The U.S. Food and Drug Administration (FDA) issued a final rule yesterday establishing a regulatory framework for laboratory-developed tests (LDTs).
The final rule modifies the definition of in vitro diagnostic products (IVDs) to explicitly include LDTs. Since IVDs are defined as devices, all LDTs will now be subject to the regulatory framework governing devices, which includes adverse event reporting, establishment registration, device listing, labeling requirements, investigational use requirements, quality system requirements and premarket review.
Until now, FDA has exercised enforcement discretion and has not enforced applicable requirements for most LDTs. The final rule includes an approach to phase out enforcement discretion for most LDTs, which include “IVDs that are manufactured and offered as LDTs by laboratories that are certified under CLIA and 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.”
FDA specifies that certain types of tests fall outside the scope of the phaseout policy. Additionally, the agency intends to continue enforcement discretion for specified LDTs.
Tests Outside the Scope of the Phaseout Policy
FDA indicated that certain tests fall outside the scope of the phaseout policy since its general enforcement discretion approach never applied to the tests, which include:
- 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 Federal Food, Drug and Cosmetic Act.
- Direct-to-consumer tests.
- Tests manufactured and offered for use exclusively for public health surveillance when: (1) they are intended solely for use on systematically collected samples for analysis and interpretation of health data in connection with disease prevention and control and (2) test results are not reported to patients or their health care providers.
Enforcement Discretion Policies
FDA intends to exercise enforcement discretion and generally not enforce all applicable regulatory requirements for specified categories of LDTs, including:
- 1976-type LDTs, which include tests that (1) use of manual techniques (without automation) performed by laboratory personnel with specialized expertise; (2) use of components legally marketed for clinical use; and (3) design, manufacture, and use within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing.
- HLA tests that are designed, manufactured, and used within a single laboratory certified under CLIA that meet 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 crossmatch tests.
- Tests intended solely for forensic (law enforcement) purposes.
- LDTs manufactured and performed within the Department of Defense or the Veterans Health Administration.
The agency also intends to exercise enforcement discretion with respect to premarket review and certain quality system requirements for other categories of tests, including:
- Non-molecular antisera LDTs for rare red blood cell (RBC) antigens when such tests are manufactured and performed by blood establishments, including transfusion services and immunohematology laboratories and when there is no alternative test available to meet a patient’s need for a compatible blood transfusion. However, this policy does not apply to molecular tests used for genotyping RBCs.
- LDTs manufactured and performed by a laboratory integrated within a health care system to meet an unmet need of patients receiving care within the same health care system. An LDT would satisfy the “unmet need” criteria when “there is no available FDA-authorized IVD that meets the patient’s needs. This may be 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.”
- Currently marketed IVDs offered as LDTs that were marketed before FDA issued the LDT final rule, as long as they are not modified in a manner that (1) changes the indications for use of the IVD; (2) alters the operating principle of the IVD; (3) includes significantly different technology in the IVD; or (4) adversely changes the performance or safety specifications of the IVD.
In addition, FDA intends to exercise enforcement discretion and generally not enforce premarket review requirements for LDTs that are approved by New York State Department of Health’s Clinical Laboratory Evaluation Program.
Phaseout Stages
FDA’s general enforcement discretion approach for LDTs will phase out over a period of four years and will be fully implemented by May 6, 2028. FDA outlines five stages of the policy:
- Stage 1: beginning on May 6, 2025, which is one year after the publication date of the final LDT rule, FDA will expect compliance with medical device reporting requirements, correction and removal reporting requirements and quality system (QS) requirements regarding complaint files.
- Stage 2: beginning on May 6, 2026, which is two years after the publication date of the final LDT rule, 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.
- Stage 3: beginning on May 6, 2027, which is three years after the publication date of the final LDT rule, FDA will expect compliance with QS requirements (other than requirements regarding complaint files which are already addressed in stage 1).
- Stage 4: beginning on November 6, 2027, which is 3.5 years after the publication date of the final LDT rule, FDA will expect compliance with premarket review requirements for high-risk IVDs offered as LDTs (IVDs that may be classified into class III or that are subject to licensure under section 351 of the Public Health Service Act), 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.
- Stage 5: beginning on May 6, 2028, which is four years after the publication date of the final LDT rule, 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.
FDA anticipates that half of LDTs subject to premarket review requirements will be reviewed under its 510(k) Third Party Review Program. AABB is approved by FDA as a third-party review organization and is available to review premarket submissions for eligible device types regulated as hematology, pathology, microbiology, general hospital and clinical chemistry devices. Additional information is available on AABB’s website.
The new final rule is scheduled to be published in the Federal Register on May 6, and will be effective 60 days after the date of publication. On May 14, FDA will host a webinar on the final rule.
Along with the final rule, FDA released several related resources, including:
AABB is continuing to assess the impact of FDA’s final rule from collection to administration. AABB will provide additional analysis on the final rule for the blood and biotherapies community as information becomes available. Those with questions are welcome to contact AABB at regulatory@aabb.org.
