Crescendo Reached on Long-standing Quest for FDA Regulation of Laboratory-developed Tests

Laboratory-developed tests (LDTs) are, as defined by the United States Food and Drug Administration, a class of IVD assays designed, manufactured, and used within a single laboratory. If a test is at least partly designed or manufactured outside of the lab in which it is to be employed, it cannot be categorized as an LDT as per FDA guidance. LDTs can be used to detect a wide range of analytes, from proteins to chemical compounds, and lately, even nucleic acids. Kalorama has recently released a full report on LDTs, their clinical applications, with a complete market analysis, which can be found here.

 LDTs are, ideally, designed to be solutions that do not otherwise exist yet on the market (viz. “We can’t order a simple quantitative blood sodium assay? Better make our own.”). In the beginning, by their very nature, they were relatively simple tests that were available only on a limited basis, so the FDA had not enforced premarket reviews of LDTs. They are instead regulated by the Centers for Medicare and Medicaid Services (CMS), where they are categorized as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). However, with advances in technology, LDTs are now being designed with greater complexity, with some now being similar to IVD tests that have undergone FDA review before entering the market. After having expressed desires to do so since making a brief, somewhat throwaway statement in a 1992 RUO policy guide, the FDA has centered on this increasing complexity as its rationale for a controversial proposal to gain more regulatory oversight over LDTs.

 The FDA made official in 2010 its intent to revise its previous LDT policy (in which there effectively was none), citing insufficient evidence in claims of an LDT’s efficacy, a lack of controls, yielding false results, or developers fudging numbers and producing fake results. The FDA had asserted that if tests fail to meet the standards to which commercially available IVD tests have to comply, their use could lead to patients undergoing unnecessary treatment, or worse, foregoing a vital treatment due to a false negative. The agency illustrated as examples of outcomes of poorly designed tests, the under- or overtreatment of heart disease, cancer patients receiving inappropriate or ineffective treatments, incorrect diagnoses of autism, and the unnecessary overprescription of antibiotic treatment, which of course, is contributing to a burgeoning crisis with treatment-resistant infections.

 In July 2014, the FDA announced the release of a draft guidance for a risk-based framework for the regulation of some LDTs, which would be phased in over a period of nine years. In the paper, the agency said its oversight would be centered primarily on tests that would pose the greatest risk to patients in the event of a false result, and that exemptions would remain in place for tests for rare diseases or those for which there is currently no approved alternative on the market. Prior to the announcement, commercially produced test kits have been regulated as medical devices, while under CLIA, LDTs were not; the FDA stated that it had the legal authority to regulate the tests, but it was exercising “enforcement discretion” not to do so, but as the tests became more widely used and less simple in design, that discretion had to end. Additionally, many LDTs were being produced by companies outside of clinicians’ labs and being brought to market without FDA oversight.

 The announcement was met with criticism, however, from the clinical research community; labs and pathologists maintained that LDTs are services, rather than devices, and that updates to regulations should be made through changes to CLIA. The American Association of Clinical Chemistry (AACC) recommended that LDT regulation should remain under CMS oversight via CLIA, unless there were certain high risks that should be subject to both CMS and the FDA; furthermore, not only are tests regulated already by CMS, but labs are also subject to oversight by state and private entities – for instance, the State of New York or the College of American Pathologists (CAP). The AACC and other groups stated that adding another, superfluous layer of regulatory oversight would hamper innovation. This was the main point outlined in a letter written to the White House transition team in 2016 by Alan Mertz, the president of the American Clinical Laboratory Association (ACLA), stating that the LDT proposal “risks [...] significantly increasing the cost of translating medical discoveries into accessible laboratory diagnostics for patients.” CAP produced a three-pronged legislative proposal of its own: first offering a risk-based stratified classification of LDTs with provisions for tests detecting rare diseases and conditions or otherwise addressing unmet needs; proposing enhanced standards though CLIA, in which accrediting bodies would be formed to determine a test’s clinical and analytical validity; and outlining a set of regulations and transitional provisions for the classification of LDTs.

 Finalization of the draft guidance was delayed until after the 2016 general election, as the new approach would depend on who would be taking office, and in January 2017, the FDA produced a discussion paper taking into account the feedback from groups representing laboratory professionals. The agency called it, “a prospective oversight framework that focuses on new and significantly modified high- and moderate-risk LDTs would best serve public health and advance laboratory medicine;” in the paper, the FDA scaled back the scope of LDTs under its watch, suggesting all LDTs currently on the market remain exempt, save for adverse event and malfunction reporting. With newly produced LDTs, low-risk and traditional tests continue to be regulated as they are with no additional oversight by the agency, but the FDA does reserve the ability to enforce premarket review if it is found that a test is not analytically or clinically valid, if the LDT’s manufacturer is deceptive in its promotion of the test, or if a test’s erroneous results could lead to serious health consequences. This framework would go into effect over the course of four years, streamlining progress from the originally proposed nine-year time frame. The FDA also addressed Mertz’s and others’ concern of regulatory duplication, suggesting that the agency and CMS should be complementary to one another rather than be redundant.

 Groups like the ACLA, AMA, American Cancer Society, and many others have expressed a degree of careful satisfaction with the new guidance and the desire to continue with discussion and collaboration on the matter. One medical device industry trade group, the Advanced Medical Technology Association (AdvaMedDx), expressed disappointment in the delayed guidance, as the group advocates for greater FDA regulatory control of LDTs.

 Despite the amended proposal, the FDA stated that the paper was not meant to be a final, binding solution, but rather an attempt at furthering public discussion on the matter; however, the agency has not, in the last eleven months, solicited any outside feedback or disclosed further plans for LDT-related guidances. It has been 25 years since the FDA began this quest, and it may be another 25 before the journey is complete; since the announcement of the guidance’s delay, the agency’s silence on the matter is deafening.