clinical validity or utility of a test, although laboratories are required to demonstrate the analytical validity of tests they develop. Consequently, restricting the sale of ASR 19s to laboratories qualified for high complexity testing under CLIA- 1988 will not ensure the safety and effectiveness of predictive genetic tests. Moreover, laboratories qualified for high complexity testing do not necessarily employ personnel with special training and/or experience in genetics, which is crucial if the laboratory is to provide an adequate and appropriate interpretation of the results of predictive tests.

The performance of predictive genetic tests should be restricted to laboratories with expertise in genetics and demonstrated proficiency in genetic testing. Unfortunately, there is no genetics specialty under CLIA. Although one is in place for cytogenetics, none exists for molecular genetics or biochemical genetics. Nor does the Department of Health and Human Services (HHS) through the Health Care Financing Administration, which administers CLIA- 1988, require that laboratories performing genetic tests participate in proficiency testing programs, which already exist, for several categories of genetic tests. With a genetics specialty under CLIA, personnel requirements for laboratories performing genetic tests could be established, as could requirements for proficiency testing. Having a specialty would not, however, address the Task Force 19s concerns about the clinical validity of genetic tests.


The following reflect our primary concerns and recommendations about the ASR proposal.

With no provision for establishing the clinical validity of predictive genetic tests, and no assurance that laboratories performing predictive tests will do so, FDA 19s proposal on ASR 19s as it relates to predictive genetic tests, affords the public inadequate protection.

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Last Reviewed: April 2006