FDA Publishes the LDT Final Rule
The LDT Final Rule was published on 5/6/2024 with an effective date 7/5/2024. The final rule can be found here: FDA LDT Final Rule
The key points included:
FDA classified LDTs as IVDs and will have oversight including registration, adverse event reporting and validation requirements.
Made changes to the definition of IVDs at 21 CFR Part 809.3(a) to include IVDs “when the manufacturer of these products is a laboratory.” By codifying into law, they are saying that tests from laboratories are also IVDs.
It is expected that there will be challenges to this rule in the coming months, but as for now, the final rule has been published. FDA is expected to hold a webinar on May 14, 2024 to provide an overview of the final rule. Details of the webinar is found here.
This LDT Final Rule is expected to have an impact to the CLIA lab, IVD manufacturers and RUO Manufacturers. The most significant impact will be the CLIA labs, but there are some collateral effect on the IVD and RUO manufacturers.
Impact to CLIA lab
Increased operational costs, quality system changes likely, validation efforts of LDTs increases.
May not be able to use RUO/IUO to validate LDTs.
Impact to IVD manufacturer
Turnaround time concern for review (due to FDA’s limited bandwidth)
Impact to RUO manufacturer
Limitation for selling to clinical laboratories – CLIA labs may not be able to use RUO/IUO reagents for their LDTs
May need FDA submissions for the RUO reagents and components. For example, a need to create a device master file.
Phaseout Approach
FDA has proposed a phaseout approach for implementing this LDT rule to give labs time to adapt. They are broken down into 5 stages.
Stage 1: Base-line QMS
Beginning May 6, 2025, FDA will expect compliance with medical device reporting (MDR) requirements, correction and removal reporting requirements, and QS requirements regarding complaint files.
Stage 2: Registration and Listing
Beginning on May 6, 2026, 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: Full QMS
Beginning on May 6, 2027, FDA will expect compliance with QS requirements (other than requirements regarding complaint files which are already addressed in Stage 1).
Stage 4: Pre-market Review for High-risk IVDs
Beginning on Nov. 6, 2027, FDA will expect compliance with premarket review requirements for high-risk IVDs offered as LDTs.
Stage 5: Pre-market Review for moderate-risk and low-risk IVDs
Beginning on May 6, 2028, FDA will expect compliance with premarket review requirements for moderate-risk and low-risk IVDs offered as LDTs (that require premarket submissions).
The LDT Final Rule also identified certain tests that are outside the scope of the phaseout approach, and where enforcement discretion will still apply.
A. Tests outside of the scope of the phaseout policy because general enforcement discretion never applied to these tests:
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.
B. Tests where Enforcement Discretion still applies:
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.
LDTs approved by NYS CLEP.
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.
Grandfathered LDTs- 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.
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.
Two Additional Guidance Documents:
Two Guidance Documents were issued as a result of the LDT Rule to provide FDA’s stance on their enforcement discretion for IVDs declared as an emergency under Section 564.
Draft Guidance – Consideration of Enforcement Policies for Tests During a Section 564 Declared Emergency (issued May 6, 2024)
Factors to Consider in Deciding to Issue an Enforcement Policy for Unapproved Tests
The need for accelerated availability of such tests
The known or potential risks of such tests. This includes the seriousness of the life-threatening disease or condition, the complexity of the technology of the test and the experience of test manufacturers among other things.
The availability of appropriate alternative tests that are authorized or approved.
The availability of sufficient mitigations to address risks of false results.
Draft Guidance – Enforcement Policy for Certain In Vitro Diagnostic Devices for Immediate Public Health Response in the Absence of a Declaration under Section 564 (issued May 6, 2024)
FDA will not object to the offerings of “immediate response” test which are tests that:
Intended to detect or diagnose a serious or life-threatening disease or condition that may be attributed to a newly identified, previously unknown, or unusual CBRN agent or agents, or a known agent or agents that result in a newly identified or unusual clinical presentation of such a disease or condition,
Needed for immediate response in an emergent situation for which there is no adequate alternatives
Intended to help the government response to a public emergent situation.
Provided that:
The test was manufactured by a CLIA lab
The test has been appropriately validated
FDA is notified of the test offering
The lab provide transparency by disclosing the information to the public that the test was offered as a part of an immediate public health response and has not been reviewed or authorized by FDA.
