ACMG and AMA Coalition Make LDT Oversight Recommendations to Congress

A coalition of organizations including the American Medical Association (AMA) and American College of Medical Genetics and Genomics (ACMG) have recommended to Congress that oversight of laboratory developed tests (LDTs) be undertaken “primarily through reform of the Clinical Laboratory Improvement Amendments [(CLIA)],” with a more limited role for the Food and Drug Administration (FDA). The coalition’s letter, sent to Chairmen and Ranking Members of the Committee on Health, Education, Labor and Pensions and the Committee on Energy and Commerce, says that congressional action is needed to “ensure that high complexity laboratory developed testing services and procedures are accurate, precise, clinically relevant, and monitored for continued quality performance.” But, the coalition argues that oversight should occur via updates to CLIA rather than “an entirely new regulatory regime.” Utilizing a modernized CLIA framework is “the most streamlined and cost-effective” as well as the “least disruptive and burdensome approach,” the coalition asserted.

The recommendations suggest CLIA could be modernized by establishing standards for clinical validity and strengthening existing standards for quality control, quality assurance, personnel standards and regular proficiency

testing. The coalition argues “in light of the extraordinary progress in diagnostic medicine, including large-scale genetic sequencing and the application of information technology, the existing CLIA requirements should be enhanced to ensure the quality of high complexity testing services and procedures based on risk.” Similarly, the Association for Molecular Pathology (AMP) issued a proposal earlier this year calling for updating CLIA provisions with a tiered, risk-based structure. (See “AMP Offers Proposal for Regulation of Laboratory Developed Tests,” National Intelligence Report, Aug. 20, 2015, p. 6). The organizations signing this most recent letter include the AMA, ACMG, AMP, American Association of Bioanalysts, American Society for Clinical Pathology, Bioreference Laboratory, Infectious Diseases Society of America, and the National Independent Laboratory Association.

Reiterating common objections to the FDA framework, the coalition claims opting for the new FDA framework rather than updating CLIA’s existing structure would stifle innovation by limiting the number of new tests being developed and would hamper access to testing because “public health, community and academic laboratories” could find the new regime “cost-prohibitive.” “In short, legislative and regulatory proposals that shoehorn clinical laboratories into an entirely new regulatory agency and set of requirements will interject tremendous instability and unpredictability that will harm access and innovation,” the coalition warns. Previously, in November 2014, ACMG joined in a coalition letter to the FDA requesting the FDA withdraw its proposed framework, arguing the framework “would impose substantial new requirements on clinical laboratories” and other health care providers without notice and comment periods required for traditional rulemaking.

Genetic Testing is Different
In connection with the current letter, ACMG also released a statement on the issues, explaining how genetic tests are different—“highly complex tests based on recently acquired and rapidly evolving knowledge” and LDTs used for genetic testing should be treated differently than “routine diagnostic tests.” Noting that genetic tests don’t provide “individualized results on their own but require expert interpretation informed by medical and family histories to ensure their safe and effective use by providers” the ACMG echoed arguments made by other stakeholders that LDTs involve the practice of medicine and thus shouldn’t be pigeonholed into a framework similar to that used for medical devices.

The ACMG further explained there are two types of genetic tests—those that target specific variations known to be linked to specific conditions versus “more open test platforms that sequence the entire genome and provide a comprehensive look at known and previously undescribed potential contributors to a disease.” The first category, says ACMG, are “more amenable to test validation and direct oversight of laboratory performance in detecting the target.” It is the open testing of the entire genome that requires professional determinations

and judgment calls based on knowledge of genetics and pathology. Both types require a “unique base of specialized medical knowledge and training to ensure both that the proper test is ordered as well as interpreted in the context of individuals and their families.” ACMG suggests that for open forms of testing an oversight model similar to that used for radiologic imaging would be more appropriate in acknowledging that the machine is the regulated device but the interpretation services are professional services.

Proposed Keys to Efficient, Effective Oversight ACMG’s position is that any oversight of LDTs must include four key features:

1. Enhanced CLIA regulations that are tiered and risk-based, with a third-party review system, public reporting of test performance, coordinated oversight between CMS and FDA, grandfathering of tests based on prior assessment of clinical validity, and adverse event reporting.
2. Increased role for third-party genetic testing laboratory accreditors that assesses analytical and clinical validity of new tests but without requiring laboratories to “provide separate clinical validity details of tests already accepted as clinically valid.” If data regarding validity is privately held rather than publicly available, third party-reviewers could review validity if the developers reveal algorithms and proprietary information; or more formal/traditional regulatory oversight would apply if trade secrets are not shared. Third-party reviewers could pre-certify moderate risks tests and low risk tests could be subject to oversight via third party accreditation inspections. Test kits and devices “for broad clinical laboratory use” would be subject to FDA processes.
3. Low and moderate risk genetic tests could be pre-certified as to clinical validity under CLIA via third-party accreditors. High risk tests would be subject to oversight under joint CLIA/FDA third-party review system. Utilize Federal Trade Commission and State Attorneys General to address marketing and sale of tests with insufficient clinical validation.
4. NIH support for common sharing of data regarding clinical significance of rare genetic variations through an Information Commons, facilitating not only test validation but also postmarket surveillance and support clinical interpretations by increasing availability of data.

Takeaway: The debate concerning LDT oversight continues and intensifies as the industry looks for Congressional action to supplant the FDA’s previously proposed framework.