By: Samantha Hong and Suzan Onel
On April 29, 2024, FDA announced the issuance of a final rule that amends FDA regulations to make explicit that in vitro diagnostic products (IVDs), including ones manufactured in a laboratory (often referred to as laboratory developed tests or LDTs), are medical devices subject to regulation under the Federal Food, Drug, and Cosmetic Act (FDCA) (“LDT Final Rule”). FDA initially proposed this rule in October 2023 after years of deliberation regarding the regulation (or lack thereof) of LDTs. The Final Rule was published in the Federal Register on Monday, May 6, 2024.
Historically, FDA has maintained that LDTs were devices subject to its jurisdiction; however, FDA exercised enforcement discretion with respect to most LDTs and generally did not enforce requirements related to registration and listing, adverse event reporting, current good manufacturing practices, or premarket review. FDA outlined this policy in a draft guidance, “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” (“2014 Draft Guidance”). In the 2014 Draft Guidance, FDA defined LDT to refer to an IVD “intended for clinical use and designed, manufactured and used within a single laboratory” that is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and that meets the requirements under CLIA for high-complexity testing.
While the issue of FDA’s authority over LDTs have been questioned by some stakeholders, the issuance of the Final Rule leaves no questions as to FDA’s position. The Final Rule amends the definition of IVD to include, “when the manufacturer of those products is a laboratory,” 21 C.F.R. § 809.3(a). This change thereby makes explicit that all LDTs meet the definition of “device” under section 201(h) of the FDCA (21 U.S.C. § 321(h)) and are thus subject to relevant regulatory requirements.[1] While the IVD definitional change is the only amendment to FDA regulations included in the LDT Final Rule—which is identical to the change included the proposed rule—the pre-publication version of the final rule spans 528 pages to address the over 6,500 comments FDA received in response to the proposed rule and to explain FDA’s enforcement discretion “phaseout” policy. The phaseout policy begins July 5, 2024 (60 days after publication) and is largely consistent with the proposed rule. However, FDA substantially expanded the list of LDTs for which FDA intends to exercise some form of enforcement discretion. We provide a summary of the phaseout policy and some of the notable exceptions below.
Enforcement Discretion Phaseout Policy
As an initial matter, consistent with its 2014 Draft Guidance, FDA reiterates that certain categories of LDTs were never subject to FDA’s enforcement discretion policy and FDA has always expected such LDTs to comply with all relevant requirements. These LDTs include the following:
- tests intended as blood donor screening or human cells, tissues, and cellular tissue-based products (HCT/P) donor screening tests required for infectious disease testing or required for determination of blood group and Rh factors (licensed as biologics under section 351 of the Public Health Service Act, 42 U.S.C. § 262);
- tests intended for emergencies, potential emergencies, or material threats declared under section 564 of the FDCA (21 U.S.C. § 360bbb-3); and
- direct-to-consumer tests.
Otherwise, FDA intends to phaseout its enforcement discretion policy with respect to LDTs over the course of 4 years. The phaseout policy includes 5 stages:
- Stage 1 – Beginning 1 year after the publication of the LDT Final Rule, or May 6, 2025, FDA expects compliance with:
- Medical device reporting requirements (21 C.F.R. Part 803)
- Correction and removal reporting requirements (21 C.F.R. Part 806)
- Quality systems requirements (21 C.F.R. § 820.198)
- Stage 2 – Beginning 2 years after publication, or May 6, 2026, FDA expects compliance with requirements not covered during other stages of the phaseout policy, including:
- Registration and listing requirements (21 C.F.R. Part 807)[2]
- Labeling requirements (21 C.F.R. Parts 801 and 809)
- Investigational use requirements (21 C.F.R. Part 812)
- Stage 3 – Beginning 3 years after publication, or May 6, 2027, FDA expects compliance with:
- Quality Systems Regulations (QSR) (21 C.F.R. Part 820) (other than requirements under 21 C.F.R. § 821.198, already addressed in Stage 1)
- Stage 4 – Beginning 3.5 years after publication, or November 6, 2027, FDA expects compliance with:
- Premarket review requirements for high-risk IVDs offered as LDTs (or IVDs that may be classified into Class III or that are biologics subject to licensure under section 351 of the Public Health Service Act), unless a premarket submission has been received by the beginning of Stage 4 in which case FDA intends to continue to exercise enforcement discretion for the pendency of its review.
- Stage 5 – Beginning 4 years after publication, or May 6, 2028, FDA expects 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 Stage 5 in which case FDA intends to continue to exercise enforcement discretion for the pendency of its review.
Phaseout Policy Carve Outs
In response to comments to the proposed rule, FDA included categories of LDTs that it determined would fall outside the scope of the phaseout policy and remain subject to varying levels of enforcement discretion with respect to the medical device requirements. Significantly, as described further below, the carve outs include LDTs that were first marketed prior to May 6, 2024, effectively allowing these devices to remain on the market without complying with the premarket review requirements if certain specified conditions are met. We summarize the most notable carve outs below.
- LDTs manufactured and performed within the Veterans Health Administration or the Department of Defense – enforcement discretion applied for all requirements.
- Forensic Use LDTs – enforcement discretion applied for all requirements.
- LDTs approved under New York State Department of Health’s Clinical Laboratory Evaluation Program (“CLEP”) – enforcement discretion applied for premarket review requirements.
- LDTs for unmet needs manufactured and performed by a laboratory integrated within a healthcare system – enforcement discretion applied for premarket review and QSR requirements (except for records and complaint files requirements found in 21 CFR part 820, subpart M).
- Currently marketed LDTs first marketed prior to May 6, 2024 that are not modified or have been modified “only in certain limited ways”[3] – enforcement discretion applied for premarket review and QSR requirements (except for records and complaint files requirements found in 21 CFR part 820, subpart M).
- 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 – enforcement discretion applied for premarket review and QSR requirements (except for records and complaint files requirements found in 21 CFR part 820, subpart M).
Notably, for LDTs approved by NYS CLEP, LDTs for unmet needs used in an integrated healthcare system, and currently marketed LDTs, in addition to standard registration and listing information, FDA is requiring the submission of labeling pursuant to 21 C.F.R. § 807.26(e) to obtain “information on test performance and a summary of the supporting validation, among other things.”
The LDT Final Rule also describes FDA’s intent to continue its current enforcement discretion policy with respect to certain specific categories of LDTs, including, for example, “1976-Type LDTs,” referring to tests that have characteristics common to LDTs offered in 1976 when the Medical Device Amendments of 1976 were enacted and feature the use of manual techniques performed by laboratory personnel with specialized expertise. Other categories of LDTs for which the agency intends to continue exercising general enforcement discretion include certain Human Leukocyte Antigen (HLA) tests and tests intended solely for forensic (law enforcement) purposes.
Importantly, FDA states repeatedly that regardless of the enforcement discretion policies set forth in the LDT Final Rule, FDA intends to carefully monitor LDTs falling within the exceptions and could pursue enforcement action against such LDTs when they lack supporting validation, clinical validity, analytical validity, safety, or are otherwise violative.
Related FDA Actions
FDA also issued two draft guidance documents simultaneously with its announcement of the LDT Final Rule relating to the agency’s enforcement discretion policies with respect to IVDs during public health emergencies. The first, Enforcement Policy for Certain In Vitro Diagnostic Devices for Immediate Public Health Response in the Absence of Declaration under Section 564, describes FDA’s proposed enforcement discretion policy for laboratory manufacturers offering certain unauthorized IVDs for immediate response to chemical, biological, radiological, or nuclear agents absent a public health emergency applicable to IVDs declared under section 564 of the FDCA. The second, Consideration of Enforcement Policies for Tests During a Section 564 Declared Emergency, describes factors that FDA plans to assess in deciding whether to issue an enforcement policy regarding test manufacturers during public health emergencies declared under section 564 of the FDCA.
What’s Next
While FDA’s longstanding position on LDTs is now formally codified in regulations, it is widely expected that there will be legal challenges to the LDT Final Rule by laboratory stakeholders. It also remains possible, though not very probable, that legislative action could modify some of the parameters of FDA’s regulation of diagnostics. That said, in the meantime, the laboratory and diagnostics industry should carefully review the Final Rule, including FDA’s discussion of the enforcement discretion phaseout policy and the various carve outs, to consider how the rule may affect their interests and compliance programs.
FDA will be hosting a webinar to provide an overview on the LDT Final Rule and describe the phaseout policy on May 14, 2024 from 1pm-2pm EST (registration is not necessary). For further questions on the LDT Final Rule, please contact us.
[1] FDA further clarified that it considers “IVDs offered as LDTs” to refer to all LDTs manufactured and offered by CLIA-certified 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.” 89 Fed. Reg. 37,286, 37,295 (May 6, 2024).
[2] FDA anticipates that a limited number of IVDs that are biologics would be subject to registration and listing requirements at 21 C.F.R. part 607. However, as discussed above, most devices licensed as biologics under section 351 of the Public Health Service Act (42 U.S.C. § 262) are intended for use as blood donor screening tests or HCT/P donor screening tests, or tests for determination of blood group and Rh factors, for which FDA’s general enforcement discretion approach has never applied.
[3] FDA states that it generally expects compliance with premarket review and QSR requirements “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.” 89 Fed. Reg. at 37,305.