State Assessments of Laboratories Providing Genetic Tests

New York State began mandatory regulation of genetic testing when it established the first program assessment for cytogenetics laboratories in the United States in 1972, with cytogenetics proficiency testing beginning in 1974 (Willey, 1992). Since 1990, New York has been the only state that has specific mandatory standards and permits for DNA genetics laboratories performing tests on its citizens. It has a list of DNA tests approved for testing, including tests for sickle cell anemia, cystic fibrosis (CF), Duchenne and Becker muscular dystrophy, Tay-Sachs, and the thalassemias (A. Willey, Director, Laboratory of Human Genetics, New York State Department of Health, personal communication, January 1993). To be included on this list of approved DNA tests, the disorders must meet identified criteria (e.g., no form of the disorder that is undetectable because a mutation at another locus is known to exist; the method must identify 90 to 95 percent of cases; reagents and processes must be generally available in the laboratory community—or must be made available; if linkage analysis is required, the markers must be a specified map distance from the disease gene). To be approved to perform DNA tests from this list, the laboratories must demonstrate that they successfully perform the accepted test methodologies. New York developed a special training program for all inspectors who survey laboratories that perform genetic testing. New York has also developed standards for proficiency testing for DNA tests, but these standards have not yet been implemented (Murphy, 1992a). The reach of the New York State program extends beyond the geographic borders of the state, since any laboratory wishing to perform a genetic test on a citizen of New York must be certified just as if it were located in New York; thus, most large commercial genetic testing laboratories who accept specimens from around the United States are licensed to meet New York DNA laboratory standards. Currently, no other state has developed as rigorous a program for the quality control of genetic testing as New York.

The California Department of Health Services contracts with private laboratories to provide newborn screening and maternal serum alpha-fetoprotein (MSAFP) testing. As part of the process it assesses the quality of the laboratories with whom it contracts. Since 1980, California has limited newborn screening to eight state-monitored laboratories, with centralized computer data collection, quality control, blind proficiency testing, and case follow-up. Fees for newborn screening are collected from the birth hospital or birth attendant. California also has centralized laboratory testing, quality control, and blind proficiency testing for its MSAFP screening program, which must be offered to every pregnant woman in California. California has developed draft regulations on DNA, cytogenetics, and microbiological testing, and for prenatal diagnosis centers and clinical centers; these draft regulations are awaiting public comment and public hearing (Cunningham, 1992).

Maryland has regulations requiring genetic testing and screening laboratories to demonstrate "continuing satisfactory performance" in external proficiency testing programs where they exist. The only approved laboratory for newborn screening in Maryland is the state laboratory, which participates in the U.S. Centers for Disease Control proficiency testing program for newborn screening (see below). Fourteen laboratories (including the state laboratory) are approved for MSAFP screening. Maryland regulations require laboratories doing Tay-Sachs testing to participate successfully in the proficiency testing program of the International Tay-Sachs Disease Quality Control Reference Standards and Data Collection Center (M. Kaback, personal communication, November 1992).

New Jersey requires its laboratories to comply with the New York system for genetic tests, and it now also recognizes College of American Pathology (CAP) proficiency testing for cytogenetics. Florida licenses cytogenetics laboratories using CAP guidelines and proficiency testing, but its legislation is now expiring. Iowa requires that MSAFP testing be done centrally in the state laboratory at the University of Iowa.

In addition, states in the Pacific Northwest Region (PacNoRGG) of the Council of Regional Networks for Genetic Services (CORN), including Washington, Oregon, Idaho, and Alaska, have adopted PacNoRGG proficiency testing standards as a condition for state laboratory license as a cytogenetics laboratory. The PacNoRGG cytogenetics proficiency test involves the provision of blind samples and requires the interpretation of clinical information on individuals and families.

Each round of proficiency testing gets more difficult as the proficiency of the participating laboratories improves.

Voluntary Quality Assurance and Proficiency Testing in Genetics

The Council of Regional Networks of Genetic Services, the College of American Pathologists, the Centers for Disease Control and Prevention, and several other organizations have developed specific genetic tests or tests for specific disorders. These include maternal serum alpha-fetoprotein, Tay-Sachs disease, and Huntington disease, for which the organizations have established voluntary proficiency tests (see Box 3-2). Other organizations interested in the quality of genetic tests include the Organization for Clinical Laboratory Genetics, the American Society for Histocompatibility and Immunogenetics, the American Association of Blood Banks, the Technical Working Group on DNA Analysis Methods (TWGDAM), the National Reference System for the Clinical Laboratory, the National Committee for Clinical Laboratory Standards (NCCLS), and the new American College of Medical Genetics (ACMG). Many of the voluntary quality assurance programs grew from the efforts of the American Society of Human Genetics (ASHG) (Punnett, 1992).

BOX 3-2

Voluntary Quality Assurance and Proficiency Testing Programs.

CORN was established in 1985 as a coordinating body for state genetic services programs organized in 10 regions. CORN is funded by the Genetic Services Program of the Maternal and Child Health Program, Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services (DHHS). Laboratory quality assurance quickly became and remains a high priority for CORN. CORN has a Quality Assurance Committee (for laboratory services), as well as other committees on quality assurance and proficiency testing, and education. CORN's national proficiency testing programs include alpha-fetoprotein, biochemical genetics, hemoglobinopathies and newborn screening, and most recently, DNA-based tests.

The College of American Pathologists developed guidelines, criteria, and methods for quality control and standards for clinical laboratories. CAP played a key role in the implementation of the Clinical Laboratory Improvement Act of 1967 (see below) when its quality assurance and proficiency testing standards and activities were recognized (''deemed") by the Secretary of Health and Human Services to fulfill the requirements of the law. Since 1967, CAP has worked to maintain itself and M.D.-pathologists as the appropriate professional group to judge the quality of clinical laboratories. CAP has voluntary proficiency testing programs for cytogenetics and MSAFP screening that are recognized by some states. With input from ASHG, CAP has spent two years developing guidelines for what it calls "molecular pathology." The ASHG role in setting standards for laboratory genetics will be assumed by the ACMG in 1993. ACMG laboratory standards for genetics are now under final revision and will be very important in quality assurance in genetic testing.

Although the Centers for Disease Control and Prevention attempted to establish its own cytogenetics proficiency testing program, it never progressed beyond a pilot program (Murphy, 1992a). CDC does run a voluntary proficiency testing program for newborn screening tests discussed below.

Costs, Benefits, and Limitations of State and Voluntary Quality Assurance Programs

In most state-run and voluntary programs, most of the costs of the quality control programs are paid by the participating laboratories. These costs could deter a research laboratory, or other small laboratory without cash reserves, from participating in the program. The costs of participation could be passed on to the consumer through higher laboratory prices, although the increases would not be a very large percentage of the current prices of most genetic tests. California now charges $40 for newborn screening and $55 for the MSAFP screening test, both of which include the cost of quality control and proficiency testing.

Rigorous state licensing provides protection to the citizens of that state, but continued reliance on the states will not afford equal protection to citizens of all states. Separate programs in each state could result in duplication of effort or in competing and, in some instances, conflicting laboratory standards. Many diagnostic laboratories do not now participate in voluntary quality assurance and proficiency testing in genetics. One incentive for such participation would be to publish the results of voluntary quality evaluations by laboratory name, as is now done by the National Tay-Sachs Disease and Allied Disorders Association, Inc., which publishes results of the quality assessment conducted by the International Tay-Sachs Disease Quality Control Reference Standards and Data Collection Center.

Federal Regulation of Clinical Laboratories

Interpretation of Laboratory Test Results

For the reasons given earlier in this chapter, the misinterpretation of test results is more likely in genetic tests than in many other areas of clinical testing, and misinterpretation may have more serious consequences particularly in fetal diagnosis. The need for adequate interpretation is even greater when the health care providers ordering tests (1) are not expert in interpreting probabilistic clinical data (Holtzman, 1991); (2) are not expert in genetics; and (3) may not be aware of the implications of both positive and negative test results in genetics. As discussed further in Chapter 6, an increasing proportion of genetic tests will be ordered by primary care physicians, many of whom have limited knowledge of genetics (Hoffman, 1991; Holtzman et al., 1991; Hofman et al., 1993). Special concerns about interpretation also arise when tests may be provided by employers as part of fitness programs or by other organizations not skilled in genetics.

Interpretation can be very complex and can depend on the results of other family members. One way of ensuring that physicians who order tests understand the implications and limitations of results is to require that the laboratory performing the test provide adequate interpretation of the result in its report (Hommes, 1992), although all genetic testing laboratories may not be prepared to provide this service. With few exceptions the interpretation of a positive genetic test result should include the chance of future disease or the chance of having an affected child. In the latter case, the interpretation should note whether the chance is dependent on the carrier status of the mate of the person tested. If misattributed paternity might alter the interpretation, this should also be disclosed. The interpretation of test results should also indicate any confirmatory tests that are available and whether repeat or other follow-up testing is recommended. It might summarize the possible interventions. Interpretation of a negative test result should include the revised estimate of the chance of occurrence and make clear that the test result pertains only to a specific disorder, and within that disorder only to disease-causing mutations detectable by the test, which may not include all such mutations.

No matter how extensive or clear the laboratory's written interpretation, many individuals and couples with positive test results will benefit from genetic counseling as well. Some laboratories employ, or are affiliated with, genetic counselors or other personnel trained in genetics who can discuss test interpretation with referring physicians.

Premarket Approval of Medical Devices

Before a medical device can be legally marketed for in vitro diagnostic use, its sponsor (manufacturer, university, or individual scientist) must obtain premarket approval (PMA) or clearance (Tsakeris and Yoder, 1992). On receiving premarket notification from a sponsor, FDA will determine whether the device is "substantially equivalent" to a legally marketed "predicate" device. "Substantial equivalence means the new device must have the same intended use as the predicate device, the same technological characteristics (or, if different,) strong comparability of intended use and performance characteristics, and [not raise] new questions of safety and effectiveness" (Tsakeris and Yoder, 1992, p. 3). For the FDA to make a determination of substantial equivalence, the manufacturer has to demonstrate equivalent performance characteristics (as good as other legally marketed devices). If so, FDA will give the device either Class I or II designation, depending on the class of the predicate device. The safety and efficacy of Class I devices can be reasonably ensured if the manufacturer adheres to general controls that include good manufacturing practices in their production. Class II devices must meet not only general controls, but also special controls, in order to reasonably ensure safety and efficacy.

If FDA fails to find the device substantially equivalent, it will require full premarket approval, designating it a Class III device. This requires the manufacturer to present evidence of the device's safety and effectiveness. Genetic tests and devices placed in Class II include MSAFP kits (MSAFP is not approved by the FDA for use as a screening test for Down syndrome, although it is widely used for that purpose) and kits for the Philadelphia chromosome, tumor markers, and gene rearrangements. Class II tests include the sweat chloride test for CF, creatine kinase test for Duchenne muscular dystrophy, phenylalanine test for PKU, tests for coagulation defects (including detection of carriers of coagulation defects), and tests for sickle cell trait or disease. The copper test for Wilson disease is Class I (Tsakeris and Yoder, 1992).

The committee reviewed FDA's current definition of "substantial equivalence." Although the current definition (Tsakeris and Yoder, 1992) is reassuringly comprehensive, the FDA could interpret substantial equivalence too broadly, permitting a manufacturer to avoid the premarket approval process by claiming, for instance, that a DNA test marketed to detect sickle cell carriers was substantially equivalent to electrophoretic tests already on the market. Once marketed to detect carriers, the DNA test, unlike the electrophoretic test, could also be used for prenatal diagnosis. This would constitute an unapproved or "off-label" use of the device. Similarly, a DNA-based test for some CF mutations might be approved for the diagnosis of CF on the basis of substantial equivalence to the sweat chloride test, although only the DNA test could be used for carrier detection or prenatal diagnosis.

Despite the FDA's current definition of substantial equivalence, off-label use once a test is legally marketed remains an area of concern. Off-label use often goes undetected or unreported, although if manufacturers are aware of off-label use of a device, they must either withhold the product from the user (laboratory) or file a premarket notification of the new use. To prevent the problem of offlabel use of genetic tests, FDA should require the manufacturer to indicate both intended and potential uses (which would include carrier screening, prenatal diagnosis, or presymptomatic testing, etc.). Increasing FDA's capability for postmarket surveillance would also reduce off-label use.

Investigational Use of New Devices

The collection of data to support PMA applications—that is, to determine safety and effectiveness—is the responsibility of the sponsor. To obtain these data the sponsor is allowed to use the device (including DNA probes and reagents) only for investigational purposes. Under FDA regulations, the device must be labeled for "investigational use only" and must be used in accord with a protocol (including specified period of study, number of sites, investigators, and patient samples) and must be approved by an IRB. Informed consent of participants in such studies may be required. This would always be the case if the participant was to be notified of the result or if a clinical decision was based on the result. Under "investigational use" exemptions, manufacturing costs can be recovered by charging for the device, but no profit can be made.

Under current FDA rules, an investigational "device and/or its results will not be used for diagnostic purposes without confirmation of the diagnosis by another, medically established diagnostic device or procedure" (R. Johnson, FDA, letter to device manufacturers, October 17, 1991, p. 3), unless an investigational device exemption has been approved by the FDA. The committee notes that, for many genetic tests involving direct determination of disease-causing mutations, the only confirmation that is possible is the clinical appearance of the disease, which may not happen until many years after the test is performed. In reply to the committee's inquiries, FDA wrote that obtaining an "approved Investigational Device Exemption (IDE) may be required for certain genetic products (e.g., when there is no confirmatory test) to assure the safe use of the device in collecting data to establish the performance characteristics of the device [emphasis added]" (Tsakeris and Yoder, 1992, p. 12).

Ensuring the Quality of Laboratories

The safety and effectiveness of genetic tests must be established before these tests are used routinely and, once that comes to pass, great care must be taken in performance of the tests and interpretation of the results. Laboratory quality control falls into three areas:

• The training and experience of the laboratory personnel: The nature of genetic tests and the implications of their interpretation suggest the need for special requirements for supervisory personnel (laboratory directors and technical supervisors) in laboratories involved in genetic testing.
• The structure and function of the laboratory itself: This requires inspectors with special training in assessing such laboratories.
• Proficiency testing: The most rigorous type should be conducted whenever possible, that is, external, blind proficiency testing in which an outside agency sends specimens to the laboratory under a fictitious patient's name. The laboratory has no way of knowing that the specimen is for assessing laboratory quality. Other types of proficiency testing involve the sending of coded samples from a central source. Proficiency testing should extend to all genetic laboratory tests and to the interpretation provided by the laboratory to referring physicians.

Voluntary quality control programs have helped to establish criteria and standards for genetics laboratories and laboratory personnel. The committee finds the current state of voluntary laboratory quality control programs in human genetics to be beneficial, but generally inadequate to address the special issues posed by genetic testing, because these programs lack essential enforcement authority. The impact of these voluntary programs should be strengthened by the publication of the names of laboratories that have satisfied the proficiency and other requirements. Before names are withheld from a published list of "quality" laboratories, any laboratory not satisfying these requirements should be given an opportunity to rectify its deficiencies.

The clinical implications of commonly performed prenatal tests, particularly the abortion of presumably affected fetuses, warrant that laboratories performing them participate in proficiency testing programs.

The performance standard for genetic testing should be as close tozero error as possible. Laboratories with any error in proficiency testing should be placed on probation, with proficiency testing repeated using blinded methods. Unless the laboratory can attain the required standard in performing and interpreting any genetic test, its certification to perform that test should be removed.

The existing CLIA88 regulations could ensure the quality of genetic laboratory testing were they to be fully implemented and applied to genetic testing. Action by DHHS would help to ensure the quality of the most frequently performed genetic tests by (1) establishing genetics as a subspecialty under the CLIA88 regulations; (2) rating specific genetic tests for complexity; and (3) requiring proficiency testing for genetic tests.

The first step would be to require all laboratories providing any genetic test to obtain a certificate from HCFA. Next, would be development of a system for verifying the accuracy and reliability of the tests they perform. Third, laboratories performing genetic tests would be subject to inspection every two years. To make this approach meaningful, the laboratory inspectors would have to be well versed in the unique aspects of genetic tests, including the interpretation included in the report of results. A specific training unit on genetic testing should be included in HCFA's educational training program for inspectors, and the same training should be required of inspectors in agencies deemed by HCFA capable of performing inspections. In addition to these steps, HCFA could determine that existing proficiency programs for genetic tests satisfy its standards; HCFA could deem these proficiency testing programs to be required by laboratories providing those tests until such time as other programs are developed (see previous section on voluntary programs and Box 3-2 in this chapter). A laboratory that failed proficiency testing in a "deemed" program would be subject to HCFA sanctions even if that program was voluntary and did not itself impose sanctions.

It is doubtful that adequate quality control can be ensured with voluntary proficiency testing. This holds for newborn and other types of screening as well. As with any genetic testing, participation in proficiency testing programs should be required of laboratories providing newborn screening tests. This could be accomplished by designating genetic screening tests as moderate or high complexity under CLIA88. HCFA should examine the proficiency testing programs for genetic screening tests described earlier in this chapter and, if they meet its criteria, deem them acceptable.

The committee recommends that HCFA create a new specialty of clinical genetics into which it can incorporate the existing subspecialty of clinical cytogenetics, and also create new subspecialties of biochemical and molecular genetics. MSAFP testing and other methods of prenatal testing for birth defects should be incorporated into one of these three subspecialties. Most genetic tests should be classified as high complexity under CLIA88, primarily to ensure that supervisory personnel have adequate training in genetics. Although genetic tests might someday be simple enough to be feasible for home use, the difficulties of interpreting results would still render them of high complexity.

Within its existing authorities, HCFA can take steps to enhance the quality of tests for rare disorders, for which specific requirements may never be established. According to a HCFA representative, requirements for proficiency testing are unlikely to be established for low-volume tests unless their clinical or public health implications are high (J. Yost, HCFA, personal communication, January 1992). The establishment of such requirements could be costly both to HCFA and to laboratories that must participate.

The committee strongly recommends that the genetics community, under the leadership of its professional societies, designate a small number of laboratories as centralized facilities for tests for rare disorders . These organizations should establish and publicize a register of the tests performed by these central laboratories and encourage referral of specimens to them. The register should be easily accessible to a wide range of health care providers. It could also be included in the data bases of the National Library of Medicine. An external proficiency testing program should be established for the central laboratories. The genetics community should also study the possibility of setting a minimum volume of a genetic test that a laboratory must perform annually in order to obtain certification for that test and ensure the quality of test performance. With its informatics and data base capabilities, the National Library of Medicine should maintain a data base of centralized laboratories performing tests for rare disorders, genetic counseling centers, and support groups, which should be available to laboratories and providers at no charge.

HCFA and CDC should give high priority to requiring established proficiency programs for genetic tests. The New York State program can be considered a model for many genetic tests, although high priority should also be extended to setting specific requirements for other frequently performed prenatal tests. HCFA should incorporate standards and procedures for assessing genetic tests in its training programs for current and new laboratory inspectors.

Laboratories in academic health centers and elsewhere that conduct research, but that also perform genetic tests as a service (providing the results to referring laboratories or physicians, or directly to patients), should be subject to the same criteria, standards, and regulation as commercial genetic testing laboratories since they fall under the purview of CLIA88. The committee recommends that HCFA inform all hospitals of their legal responsibilities to register with HCFA every laboratory that provides results used in clinical decisions to physicians or patients.

The committee recommends that genetics laboratories provide reports in an easily understandable form for referring physicians who are not genetic specialists. These reports, including interpretation of the results, should be reviewed by HCFA as part of its inspection of laboratories performing genetic tests.

To ensure that physicians and patients receive consistent and accurate information, ''package inserts" (information and instructions both for physicians and patients) should be provided by the manufacturer of genetic test kits through the laboratory from which the physician orders the test.

Ensuring the Safety of New Tests

Because genetic tests seldom will have perfect sensitivity or specificity, particularly when used for predictive purposes, because of the novelty of some genetic testing technologies, and because of the possibilities of misinterpretation of test results, full premarket approval is needed for all new genetic tests; that is, genetic tests should be in Class III. The concerns of the committee will be addressed only if FDA uses criteria for review that address these issues.

In its recent reply to the committee's inquiries, FDA indicated (Tsakeris and Yoder, 1992, p. 8) that a sponsor may be asked to provide information that includes when appropriate

• analytic sensitivity/limits of detection;
• analytic specificity/cross-reactivity/interference studies;
• accuracy studies;
• precision studies;
• reportable range;
• clinical sensitivity and specificity; and
• stability data.

The committee believes that data on all of these areas should be provided in premarket approval submissions for genetic tests. Specifically, sponsors should present evidence of sensitivity in terms not only of the ability of the test to detect specific mutations (analytic sensitivity) but of the proportion of people with clinically significant disease that are detected by the test (i.e., who have the specific mutation detected by the test; clinical sensitivity). One area of concern, for example, is the possibility of FDA approval of a (hypothetical) test kit for CF carriers that detects six mutations and might have 100 percent analytical sensitivity, but only 85 percent clinical sensitivity. The determination of an acceptable clinical sensitivity should be on a test-by-test basis, by taking into consideration not only the benefits of making correct predictions but the risks of making wrong ones.

The FDA should develop guidance to manufacturers for preparing premarket applications for genetic test devices. The application should include

• the intended and potential use(s) of the test (e.g., presymptomatic diagnosis or prediction, carrier screening, prenatal diagnosis);
• for each intended use, data on the sensitivity and specificity of the test, with clinical manifestations serving as an end point in the absence of a "gold standard" test;
• procedures to be used by clinical laboratories to demonstrate their reliability (precision and accuracy) and proficiency in performance of the test; and
• description to be given to health care providers and to patients regarding the objectives of the test and the interpretations of negative or positive findings.

For very rare diseases, it may take a long time to collect sufficient data on specificity and sensitivity. For diseases of late onset, a long lag will occur between the time of the test and the appearance of disease, and it will be difficult for applicants to provide adequate data on safety and effectiveness for subjects of the type in whom the test would be applied (e.g., presymptomatic individuals). It may also be impossible to assess the sensitivity and specificity of prenatal tests by independent tests or histopathological examination of aborted fetuses. In all such cases, the committee recommends that data of the type described in the section "Collection of Data for Test Validation" be required. If these preliminary data suggest that the test is safe and effective for its intended use, the FDA should grant the applicant "provisional premarket approval" in order not to unduly delay submission for PMA. Under this category, the test could be made more widely available, but the manufacturer would be responsible for obtaining and submitting additional periodic postmarket data of an adequate sample of subjects, until sufficient data are available to warrant full premarket approval. These data would be collected from patients' physicians either directly by the manufacturer or by the laboratories to whom it sells the device. The protocol used in the investigational phase (before provisional approval) would still apply, and informed consent would still be needed.

Once provisional premarket approval has been granted, however, the laboratories performing the test could charge a fair market price for the device or test kit. The committee recommends that people receiving the test during this provisional period be informed that the safety and effectiveness of the test have not been fully determined. If the manufacturer is to contact physicians directly, testees must be informed if the manufacturer will have their names. Once provisional premarket approval is granted, manufacturers should be allowed to charge a market price for the test. This process may require new legislation.

Provisional premarket approval, with periodic postmarket study for which the sponsor would be responsible, could also be used to cover the development of tests for rare conditions (which is the intent of the humanitarian device exemption). The committee therefore recommends that Congress consider the need for legislation in the spirit of the Orphan Drug Act that would give manufacturers the incentive to develop diagnostic medical devices for genetic tests of limited marketability.

The appearance of clinical disease is the only possible confirmation of many genetic tests, and that may not occur until many years after testing. Investigators should be permitted to convey the results of investigational tests to subjects who are aware of the investigational nature of the test. Thus, clinical decisions could be made on the basis of the results as long as the investigator has an approved investigational device exemption. FDA should make it clear that in such cases, with an approved IDE, results could be communicated to the patient or to his or her physician so that interventions can be instituted accordingly.

Since many IRBs are not experienced in the review of investigational genetic testing protocols, the committee recommends that the National Institutes of Health (NIH) Office for Protection from Research Risks (OPRR) and the National Center for Human Genome Research Ethical, Legal, and Social Implications (ELSI) Program coordinate efforts to assist IRBs in coping with this responsibility, and ELSI should consider supporting efforts to assist IRBs in this task. Other federal agencies (such as the FDA) and professional groups should also consider developing guidelines to help IRBs cope with this added responsibility (such as the informed consent guidelines for research involving genetic testing developed by the Alliance of Genetic Support Groups and the ASHG). The formation of a national advisory body on genetic testing could also be helpful in educating IRBs concerning research involving genetic testing (see Chapter 9). IRBs used by commercial organizations should also have a broad, unbiased membership.

Compliance with FDA requirements for premarket approval and approved investigational device exemption is essential to ensuring safe and effective use of a genetic test, just as compliance with CLIA88 is essential for any laboratory performing genetic tests for clinical purposes. The committee recommends that the FDA publicize widely to potential sponsors, including academic centers, that DNA probes and other reagents essential to the performance of genetic tests are medical devices. Consequently, whenever they are used for clinical purposes, genetic test devices (i.e., test kits, reagents, probes, etc.) either must be labeled "for investigational use only" (and must comply with FDA requirements for such use) or must have been approved or or cleared for marketing by FDA. When genetic test devices are used investigationally for clinical purposes, manufacturers—including commercial or academically based laboratories preparing their own devices—should apply for FDA approval of an investigational device exemption, including an IRB approved protocol, and periodic reports on the results of their investigations.

To speed the widespread availability of investigational devices of limited marketability, FDA should grant provisional premarket approval, as described earlier, when adequate preliminary evidence of safety and effectiveness has been collected. In addition, the NIH and private funding agencies should support meritorious studies designed to assess the safety and effectiveness of investigational genetic testing devices. To speed the collection of data on tests of limited marketability, national collaborative studies should be encouraged. Funding agencies should also support long-term studies on safety and effectiveness of genetic test devices (through the phase of provisional premarket approval) for diseases in which a long lag will occur between the time of the test and the clinical appearance of the disease.

The committee recommends that all genetic tests should either be designated as investigational devices—subject to IRB approval and FDA regulation—or be submitted to the FDA for premarket approval. FDA should clarify that when an approved IDE is obtained for a test for which no independent confirmatory test is available, the results may be given to the patient's health care provider or to the patient. When a device with an approved IDE is used to provide clinical information, the laboratory performing the test should be allowed to charge for the costs of testing, record keeping, and complying with reporting requirements. Because the investigational phase of new genetic tests may be prolonged, the laboratories performing these tests should be subject to external quality assessment. The committee recommends that HCFA inform every organization (e.g., academic health center or other hospital) that all laboratories in which investigational devices are being used for genetic testing are covered by CLIA88 and must register with HCFA to obtain CLIA88 certificates and be inspected.

The FDA has taken important first steps to increase the pool of advisors expert in genetics by inviting applications for service as FDA advisors ("special government employees") under its Clinical Chemistry and Toxicology Devices Panel of Experts. The agency should also consider developing workshops on critical aspects of genetic testing technology for manufacturers and clinical laboratories.

The committee is concerned that screening tests may become routine standard of care without adequate studies of their safety, effectiveness, or clinical utility. To ensure that adequate studies are conducted, the committee recommends that any new screening test should comply with FDA rules regarding investigational devices, including a protocol reviewed by an IRB. The committee recommends that the decision to move from "pilot" or "investigational" use to rou tine practice involve review of data collected in the pilot study and elsewhere by both FDA and a policy-making body, usually at the state level, that is independent of the organization directly responsible for conducting the pilot study. A national oversight body (see Chapter 9 ) could facilitate collection and dissemination of data from pilot "investigational" studies. An adequately conducted pilot study in one or a few states need not be repeated in others as long as the other state(s) can maintain the same standards of the pilot study in routine operation. The committee also recommends that some mechanism be found to resolve the dilemma posed by the need to demonstrate that the device is safe and effective for its intended use, whether or not it will be commercially marketed.

The preceding sections, as well as other chapters in this report, indicate that genetic tests for screening and other purposes differ in many respects from other laboratory tests. Some federal agencies, particularly FDA, have recognized this by planning special guidance for manufacturers of genetic tests and by inviting geneticists to participate on advisory groups. The committee welcomes such activity and encourages other agencies to do likewise. In particular, the committee recommends a Genetic Device Advisory Panel to provide FDA with continuing and timely access to expert advice. In addition, the Clinical Laboratory Improvement Advisory Council should appoint a subcommittee on genetics to make recommendations on improving the quality of laboratories performing genetic tests under CLIA88.