Key Takeaways:

• The Food and Drug Administration (FDA) published its long-awaited Final Rule that will regulate laboratory developed tests (LDTs) as in vitro diagnostic (IVD) medical devices.
• FDA published a four-year enforcement discretion phaseout plan as part of its implementation of the Final Rule.
• The agency offered exemptions from some regulatory requirements for tests and laboratories that meet certain criteria including tests marketed before publication of the Final Rule and tests approved by the New York Department of Health (NYS DOH) Clinical Laboratory Evaluation Program (CLEP).

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Summary

On April 29, 2024, FDA finalized the long-awaited rule to assert authority over the regulation of laboratory developed tests (LDTs) under FDA’s existing regulatory framework for medical devices under the Federal Food, Drug, and Cosmetic Act (FDCA). While FDA has always maintained its authority to regulate LDTs as medical devices, for more than two decades FDA has exercised “enforcement discretion” over LDTs and left regulation to states under the Clinical Laboratory Improvement Amendments (CLIA) program. Numerous prior administrations have pursued regulation of LDTs as medical devices through guidance documents but never finalized a policy or promulgated regulation. Additionally, Congress has considered numerous legislative efforts to regulate LDTs, including most recently with the VALID Act which would regulate all tests under a new category of in vitro clinical tests (IVCTs).

For the first time in the agency’s history, the Final Rule revises FDA’s definition of in vitro diagnostic (IVD) products for human use at 21 C.F.R. 809.3 to explicitly state that all in vitro diagnostic tests are devices, including when the test is performed in a single laboratory. As part of the implementation, FDA will follow a four-year phaseout period, during which LDTs will be expected to come into compliance with the new applicable requirements, with certain exceptions. The phaseout period provides the same timelines and stages that were laid out in the October 2023 notice of proposed rulemaking (NPRM). While the final rule exempts a number of additional categories of LDTs —including LDTs that are currently on the market and LDTs that obtain approval from the NYS DOH — from certain aspects of medical device pre-market review, those tests would still be subject to registration and listing, adverse event reporting, and labeling requirements. Additionally, any future modifications of those tests based on new data would require pre-market review.

Implementation Timeline
 
FDA proposed a five-stage phase-out enforcement discretion plan that is consistent with the plan announced in the October NPRM. Below is a recap of the stages along with the revised dates.

• May 2025 – Stage 1: FDA will expect compliance with medical device reporting (MDR) requirements, correction and removal reporting requirements, and maintenance of complaint files under the FDA quality system (QS) requirements in 21 C.F.R. § 820.198.
• May 2026 – Stage 2: FDA will expect compliance with requirements not covered during other stages of the phaseout policy, including registration and listing requirements, labeling requirements, and investigational use requirements.
• May 2027 – Stage 3: FDA will expect compliance with QS requirements under Part 820 other than requirements under § 820.198 (complaint files), which are already addressed in Stage 1.
• November 2027 – Stage 4: FDA will expect compliance with premarket review requirements for high-risk IVDs offered as LDTs, unless a premarket submission has been received by the beginning of this stage in which case FDA intends to continue to exercise enforcement discretion for the pendency of its review.
• May 2028 – Stage 5: FDA will expect compliance with premarket review requirements for moderate-risk and low-risk IVDs offered as LDTs (that require premarket submissions) unless a premarket submission has been received by the beginning of this stage, in which case FDA intends to continue to exercise enforcement discretion for the pendency of its review.

Enforcement Discretion Phaseout Exemptions
 
1.  Existing Tests on Market as of May 6, 2024

• Currently marketed LDTs that were marketed prior to the date of issuance of the final rule publication date of May 6, 2024 will be exempt from premarket review and QS requirements as long as their modifications do not rise to the level where a premarket review would be required. (Stages 1 and 2 of the implementation plan still apply.)
• FDA offers the following examples of modifications that would necessitate a premarket review and would therefore not fall within the exemption discussed above.
  1. Changing the indications for use of the IVD;
  2. Altering the operating principle of the IVD (e.g., changes in critical reaction components);
  3. Including significantly different technology in the IVD (e.g., addition of artificial intelligence or machine learning to the test algorithm, a change from targeted sequencing to whole genome sequencing, a change from immunoassay to mass spectrometry, or a change from manual to automated procedures); or
  4. Adversely changing the performance or safety specifications of the IVD.
• Importantly, FDA intends to request that laboratories offering currently marketed IVDs submit labeling to FDA, including performance information and a summary of supporting validation, to help FDA more closely monitor these tests.

2.  New York State CLEP

• FDA intends to exercise enforcement discretion and generally not enforce premarket review requirements for LDTs approved by NYS DOH Clinical Laboratory Evaluation Program (NYS CLEP). This policy applies to tests that are approved, conditionally approved, or within an approved exemption from full technical documentation under CLEP.
• It is important to note FDA otherwise intends to maintain the enforcement discretion phaseout outlined above for the remaining requirements. (Stages 1, 2, and 3 still apply.)

3.  Tests for Unmet Needs and for Certain Blood Transfusions

• FDA declined to implement a broader exemption for Academic Medical Centers (AMCs), however, FDA intends to exercise enforcement discretion and generally not enforce premarket review and most QS requirements (except for requirements under Part 820, subpart M) for LDTs manufactured and performed by a laboratory integrated within a healthcare system to meet an unmet need of patients receiving care within the same healthcare system.
  • An LDT is considered to be for an “unmet need” if there is no available FDA-authorized IVD that meets the patient’s needs, because:
    • (1) there is no FDA-authorized IVD for the disease or condition (for example, because it is for a rare disease or condition);
    • (2) there is an FDA-authorized IVD for the disease or condition but it is not indicated for use on the patient, or a unique attribute needs to be added to the LDT to meet the patient’s needs; or
    • (3) there is an FDA-authorized IVD but it is not available to the patient.
  • Enforcement discretion for these tests would end when an FDA authorized test becomes available that meets the patients’ needs.
  • This unmet need policy only applies to LDTs that are appropriately validated. FDA acknowledged that validation may vary depending on various factors, such as the accessibility of specimens and population of affected patients and is considering whether to issue guidance regarding validation of tests, including for rare diseases. 
• Likewise, non-molecular antisera LDTs for rare red blood cell (RBC) antigens are also exempt from premarket review and most QS requirements, where such tests are manufactured and performed in blood establishments, including transfusion services and immunohematology laboratories and where there is no alternative available to meet the patient’s need for a compatible blood transfusion.
• FDA otherwise intends to maintain the enforcement discretion phaseout outlined above for the remaining requirements. (Stages 1 and 2 still apply.)

4.  Other Category of Exempt Tests: Consistent with the proposed rule, FDA intends to exercise enforcement discretion and generally not enforce any medical device requirements for:

• “1976-Type LDTs”;
• Certain human leukocyte antigen (HLA) tests;
• Tests intended solely for forensic law enforcement; and
• LDTs manufactured and performed within the Veterans Health Administration (VHA) or the Department of Defense (DoD). This policy applies only to LDTs used for patients that are being tested and treated within the DoD or VHA.

Modifications to LDTs

As explained above, limited modifications can be made to tests that were first marketed prior to the issuance of the Final Rule and that will remain on the market pursuant to the enforcement discretion policy. The Final Rule also described FDA’s enforcement approach with respect to the premarket review requirements for certain other modifications to laboratory tests.

• High-complexity CLIA laboratories can make certain changes to another manufacturer’s lawfully marketed IVD that was cleared through the premarket notification pathway under Section 510(k) of the FDCA or authorized under the De Novo pathway under Section 513(f) of the FDCA. The changes must be made following design controls and other applicable QS requirements and in a manner that does not significantly affect the safety or effectiveness of the test and does not constitute a major change or modification in intended use, and where the modified test is performed only in the laboratory making the modification. This policy, however, does not apply to modifications of IVDs approved under a premarket approval (PMA) application under Section 515 of the FDCA.
• Laboratories making changes to their own IVDs would need to follow FDA’s existing regulations governing when a premarket submission is needed for a medical device, such as when a PMA approved device is modified in a way that changes the safety or effectiveness of the device or a 510(k) cleared device is modified outside the scope of the 510(k) exemption. Such modifications for an IVD typically include changes to the operating principle, intended use, and other changes that could impact the test’s performance.
• For IVDs that are approved or cleared with a predetermined change control plan (PCCP), modifications made in accordance with the PCCP would not need to be submitted to FDA for review. A PCCP provides the opportunity for a manufacturer to prospectively outline how changes to a device will be validated and implemented, so this will necessarily be limited to the types of changes the test developer can anticipate in advance. FDA may only approve or clear a PCCP that is submitted in a PMA, supplemental PMA, or 510(k) notification, so laboratories that intend to continue marketing their current LDTs cannot submit a PCCP for their existing tests. FDA intends to issue draft guidance on PCCPs for medical devices this year.
• FDA also intends to issue guidance on its enforcement policy regarding certain common changes to IVDs, such as extension of specimen stability and certain alternative specimen types.

Scope of Enforcement Discretion Policy
 
Tests Within the Scope of Policy
 
Although FDA’s previous enforcement discretion approach had a narrower definition of LDTs, FDA recognized that not all laboratories "understood the limited nature of FDA’s general enforcement discretion approach and have been offering IVDs" as LDTs even when they are not "designed, manufactured, and used within a single laboratory" as required by the previous enforcement discretion policy. The Final Rule announced an enforcement discretion policy for “IVDs offered as LDTs,” which FDA describes as “IVDs that are manufactured and offered as LDTs by laboratories that are certified under CLIA and that meet the regulatory requirements under CLIA to perform high complexity testing, and used within such laboratories, even if those IVDs do not fall within FDA’s traditional understanding of an LDT because they are not designed, manufactured, and used within a single laboratory.” Expanding the enforcement discretion to such tests will allow for more consistency moving forward, according to the agency. FDA cautioned, however, that the enforcement discretion policies announced in the rule do not confer lawful marketing status on any IVD being marketed pursuant to the policies and that FDA will take action against any IVD if necessary to protect public health. An area of likely enforcement includes tests where the labeling or promotion includes false or misleading claims or claims that lack appropriate substantiation.

As explained above, AMCs did not receive a special category for exemption as was requested in multiple comments to the proposed rule. FDA believes that it is not necessary or appropriate to have a specific enforcement discretion policy applicable specifically to LDTs offered by AMC laboratories.

Tests Outside the Scope of Policy

The following tests are not within the scope of the phaseout policy, and FDA continues to expect that marketers of these tests continue to comply with applicable medical device and/or biologic regulations.

• Tests that are intended as blood donor screening or human cells, tissues, and cellular and tissue-based products (HCT/P) donor screening tests required for infectious disease testing under § 610.40 (21 CFR 610.40) and § 1271.80(c) (21 CFR 1271.80(c)), respectively, or required for determination of blood group and Rh factors under § 640.5 (21 CFR 640.5).
• Tests intended for emergencies, potential emergencies, or material threats declared under Section 564 of the FDCA. Such tests could become subject to specific enforcement discretion policies. 
  • Concurrently with the issuance of the Final Rule, FDA published two draft guidance documents on the topic. One provides the agency’s thinking about an enforcement discretion approach for laboratories offering IVDs for immediate response to a public health emergency (PHE) declared under Section 564 and the other provides insights into the agency’s approach to a policy for IVDs in response to an emergent situation in the absence of such a declaration.
• Direct-to-consumer (DTC) tests, i.e. tests that do not include meaningful involvement by a licensed healthcare professional. 

Tests manufactured and offered for use exclusively for public health surveillance, where the test results are not reported to patients or their healthcare providers, are also not subject to or affected by the phase out policy. Such tests are intended solely for use on systematically collected samples for analysis and interpretation of health data in connection with disease prevention and control. Public health surveillance test results are not intended for clinical decision making, because the results of these tests are generally used for trending on a population basis or public health outbreaks.

Potential Next Steps

In the preamble to the Final Rule, FDA provided a lengthy response to the thousands of comments that were submitted to the docket in response to the proposed rule. Now that the rule has been finalized, there is a strong likelihood that some industry participants may challenge the rulemaking in litigation. In addition, some lawmakers have indicated a willingness to work on legislation to address the agency’s oversight over LDTs. For example, Senator Bill Cassidy, M.D. (R-LA), ranking member of the Senate Health, Education, Labor, and Pensions (HELP) Committee, released a statement following the release of the Final Rule that “The FDA does not have the authority to unilaterally increase its regulatory jurisdiction. This rule will undermine access to essential laboratory tests, increase healthcare costs, and ultimately harm patients.” Laboratories, in the meantime, will need to assess their current LDTs — and their plans to modify any existing tests — and develop a strategy to come into compliance with applicable device requirements.