On May 6, 2024, the Food and Drug Administration (FDA) published its final rule for laboratory developed tests (LDTs). The final rule cemented the agency’s forecasted decision to increase the FDA’s regulatory oversight of LDTs as medical devices. The agency’s final rule amends the definition of in vitro diagnostics (IVDs) at 21 C.F.R. § 809.3(a) to clarify that IVDs, which include LDTs, are medical devices even if manufactured in a laboratory, and describes the agency’s stage-based approach to ending enforcement discretion over these products. However, the final rule also includes significant concessions to the industry as compared to the proposed rule.
Although most laboratories will likely have to comply with certain FDA requirements–such as registration, listing, labeling and complaint reporting–in response to the significant stakeholder commentary and reaction to the proposed rule, the FDA will not require premarket approval for three unexpected categories of LDTs: (1) “currently marketed IVDs offered as LDTs;” (2) LDTs approved by the New York State’s Department of Health Clinical Laboratory Evaluation Program (NYS CLEP); and (3) LDTs used in a single healthcare system for “unmet needs.” Translated, the final rule provides several potential avenues for currently marketed LDTs to escape seeking premarket approval or clearance, at least until the laboratory makes a modification to the test or, in the case of a health system, the agency approves an IVD for the identified unmet need. Notwithstanding these allowances, the FDA warns that, like all enforcement discretion policies, it may update this policy “as circumstances warrant,” and it retains discretion to pursue enforcement action at any time against any LDTs as appropriate to protect the public health.
The Final Rule (Briefly)
Addition to IVD Regulatory Definition
As previewed by the proposed rule, the FDA is amending the definition of “in vitro diagnostic products” in its regulations to add the line “including when the manufacturer of these products is a laboratory.” The agency’s textual change is designed to make it clear that the site of manufacture does not exempt LDTs from being regulated as medical devices.
FDA’s Tailored Phase Out-Plan
The FDA is phasing out its enforcement discretion policy for some, but not all, LDTs. The agency’s final rule maintains the proposed multi-year phaseout schedule consisting of the following five stages.
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- Stage One: By May 6, 2025, the FDA expects compliance with medical device reporting requirements, correction and removal of reporting requirements, and the Quality System (QS) requirement to maintain and review records of complaints.
- Stage Two: By May 6, 2026, the FDA expects compliance with registration and listing requirements, labeling requirements, and investigational use requirements.
- Stage Three: By May 6, 2027, the FDA expects compliance with the remaining QS requirements, including recordkeeping requirements (e.g., maintaining device master records, device history records, and quality system records for the required retention period).
- Stage Four: By November 6, 2027, the FDA expects compliance with premarket review requirements for high-risk LDTs (e.g. those IVDs classified, or that may be classified, as Class III or otherwise require a biologics license pursuant to Section 351 of the Public Health Service Act).[1]
- Stage Five: By May 6, 2028, the FDA expects compliance with premarket review requirements for moderate risk and low risk LDTs that would otherwise require premarket submission.[1]
The agency notes that compliance is expected under stages four and five “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.” The agency warns stakeholders that it remains “illegal to offer IVDs without complying with applicable requirements,” and “[r]egardless of the phaseout timeline and enforcement discretion policy … FDA retains discretion to pursue enforcement action for violations of the FD&C Act [Food, Drug, and Cosmetic Act] at any time, and intends to do so when appropriate.”
Tests Already Regulated by the FDA
The FDA reminds the industry that certain LDTs were excluded from its historic enforcement discretion policy, and thus have always been regulated as medical devices, notwithstanding any contrary views in the industry. Because they are already regulated, these tests fall outside of the scope of the FDA’s new phaseout policy described above: tests intended as blood donor screening or human cells, tissues, and cellular and tissue-based products (HCT/P); donor screening tests required for infection disease testing or required for blood group and Rh factor determinations; tests intended for emergencies, potential emergencies, or materials threats declared under Section 564 of the FD&C Act (e.g., tests approved pursuant to an emergency use authorization); direct-to-consumer tests without meaningful involvement by a licensed healthcare professional; and tests for public health surveillance.
LDTs Exempt from All FDA Requirements
As proposed, the final guidance maintains the FDA’s “enforcement discretion”-based exemptions from all FDA requirements the following LDTs, which the FDA views as unlikely to pose significant risks.
1976-Type LDTs
These are LDTs that have characteristics common among LDTs offered in 1976, including LDTs that: (1) use manual techniques (without automation) performed by laboratory personnel with specialized expertise; (2) use components legally marketed for clinical use; and (3) are designed, manufactured, and used within a single Clinical Laboratory Improvement Amendments (CLIA)-certified high-complexity laboratory.
HLA Tests
Human Leukocyte Antigen (HLA) tests designed, manufactured, and used within a single laboratory certified under CLIA that meets the requirements to perform high-complexity histocompatibility testing when used in connection with organ, stem cell and tissue transplantation to perform HLA allele typing, for HLA antibody screening and monitoring, or for conducting real and “virtual” HLA cross match tests.
Forensic Tests
Tests intended solely for forensic (law enforcement) purposes.
Military Tests
LDTs manufactured and performed within Department of Defense or the Veterans Health Administration.
LDTs Exempt from Premarket Review and in Some Cases Certain QS Requirements
In deference to the significant pushback from stakeholders and Congress following the agency’s proposed rule, the final rule outlines a “targeted enforcement discretion policy” for most other types of LDTs. Notably, however, the following LDTs are not exempt from all requirements, but are exempt from the most burdensome requirement—premarket review:[2]
NYS CLEP
LDTs approved or conditionally approved by NYS CLEP will not be subject to premarket review requirements. The FDA clarifies that this discretion only applies to the version of the test approved by NYS CLEP. These tests will need to still meet the requirements of Stages One through Three above, including registration, listing, labeling, adverse event reporting and certain QS requirements (e.g., design controls, purchasing controls, acceptance activities, corrective and preventive actions, and records requirements). The FDA predicts that may of NYS CLEP approved tests already meet many of these standards.
LDTs by Healthcare System Labs to Meet “Unmet Needs”
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 will not be subject to premarket review requirements and QS requirements other than manufacturing record keeping requirements. These laboratories will nonetheless be required to comply with other agency requirements as described in its staged approach, such as listing and labeling.[3]
The agency notes this exception is intended to be targeted and “not serve as an alternative ‘pathway’ to market for LDTs for unmet needs.” The FDA explains that this exception does not apply to the use of LDTs for unmet needs for patients being treated at affiliated hospitals with a different corporate ownership than the laboratory. Instead, the laboratory and the treating physicians must be “in the same corporate entity,” and thus share responsibility and liability for outcomes, to help mitigate risk.
The FDA further explicitly defines what it considers an unmet need as being “where there is no available FDA-authorized IVD that meets the patient’s needs.” The FDA explains this may be because there is no FDA-authorized IVD for the disease or condition (e.g., a rare disease or condition); or, if there is an FDA-authorized IVD for the disease or condition, it is not sufficient or available to the patient for some reason. The agency warns that enforcement discretion for unmet needs will only last until the agency authorizes an IVD that would otherwise meet the needs of the patient, at which time the LDT’s manufacturer would need to seek premarket authorization or marketing clearance to continue to provide the test.[4]
Grandfathered LDTs
LDTs marketed prior to the final rule that are not modified or are only modified in limited ways, will not be subject to premarket review requirements and QS requirements other than manufacturing record keeping requirements. These grandfathered LDTs must still comply with other applicable requirements including corrections and removals reporting requirements, registration and listing requirements, and labeling requirements.
Laboratories relying on this grandfathering exception can only do so as long as its LDTs are not modified “in certain significant ways” following the issuance of the final rule. When an LDT is modified (individually or in the aggregate), in that there has been a change in the indications for use; an alteration in the operating principle of the test (e.g., changes in critical reaction components); inclusion of significantly different technology in the test (e.g., the 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, any adverse change in the performance or safety specification of the test, the FDA’s enforcement discretion policy will end and the manufacturer must seek premarket authorization or marketing clearance to continue to provide the test.
Antisera LDTs for Rare RBC Antigens
Non-molecular antisera LDTs for rare red blood cell (RBC) antigens 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, will not be subject to premarket review requirements and most QS requirements. This does not apply to molecular tests for genotyping RBC antigens. These tests still must be validated, and comply with the other requirements (e.g., adverse event reporting, registration, listing, labeling).
The agency cautions that its enforcement discretion policy “does not confer lawful marketing status on any IVD being marketed.” The FDA plans to use registration, listing and labeling to help it identify and address LDTs without premarket approval that raise specific concerns, such as LDTs that are potentially inaccurate or poorly validated. Moreover, although many of the QS requirements will not be enforced against several of the categories above, the FDA still expects test manufacturers to comply with the records requirements designed to “facilitate FDA’s review of these IVDs during inspections,” alluding that inspections may be forthcoming. Accordingly, the targeted enforcement discretion approach appears to align with the FDA’s desire to methodically, though pointedly, track the scope of this industry and the outcomes driving health decisions.
What’s Next?
As the dust settles from this regulatory shift, industry is assessing its next moves. The FDA’s decision to implement targeted enforcement discretion for some, though not all, requirements for certain categories of LDTs, including LDTs currently on the market, may decrease the likelihood of significant legal challenges in the short term. That said, the industry should not view the agency’s grandfathering concessions as a “get out of regulation free” card. Although this continued discretion will ease some regulatory burdens, laboratories are likely to still be subject to several requirements related to registration, listing, labeling, and complaint reporting. Accordingly, laboratories should begin to identify where their testing falls and start to create processes and systems designed to comply with these requirements.
If you would like additional information or guidance on how to prepare your laboratory for these regulations, please contact the authors.
[1] The agency notes that compliance is expected under stages four and five “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.”
[2] The agency notes it intention to issue a separate enforcement discretion policy for certain tests in emergent situations.
[3] Although a sponsor is generally not required to submit a label to the agency outside of a premarket application or petition for clearance, it otherwise is required to comply with all labeling requirements under the final rule. To help the agency monitor LDTs prior to the date it intends to end enforcement discretion for applications and clearance petitions, the agency is “requesting” laboratories submit labeling for LDTs to “facilitate FDA surveillance for potentially poor performing LDTs that should otherwise be addressed.”
[4] The agency notes this exception only applies to LDTs that are validated and is considering issuing additional guidance on the validation process for unmet needs.
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