Cathy Fomous, Ph.D.
NIH Office of Biotechnology Activities
6705 Rockledge Drive
Bethesda, MD 20817
Dear Dr. Fomous:
The Draft Report of the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) cited above is notable, on the one hand, for its accurate diagnosis of the manifold problems in the oversight of genetic testing and, on the other, for its complete failure to identify an appropriate treatment for these problems. The seriousness of mistaken results in genetic testing is so grave that oversight cannot be entrusted to self-interested parties or voluntary efforts by lackluster federal agencies. Mandatory proficiency testing (PT) through the Centers for Medicare & Medicaid Services (CMS) and expanded clinical validity review through the Food and Drug Administration (FDA) are the only responsible ways forward, but neither was proposed in the Draft Report.
These comments will focus on the roles of federal agencies in the regulation of genetic tests. We do not address the functions of the states, professional societies or voluntary accrediting bodies.
As the Draft Report makes clear, federal regulatory authority is divided awkwardly between two federal agencies: CMS and the FDA. CMS’ authority stems from the Clinical Laboratory Improvement Amendments of 1988 (CLIA). In essence, that Act delineates CMS’s authority over laboratories and prescribes a series of recordkeeping, quality assurance, personnel and other standards. Primary among these is PT: whether the laboratory can consistently characterize standard specimens with known properties. Traditionally, any requirement for PT under CLIA has been mediated through the creation of specialty areas.
The FDA exerts its authority through the Food, Drug, and Cosmetic Act’s Medical Device Amendments, first enacted in 1976. These provide the authority for the FDA to require premarket review for some diagnostic tests, including genetic tests. While the FDA has exerted this authority over test kits for which manufacturers sought FDA approval, it has failed to exert this authority over most laboratory-developed tests (LDTs), which represent the vast majority of genetic tests developed to date. There are currently more than 1,200 LDTs while, according to the Draft Report, only about a dozen genetic tests have been approved by the FDA.
Thus, while CMS focuses on laboratory quality, the FDA focuses on the actual tests, and seeks to establish their safety and effectiveness. To this end, the FDA evaluates the actual test performance characteristics of the test (e.g., sensitivity, specificity, positive predictive value, negative predictive value), not merely whether the test can correctly identify a standard specimen. While CMS can oversee analytical validity, the FDA can assure clinical validity.
While the complexity of this regulatory schema is enough to befuddle even the most ardent policy wonk, patients are left in the dark. For the average patient administered a genetic test, there is no perceivable difference between an LDT and a commercial test kit and no independent source from which to determine the quality of the testing.
In 1997, the National Institutes of Health and the Department of Energy commissioned a report that explicitly called for mandatory PT for all genetic tests through CLIA. The report also emphasized that “no clinical laboratory should offer a genetic test whose clinical validity has not been established,” an implicit endorsement of expanded FDA regulation. In 2001, the Secretary’s Advisory Committee on Genetic Testing (SACGT), a Clinton-era predecessor to the SACGHS, said that “the benefits of additional oversight of genetic tests outweigh the risks … additional oversight is warranted for all genetic tests.” The committee went on to recommend both that CLIA provide independent verification of analytical validity (presumably through PT) and that “FDA should be the federal agency responsible for the review, approval, and labeling of all new genetic tests.” As the Draft Report acknowledges, these recommendations have been almost entirely ignored. Indeed, the present report, unless substantially altered, seems destined to lay the paper trail for disregarding them in the future as well.
Regulation of Analytical Validity under CLIA
The Draft Report does a commendable job of cataloguing the many deficiencies in CMS’s implementation and enforcement of CLIA. Rather than describe them, these quotes from the report speak for themselves:
[PT] is considered to be the most rigorous form of performance assessment currently available. (p. 15)
Proficiency testing and quality assurance are essential for the continuous quality management and maintenance of process standards for laboratories performing genetic testing. (p. 16)
In principle, genetic tests and all other high-complexity tests should be required to undergo PT. (p. 17)
Genetic tests and the laboratories performing them should be expected to meet the same high standards of accuracy, validity, and utility to which other medical information is subject. (p. 27)
Assuring the analytical … validity of genetic testing is paramount (p. 67)
Congress wanted proficiency testing to “be the central element of determining a laboratory’s competence since it purports to measure actual test outcomes rather than merely gauging the potential for accurate outcomes.” (p. 77)
Some laboratories offering health-related tests [e.g., in vitro fertilization clinics or facilities offering tests for gender or nutrigenomic tests] are not required to follow CLIA regulations. (p. 107)
CLIA inspectors may not be sufficiently trained to evaluate laboratory developed genetic tests. (p. 108)
Most of the analytes [substances to be analyzed] that pertain to genetic testing … are not among the 83 analytes regulated by CLIA. (p. 108)
Having acknowledged the overwhelming evidence of CMS’s deficiencies with respect to CLIA, one might have expected forceful recommendations from the Draft Report. In particular, one might logically expect the Draft Report to have endorsed a PT requirement, whether through the creation of a genetic testing specialty or under any other mechanism under CLIA. But what we get instead is this extremely limited justification for not endorsing a genetic testing specialty:
SACGHS carefully considered the recommendations of prior groups as well as the perspectives of stakeholders who support the specialty. In the end, the Committee came to the conclusion that identified gaps can be addressed without the creation of a genetic testing specialty. (p. 111)
Thus, despite rigorous documentation of the centrality of PT and the limits of current CMS oversight, the Draft Report provides no rationale whatsoever for failing to endorse a genetic testing specialty. This is contrary to Congressional intent. As the Draft Report says,
Congress intended HHS to require PT of all laboratories for each type of clinical test they performed, unless the Secretary determined that was not feasible. Congress did not intend for the Secretary to exempt analytes from proficiency testing merely because such testing is not currently available or because it is difficult to obtain consensus on the best method of proficiency testing. (p. 108)
Regulation of Clinical Validity under the FDA
The Draft Report is equally adept at cataloguing the deficiencies in current FDA regulation of genetic tests. Again, let the Draft Report speak for itself:
Assuring the … clinical validity of genetic testing is paramount. (p. 67)
When a laboratory test is performed, the manufacturer, regulatory agencies, credentialing organizations, the laboratory, the ordering physician, and the patient need to have a high level of confidence that reported results are reliable. (p. 71)
FDA is not currently assessing the clinical validity of most genetic tests. (p. 98)
Significant harms (real or potential) can occur if a genetic test is used before its clinical validity is understood. (p. 110)
There is no complete or official source of information on the number and types of genetic tests that are clinically available in the United States. (p. 107)
There is no national mechanism for reporting these reagents [used in genetic testing] when they are faulty because manufacturers are not required to be registered or to list these products with FDA … Similarly, if a laboratory-developed test is faulty due to design or validation failures, there is no mechanism to report the faulty test. (p. 107)
Lack of postmarket evidence constrains the ability to understand the impact of tests and therapies after they enter clinical and public health practice. (p. 120)
Despite these well-documented reasons for expanded FDA regulation of genetic tests, the Draft Report simply endorses the status quo. As in its justification of its failure to endorse a genetic testing specialty, the Draft Report provides only the most meager of explanations for its failure to recommend vigorous FDA oversight:
SACGHS agrees that applying the same regulatory framework to every genetic test is infeasible given the number of tests in use and in development and the costs and resources that would be needed to support such a structure. Moreover, such a policy could unnecessarily delay patient access to important new technologies. (p. 113)
It is surely true that the backlog of unregulated LDTs is daunting; this is the cost of a decade of ignoring repeated blue ribbon panel recommendations as an industry is expanding. But the FDA has an established history of evaluating the safety and efficacy of products already on the market: the Drug Efficacy Study Implementation Review for prescription drugs and the Monograph process for over-the-counter drugs. Moreover, the rudiments of a priority-based approach to genetic testing can be divined from the agency’s recent effort to regulate in vitro diagnostic multivariate index assays (IVDMIAs). (These are assays that typically combine genetic information with algorithms to generate estimates of disease likelihood.) If the agency is to begin to exert authority over the more than 1,200 unregulated genetic LDTs, it can do so by establishing priorities based on some combination of current or predicted future use, possible harm to patients, complexity and potential clinical utility. Some of these are features of the current medical device approval process itself.
Clearing the backlog of unregulated LDTs would certainly cost money. But we are struck by the blithe dismissal of vigorous FDA regulation partly on financial grounds, while the authors are happy to endorse a series of incentives, studies and consortia, with some Task Force members or their institutions as likely beneficiaries.
The Draft Report evinces, without any supporting documentation, concern that regulation would delay patient access to genetic technologies. But is the continued sale of an expanding number of unregulated, potentially harmful genetic tests a preferable alternative? As the Draft Report makes clear, the FDA is the only agency with the full complement of expertise, experience and facilities to regulate such tests. Further, FDA involvement would address the market inequity in which a minority of tests undergoes full FDA review, while others (including such major tests as those for the BRCA genes) are subject only to the minimal constraints of CLIA.
On a separate matter, the Draft Report acknowledges that no-one knows the number and identity of currently available genetic tests and therefore recommends the creation of a registry. But rather than a mandatory registry, which would be essentially complete and could be rapidly implemented, the report recommends a five-year trial period of voluntary registration. Of course, we currently have a voluntary system (GeneTests, a publicly funded website that has existed for 14 years), but it has yielded the unacceptable status quo decried by the Draft Report. Moreover, there is ample precedent for mandatory FDA registries (e.g., the Human Cells and Tissue Establishment Registration system which requires the registration of facilities and products involving human cells, tissue, and cellular and tissue-based products). We can see no justification for the failure to endorse a mandatory approach, particularly when the paperwork burden of complying would be so minimal. By the time the voluntary system can be declared a failure, the number of tests will have expanded dramatically and patients will have been placed at needless risk in the interim.
As noted, the current Draft Report is merely the latest in a series of government reports that have similarly diagnosed the ills in the genetic testing oversight system. But, reflecting the ideology of the current administration, it diverges from the previous reports by recommending a treatment regimen that would preclude the government from using the oversight tools it already has. Moreover, the report fails to adequately justify its recommendations to not use those oversight tools. Perhaps this is related to the makeup of the Task Force: of its 33 members, all but one (a “consultant pathologist”) was drawn from government, industry or academia (the home base for many LDTs). Not a single consumer or patient group was represented. Undoubtedly some Task Force members do not agree with the thrust of the recommendations, but it is clear that the Task Force was overwhelmingly comprised of those with an interest in the status quo.
The stakes in genetic testing and oversight are every bit as high as the report suggests. Faulty test results can result in unnecessary abortions, incorrect treatment decisions, needless anxiety, and more. If the authors of this report truly believed the problem is as serious as they say it is, they would recommend stringent government oversight. Instead they have resorted to a wish list of voluntary measures, many of which will never see the light of day in any meaningful form.
Peter Lurie, M.D., M.P.H.
Sidney M. Wolfe, M.D.
Public Citizen’s Health Research Group
Neil A. Holtzman, M.D., M.P.H.
Johns Hopkins School of Medicine
1997 NIH/DOE Genetic Testing Report
 The assurance of clinical utility (the overall usefulness of the tests) is discussed at some length in the Draft Report, but is not the subject of these comments.
 Secretary’s Advisory Committee on Genetic Testing. Enhancing the Oversight of Genetic Tests: Recommendations of SACGT. July 2000. Available at: http://osp.od.nih.gov/office-biotechnology-activities/sacgt/reports/oversight_report.pdf.
 In 2000, the Department of Health and Human Services (which houses both CMS and the FDA) announced its intention to create a genetic testing specialty by publishing a “Notice of Intent” in the Federal Register. CMS repeatedly assured the CLIA Advisory Committee of its intent to propose such a specialty and in its regulatory agenda in April 2006 identified November 2006 as the target date for its release. However, that summer the agency abruptly changed course and in August 2007 denied a September 2006 petition from the Genetics and Public Policy Center, Public Citizen, and the Genetics Alliance seeking such a specialty. See https://www.citizen.org/pressreleases/federal-agency-rejects-enhanced-oversight-genetic-tests-places-cost-considerations.
 Draft Guidance for Industry, Clinical Laboratories, and FDA Staff?In Vitro Diagnostic Multivariate Index Assays. July 26, 2007. http://www.fda.gov/cdrh/oivd/guidance/1610.html. Now available at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM071455.pdf.