On May 6, 2024 the FDA published its much-anticipated Final Rule¹ on Lab-Developed Tests (“LDTs”) to make explicit that in vitro diagnostic products (“IVDs”) are devices under the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) including when the manufacturer of the IVD is a laboratory. The Final Rule follows the agency’s Proposed Rule², which was published on October 3, 2023. The Final Rule takes effect on July 5, 2024, which is 60 days from its publication in the Federal Register.

Critically, the Final Rule ends FDA’s longstanding policy of not actively regulating LDTs pursuant to its enforcement discretion (although the agency has long maintained it can regulate LDTs in the same way as commercial IVDs).

The FDA, in the preamble to the Final Rule, noted that regulation was needed due to a change in the LDT landscape, as LDTs have proliferated in use and guide critical healthcare decisions. The preamble explains that the “risk associated with most LDTs today are therefore much greater than they were . . . and most LDTs today are similar to other IVDs that have not been under FDA’s general enforcement discretion approach.”³ In the Proposed Rule, FDA further explained that LDTs are indeed “marketed to the same patients, sometimes on a national scale.”⁴ FDA also noted concern that firms were offering IVDs as “LDTs” when they are not LDTs as defined on the FDA’s website. 

Key provisions of the Final Rule are as follows:

• The definition of an IVD now also includes “when the manufacturer of these products is a laboratory.” The simple addition of this phrase to the definition of an IVD has the effect of FDA oversight over LDTs. 
• The Final Rule employs the following 4-year phaseout period for FDA’s enforcement discretion of LDTs:
  • Stage 1: Beginning one year after May 6, 2024, FDA will expect compliance with MDR requirements, correction and removal reporting requirements, and quality system (“QS”) requirements under 21 C.F.R. § 820.198 (complaint files).
  • Stage 2: Beginning 2 years after May 6, 2024, 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 3 years after May 6, 2024, FDA will expect compliance with QS requirements under 21 C.F.R. § 820 (other than requirements under § 820.198 (complaint files), which are already addressed in stage 1);
  • Stage 4: Beginning 3½ years after May 6, 2024, 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; and
  • Stage 5: Beginning 4 years after May 6, 2024, 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. 

The FDA identified certain categories of LDTs, which it intends to continue its enforcement discretion to varying degrees.

Specifically, FDA intends to continue the general enforcement discretion approach and generally not enforce any applicable requirements for the following LDTs:

• 1976-Type LDTs
• Human Leukocyte Antigen (“HLA”) tests that are 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 crossmatch tests.
• Tests intended solely for forensic (law enforcement) purposes.
• LDTs manufactured and performed within the Department of Defense (“DOD”) and Veterans Health Administration (“VHA”) used for patients being tested and treated within the DOD or VHA.

FDA also generally intends to exercise enforcement discretion with respect to premarket review requirements for the following tests:

• LDTs approved by the New York State Department of Health Clinical Laboratory Evaluation Program in connection with premarket review requirements.

Finally, FDA also intends to exercise enforcement discretion and generally not enforce premarket review and most QS requirements (except for requirements under § 820, subpart M (Records)) for three categories of IVDs:

• 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.
  • For these LDTs, FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records)). FDA considers an LDT to be for an unmet need where 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.
• LDTs that were first marketed prior to the date of issuance of this rule (hereinafter, “currently marketed IVDs offered as LDTs”).
  • FDA intends for this policy to apply to currently marketed IVDs offered as LDTs as long as they are not modified following the issuance of this final rule, or are modified but only in certain limited ways. Under this policy, FDA generally expects compliance with premarket review and QS requirements for currently marketed IVDs offered as LDTs when a laboratory’s modifications (individually or in aggregate):
    • change the indications for use of the IVD;
    • alter the operating principle of the IVD (e.g., changes in critical reaction components);
    • include 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
    • adversely change the performance or safety specifications of the IVD.

FDA will also request that laboratories offering currently marketed IVDs offered as LDTs submit labeling, including IVD performance information and a summary of supporting validation. FDA will analyze this information and take action where claims are not adequately substantiated.

• 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.

Implications of the Final Rule

In the wake of the Final Rule, laboratories must assess each individual LDT offering to identify what requirements must be met under the Final Rule and the corresponding timeline for compliance. In addition, laboratories must ensure they are in compliance with existing FDA requirements and guidance related to devices.

END NOTES

¹ 89 Fed. Reg. 37286 (May 6, 2024), available here.

² 88 Fed. Reg. 68006 (Oct. 3, 2023), available here.

³ Final Rule at 37289

⁴ Proposed Rule at 68010.