FDA has finalized its landmark proposed rule that will amend the definition of “in vitro diagnostic (IVD) products” in 21 CFR 809.3 to make explicit that IVDs are medical devices under the Federal Food, Drug, and Cosmetic Act (FDCA), “including when the manufacturer of the IVD is a laboratory.” We previously analyzed the October 2023 proposed rule (Notice of Proposed Rulemaking (NPRM)) online here, providing background in that article on FDA’s decades-long history of exercising enforcement discretion over LDTs, as well as Congressional efforts to either codify a specific delegation of authority to regulate LDTs or to affirmatively remove LDTs from FDA’s oversight.

In announcing the Final Rule, FDA Commissioner Robert Califf expressed concern that “LDTs are being used more widely than ever before — for use in newborn screening, to help predict a person’s risk of cancer or aid in diagnosing heart disease and Alzheimer’s,” suggesting the greater need for governmental oversight of the tests. The Final Rule also reiterates FDA’s position that a general enforcement discretion approach is no longer appropriate given the significantly increased complexity of LDTs compared to when the policy was initially put in place.

Enforcement timeline and phaseout policy

Similar to the proposed rule, the Final Rule will gradually transition from FDA’s long-standing practice of exercising enforcement discretion over LDTs to the agency’s requiring compliance with all applicable FDA regulatory requirements over the course of four years, following official publication of the Final Rule on May 6. Thus, on May 6 of each of the following years (except for Stage 4), the corresponding stages will begin as the Phaseout policy

• Stage 1: On May 6, 2025 (one year after publication of the final rule), FDA will begin to enforce the requirement under 21 CFR 820.198 for complaint files which will serves an and input for medical device reporting (MDRs) and correction and removal reporting on LDTs, as well as complaint record keeping.
• Stage 2: In 2026 (two years after publication of the final rule), FDA will begin to enforce additional medical device requirements on LDTs, including registration and listing, labeling, and investigational use requirements.
• Stage 3: In 2027 (three years after publication of the final rule), FDA will begin enforcing the rest of the amended Quality System Regulation (21 CFR Part 820) on LDTs (other than those on complaints as an input to MDR, which are imposed in Stage 1) with a heavy emphasis on design controls.
• Stage 4: On November 6, 2027 (three and a half years after publication of the final rule), FDA will begin to apply premarket review requirements for high-risk IVDs offered as LDTs, meaning those that may be classified as Class III devices or biologics requiring licensure and where an application has been submitted before November 6, 2027, the agency will continue its enforcement discretion while it reviews the application. Notably, marketed high-risk IVDs offered as LDTs that file a PMA before the start of Stage 4 will be able to continue marketing their tests while the marketing application is pending.[1]
• Stage 5: On May 6, 2028 (four years after publication of the final rule), FDA will stop using enforcement discretion for moderate-risk and low-risk IVDs offered as LDTs, meaning those that require premarket submissions and will similarly continue to exercise enforcement discretion for applications submitted before May 6, 2028 while it review the application.

With respect to the Stages 4 and 5 in which FDA will begin to require premarket review and clearance for LDTs, the Final Rule acknowledges that it is a known practice for labs to use another manufacturer’s lawfully marketed test and make modifications. The Final Rule makes clear that the agency plans to exercise enforcement discretion over such modified third party-developed and legally marketed tests if:

1. the original test received marketing authorization via the 510(k) or De Novo pathway
2. the lab modifying the test is a high-complexity CLIA certified lab,
3. the design controls and other quality system requirements for which FDA expects compliance under Stages 1-3 are followed,
4. the modifications could not significantly affect the safety or effectiveness of the test and would not constitute a major change or modification in the intended use, and,
5. the modified test must only be performed in the lab that makes the modification.

To be clear, FDA would expect a premarket submission from labs modifying a third party’s 510(k) cleared or De Novo authorized test if the changes being implemented by the clinical laboratory would have required a new premarket submission had they been implemented by the original manufacturer. Thus, FDA’s rule allows for labs to modify legally marketed tests without seeking a new premarket authorization, but also creates a scenario where a lab could be required to seek premarket clearance for a test prior to Stage 5 (i.e., if certain significant changes are made to the original test). As indicated by the requirements above, this enforcement discretion policy will not apply when the underlying third-party developed test is a Class III test legally marketed under a PMA approval.

Continue reading: the original Hogan Lovells Engage blog post with additional insights including: Changes from the proposed rule, Questions that remain unanswered, and What’s Next?