In an April 4, 2019 Press Release, the U.S. Food and Drug Administration (FDA) announced its issuance of a Warning Letter to Inova Genomics Laboratory (Inova) in Virginia for marketing genetic tests for predicting medication response and patient receptivity to drugs (among other things). FDA identified three genetic tests, including one called “MediMap Plus,” which was designed to provide insight into how a patient would respond to drugs used for anesthesia, cancers, infections, attention-deficit/hyperactivity disorder, depression, anxiety, and diabetes. FDA deemed the tests to be adulterated and misbranded because Inova had not sought premarket clearance.

Laboratory-Developed Tests and FDA Enforcement.

In an October 3, 2014 Notice (the “2014 Notice”) issued by the FDA, the FDA described “laboratory developed tests” (LDTs) as a category of in vitro diagnostic devices (IVDs) that are, “intended for clinical use and designed, manufactured and used within a single laboratory.” As described by the American Association for Clinical Chemistry in a 2017 Position Statement, LDTs are for in-house use and are not commercially distributed to other laboratories. LDTs often relate to medical conditions for which a commercial test does not exist. LDTs currently are regulated by the Centers for Medicare and Medicaid Services as high-complexity tests— the most stringent standards—under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

In 1976, Congress enacted the Medical Device Amendments, which amended the Federal Food, Drug, and Cosmetic Act (the FDCA) to create a comprehensive system for the regulation of medical devices intended for use in humans. At that time, the definition of a device was amended to make explicit that it encompassed IVDs. Although the FDA has taken the position that the expanded definition of IVDs gives the FDA the authority to regulate LDTs,

the FDA has exercised its enforcement discretion by not enforcing applicable provisions under the FDCA and the FDA regulations with respect to LDTs.

Notwithstanding the FDA’s history of non-enforcement, the FDA has argued in recent years that the dramatic increase in the number of and complexity of LDTs, particularly in the field of genetic testing, necessitates that some LDTs be cleared or approved by the FDA to ensure their safe and effective use in patient care. See, 2014 Notice and the FDA’s “Discussion Paper on Laboratory Developed tests (LDTs)” dated January 13, 2017. As described by the FDA, “LDTs have evolved and proliferated significantly since the FDA first obtained comprehensive authority to regulate all in vitro diagnostics as devices in 1976. Some LDTs are now much more complex, have a nationwide reach and present higher risks, such as detection of risk for breast cancer and Alzheimer’s disease, which are similar to those of other IVDs that have undergone premarket review.”

Warning Letter to Inova Genomics Laboratory. 

The FDA’s Warning Letter cites Inova for illegally marketing certain genetic tests (the “MediMap Tests”) without seeking and obtaining premarket clearance from the FDA. As described in the Warning Letter, “FDA is concerned that the clinical validity of [Inova’s] MediMap Tests has not been established for their intended uses. Specifically, we are unaware of data establishing the relationships between the genotypes assessed by your tests and your assertions regarding drug response for multiple drugs.” The FDA wrote that the MediMap tests, “pose significant public health concerns as inaccurate test results could impact the decision-making of healthcare providers and patients in ways that are seriously detrimental to patient health the tests posed significant public health.” In conclusion, the FDA warned Inova that its failure to submit its MediMap Tests to the FDA for premarket approval could result in FDA regulatory actions which could include, but are not limited to, “seizure, injunction, and civil money penalties.”

As described in the Warning Letter, the FDA first notified Inova regarding its concerns during a March 13, 2019 teleconference. During the teleconference, the FDA requested that Inova, “change the MediMap tests and labeling to address the concerns outlined in FDA’s November 2018 safety communication, including removing from the labeling (e.g., patient test reports and promotional material) claims regarding drug responses for specific medications unless and until FDA reviews the information submitted to support such claims and grants marketing authorization.” According to the Warning Letter, Inova provided a written response to the FDA’s concerns on March 21, 2019. In its written response, Inova declined to make the FDA’s requested testing and labeling changes. As quoted by the FDA in the Warning Letter, Inova wrote that the MediMap Tests are LDTs and that Inova is, ‘“properly operating within the scope of FDA’s LDT exemption and thus is not subject to FDA’s premarket review or labeling requirements.”’

In direct response to Inova’s assertion that the FDCA’s premarket approval and labeling requirements are not applicable to Inova and the MediMap Tests, the FDA used the Warning Letter to assert its authority to enforce the FDCA in relation to LDTs notwithstanding its “past pattern of practice” to refrain from such enforcement actions.  As stated in the Warning Letter:

FDA has not created a legal “carve-out” for LDTs such that they are not required to comply with the requirements under the Act that otherwise would apply. FDA has never established such an exemption. As a matter of practice, FDA, however, has exercised enforcement discretion for LDTs, which means that FDA has generally not enforced the premarket review and other FDA legal requirements that do apply to LDTs. Although FDA has generally exercised enforcement discretion for LDTs, the Agency always retains discretion to take action when appropriate, such as when it is appropriate to address significant public health concerns.

In response to the Warning Letter, Inova decided to stop performing its suite of pharmacogenetic tests. Inova has stated that it began offering its genetic tests as a tool to prescribing physicians based on information from the National Institutes of Health-supported Clinical Pharmacogenetics Implementation Consortium (CPIC) and other industry guidelines. Since the Warning Letter, an investigator from the CPIC has challenged FDA’s assertion that the relationship between certain genotypes tested by Inova and drug response has not been established.

What’s to Come.

The Warning Letter and statements in the associated press release by the Directors of the Center for Devices and Radiological Health (CDRH) and Center for Drug Evaluation and Research (CDER) signal the FDA’s renewed interest in LDTs and enforcement against healthcare providers that develop medium and high-risk LDTs without first seeking FDA clearance or approval. FDA’s concern has been, and will continue to be, tests that impact the decision making of healthcare providers, such as selecting or changing drug treatment.

Given the Warning Letter’s focus on clinical validity, which echoes prior concerns expressed by FDA on genetic tests that have not sought premarket clearance, healthcare providers and companies that market genetic tests should ensure that they have robust evidence to support the analytically and clinical validity of their tests.