FDAs Proposed New Rule on Laboratory Developed Tests (LDTs)

Boston MedTech Advisors Blog, January 2024

Laboratory developed tests (LDTs) are in vitro diagnostic products (IVDs), intended for clinical use, that are designed, manufactured, and used within a single clinical laboratory that is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) for high complexity testing. These tests must be ordered by physicians (or other persons authorized by applicable state law) and can be used to measure or detect a wide variety of analytes, such as proteins, chemical compounds (like glucose or cholesterol), or DNA, in a sample taken from a human body.

Historically, FDA has generally exercised enforcement discretion over most LDTs, not enforcing applicable requirements (e.g., premarket review and filing requirements), because LDTs were relatively simple and generally available on a limited basis when they were initially introduced. However, the risks associated with most modern LDTs are much greater than the risks that were associated with LDTs used decades ago.

Most recently, on October 3, 2023, FDA released a proposed rule “Medical Devices; Laboratory Developed Tests” which is intended to expand the definition of IVDs to include devices manufactured by a laboratory and phase out, over a period of four years, the general enforcement discretion approach to these devices in order to increase oversight of LDTs. After this phaseout, FDA would require LDTs to meet the same applicable requirements as IVDs, except where meeting certain requirements under CLIA can be leveraged.

Concerns about the safety and effectiveness of these tests have been raised for many years. FDA has identified problems with several high-risk LDTs, including claims of inadequate clinical evidence, lack of appropriate controls yielding erroneous results, and falsification of data. Faulty LDTs could lead to incorrect diagnosis, leading to patients not getting effective therapies, or to patient exposure to inappropriate, unnecessary, or harmful therapies. Therefore, FDA has asserted that there is a public health need for greater oversight of LDTs.

Discussions regarding the role of FDA in regulating LTDs and the need for greater oversight have been ongoing since the 1990s. In 1992, FDA released a draft Compliance Policy Guide titled “Commercialization of Unapproved In Vitro Diagnostic Devices Labeled for Research and Investigation,” in which the Agency stated that LDTs (referred to as “unapproved products for diagnostic purposes”) were subject to the same regulatory requirements as any unapproved medical device. This draft guide was immediately challenged by a citizen petition filed to object to FDA’s assertion on four grounds: the proposal was inconsistent with CLIA, FDA lacked statutory authority to regulate in-house assays, the proposal would violate the Administrate Procedure Act, and that it would diminish the quality of healthcare.¹ FDA formally denied this petition in 1998, and the final rule, released in 1997, stated that “FDA believes that clinical laboratories that develop such tests are acting as manufacturers of medical devices and are subject to FDA jurisdiction under the act,” although no actions to enforce this jurisdiction were taken.²

In the subsequent decades, as genetic testing expanded widely and allowed for the development of much more complex LDTs with higher risk results, studies through the Government Accountability Office highlighted misleading or inaccurate results from several companies, resulting in FDA sending numerous letters to companies involved in such products. In June 2010, FDA held a public meeting on their oversight of LDTs which resulted in draft guidelines released on October 3, 2014 (“Framework for Regulatory Oversight of Laboratory Developed Tests [LDTs]).³ This draft guidance described the proposed oversight, including requirements for notification, reporting, risk-based approach to premarket review, and quality system regulation. This proposal was met with a strong, and mixed, response on the need to ensure safety while avoiding undue regulatory burden that could stifle innovation and reduce critical accessibility of medical services. Discussions and congressional hearings continued until the FDA announced in 2016 that they intended to suspend plans to move forward with the LDT proposal.

In 2020, the ‘Verifying Accurate, Leading-edge In-Vitro Clinical Tests Development’ (VALID) Act was introduced in Congress. This proposed giving FDA expanded authority over LDTs, including separation of in vitro clinical tests from the existing medical device regulation, and establishment of a regulatory framework for LDTs and IVDs through a new FDA Center. Passage would require laboratories to comply with new requirements for registration with FDA such as, depending on the risk classification of the LDT, premarket approval and adverse event reporting. This act did not pass. New drafts of the VALID Act were reintroduced in 2021 and 2022 but similarly did not move forward.

Most recently, on October 3, 2023, FDA released a proposed rule “Medical Devices; Laboratory Developed Tests”⁴ which is intended to expand the definition of IVDs to include devices manufactured by a laboratory and phase out, over a period of four years, the general enforcement discretion approach to these devices in order to increase oversight of LDTs. After this phaseout, FDA would require LDTs to meet the same applicable requirements as IVDs, except where meeting certain requirements under CLIA can be leveraged. FDA intends to continue adopting enforcement discretion policies for certain types of IVDs in certain circumstances, as appropriate. Regardless, FDA retains discretion to pursue enforcement action at any time against violative IVDs when appropriate.

The timeline, following the finalization of the phase out policy, is:

One year: End the general enforcement discretion approach with respect to Medical Device Reporting (MDR) requirements and correction and removal reporting requirements.
Two years: End the general enforcement discretion approach with respect to requirements (e.g., labeling, registration/listing) other than MDR, correction and removal reporting, Quality System (QS), and premarket review requirements.
Three years: End the general enforcement discretion approach with respect to QS requirements.
Three years (but not before October 1, 2027): End the general enforcement discretion approach with respect to premarket review requirements for high-risk IVDs.
Four years (but not before April 1, 2028): End the general enforcement discretion approach with respect to premarket review requirements for moderate risk and low risk IVDs (that require premarket submissions).

FDA views this phaseout of FDA’s general enforcement discretion approach for LDTs as important to ensure the safety and effectiveness of LDTs and may also foster the manufacturing of innovative IVDs for which FDA has determined there is a reasonable assurance of safety and effectiveness.

On January 18, 2024, FDA and the Centers for Medicare & Medicaid Services (CMS) issued a joint statement on LDTs in which CMS expressed support for FDA’s proposal. CMS regulates laboratories, through CLIA, by establishing quality standards for all laboratory testing to help ensure the accuracy, reliability and timeliness of patient test results. However, CMS does not have the expertise to assure that tests work. Therefore, FDA oversight of the analytical and clinical validity of LDTs is considered complementary to CMS efforts to assure clinical accuracy of LDT test results.⁵

FDA sought comments in a 60-day period on this proposed rule, which ended on December 4, 2023, and resulted in over 6,500 comments. Many comments, and letters such as that sent by the American Heart Association,⁶ voiced strong concerns that LDTs are tools developed and used in the context of clinical care that are needed for essential patient testing; enforcing the broad new rule as proposed would result in a loss of patient access to critical care.

FDA is expected to review comments and publish a final rule in April of 2024.⁷ Although final FDA oversight of LDTs may take years, the constant push by FDA suggests that it would be prudent for LDT manufacturers to begin early regulatory diligence of potential regulatory pathways for marketing and work toward compliance with FDA requirements.

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References:

Citizen Petition to the Food and Drug Administration 92P-0405. Hyman, Phelps, & McNamara. October 22, 1992. http://www.hpm.com/pdf/CITIZEN%20PETITION%201992.pdf
62 Fed. Reg. 225 (November 21, 1997)
Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” October 2014 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/framework-regulatory-oversight-laboratory-developed-tests-ldts
Proposed rule “Medical Devices; Laboratory Developed Tests” October 2023 https://www.federalregister.gov/documents/2023/10/03/2023-21662/medical-devices-laboratory-developed-tests
FDA and CMS: Americans Deserve Accurate and Reliable Diagnostic Tests, Wherever They Are Made. January 18, 2024 https://www.fda.gov/medical-devices/medical-devices-news-and-events/fda-and-cms-americans-deserve-accurate-and-reliable-diagnostic-tests-wherever-they-are-made?utm_medium=email&utm_source=govdelivery
“AHA Letter to the FDA on Laboratory Developed Tests (LDTs) Proposed Rule” December 2023. https://www.aha.org/lettercomment/2023-12-01-aha-letter-fda-laboratory-developed-tests-ldts-proposed-rule
View Rule “Medical Devices; Laboratory Developed Tests” https://www.reginfo.gov/public/do/eAgendaViewRule?pubId=202310&RIN=0910-AI85