Medical Technologies
Proposed FDA Regulations on LDT's What You Should Know
On April 29, 2024, the U.S. Food and Drug Administration (FDA) published a final rule on the enforcement and oversight of laboratory-developed tests (LDTs), effective July 5, 2024. The final rule amends its regulations to make explicit that IVDs are devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act), including when the manufacturer of the IVD is a laboratory. An LDT is an in vitro diagnostic (IVD) product developed, manufactured, and used inside a single laboratory certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and meets the CLIA requirements to perform high-complexity testing. The publication of this rule marks the end of a long-standing policy by the FDA to exercise enforcement discretion over LDTs, meaning it has[GM3] [DT4] largely not exercised its ability to regulate these tests. The final rule establishes a timeline for LDT manufacturers to comply with FDA IVD requirements. This justification is based on many laboratory-manufactured tests, for example, being developed with the same materials, technologies and scientific concepts as well as requiring the same level of experience and/or training to operate, as IVDs from conventional manufacturers. Also, many LDT developers and IVD companies manufacture tests intended for the same or similar purpose, thus targeting patients with similar health concerns. Consequently, with few exceptions, LDT developers will overtime be held to the same requirements and FDA regulations as traditional IVD companies.
A large portion of the final rule lays out why the FDA has the legal authority to regulate LDTs, and the history around why it has changed its stance on exercising enforcement discretion over LDTs. It is noted that a lot has changed since the Medical Device Amendments (MDA) were originally enacted in 1976, and with how LDTs have evolved, there are considerable questions about the safety and effectiveness of many LDTs currently available in the market. Moreover, it is important to recall that the FDA has spent the past four years requiring LDTs for SARS-CoV-2 and more recently with Mpox, to obtain emergency use authorization (EUA) after an initial review of analytical and clinical validation data. Perhaps this requirement was a prelude to the coming LDT regulatory enforcement, and an opportunity for both labs and the FDA to prepare for this expanded oversight role on LDTs.
Enforcement Discretion Exceptions
It is important to point out that not all LDTs will be subject to FDA oversight and review. The FDA does carve out a few exceptions to the end of the enforcement discretion on LDTs. These exceptions include:
- Tests described by the FDA as “1976-Type LDTs” will still be subject to enforcement discretion because these tests are highly manual, performed by very experienced laboratorians, utilize materials only marketed for clinical use, and are designed, manufactured, and performed only within a single CLIA laboratory.
- LDTs designed, manufactured, and performed at a single CLIA laboratory for Human Leukocyte Antigen (HLA) as part of histocompatibility testing before transplant are also still subject to enforcement discretion.
- Forensic and public health surveillance tests do not provide specific results to patients and their healthcare providers.
- LDTs are manufactured and run by the Veterans Health Administration (VHA) or the Department of Defense (DoD).
Other exceptions to the end of the FDA’s enforcement discretion are listed below. For the below exceptions, laboratories must still follow design controls and other quality system (QS) [MR1] [TD2] requirements for the modification, as the exception is only to the requirement for a premarket review.
- LDTs are approved by the New York State Clinical Laboratory Evaluation Program (NYS CLEP).
- Minor changes to another manufacturer’s lawfully marketed 510(k) cleared or de novo authorized test, if the modified test will only be used in the laboratory that made the modification. The modification(s) made must not significantly affect the safety or effectiveness of the test and is not a change to the test’s intended use.
- Additionally, the FDA will continue to exercise enforcement discretion and not enforce premarket review requirements and most QS requirements (apart from requirements under part 820, subpart M pertaining to Records) for:
- LDTs are manufactured and run by a laboratory integrated into a healthcare system that has patients within the same healthcare system with an unmet need.
- LDTs that were marketed prior to the issuance date of this rule and remain unmodified. However, if an LDT is modified (individually or in aggregate) in such a way that it:
- changes the indications for use of the IVD;
- alters the operating principle of the IVD;
- Includes substantially different technology in the IVD; or
- Negatively changes the performance or safety specifications of the IVD,
then the FDA will expect the laboratory developer to comply with the premarket review and QS requirements for the modified LDT.
- Non-molecular antisera LDTs for rare red blood cell (RBC) antigens, when tests are manufactured and performed in blood establishments like transfusion services and immunohematology laboratories, and where there is no alternative available to meet the patient's need for a compatible blood transfusion.
Implementation Timeline
The final rule outlines a gradual phase-out of the enforcement discretion for applicable LDTs over a period of four years. There are five stages to the rollout.
- Stage One begins one year after the final rule is published and ends the enforcement discretion around medical device reporting (MDR) requirements, correction and removal reporting requirements and QS requirements under 21 CFR 820.198 (complaint files). This phase seems to be geared toward helping the FDA monitor LDTs with issues that pose serious risks to public health.
- In Stage Two, the FDA will end its enforcement discretion for requirements not addressed in other stages of the phase-out policy. The timeline for stage two is two years after the final rule is published. Examples of requirements for this stage include FDA registration and listing (21 U.S.C. 360 and 21 CFR 607 and 21 CFR 807, excluding subpart E), labelling (21 U.S.C. 352, 21 CFR 801 and 21 CFR 809, subpart B), and investigational use requirements (21 U.S.C. 360j(g) and 21 CFR 812).
- For Stage Three, the FDA will end the enforcement discretion regarding current Good Manufacturing Practices (cGMP[MR1] [TD2] ) and QS requirements (except for requirements under 21 CFR 820.198 (complaint files), which was addressed in Stage one), three years after the final phaseout policy is enacted. The quality system and cGMP requirements are detailed in 21 USC 360j(f) and 21 CFR 820. With this rollback of the enforcement discretion, the FDA is emphasizing that LDTs are no different than IVDs simply because they are manufactured by a single laboratory and are holding manufacturing labs to the same quality standards as non-laboratory IVD manufacturers. However, the FDA does state that if all manufacturing activities take place in one CLIA laboratory and the LDT is not run outside that laboratory, some aspects of the QS requirement may be waived. It is imperative for laboratories to discuss this with the FDA through the Q-submission process. CLIA laboratories should already have a QS in place that complies with the Centers for Medicare & Medicaid Services (CMS)[GM3] [TD4] requirements, some of which may complement FDA manufacturing requirements; however, CMS QS requirements may leave gaps the FDA is trying to address. Specifically, the FDA is requiring manufacturing labs to comply with design controls (under 21 CFR 820.30), purchasing and supplier controls (under 21 CFR 820.50), acceptance activities like receiving, in-process, and finished device acceptance (under 21 CFR 820.80 and 21 CFR 820.86), corrective and preventative actions (CAPA, under 21 CFR 820.100), and records requirements (under 21 CFR820 subpart M). The FDA has previously stated it is working to update its QS requirements to better align with international standards, such as ISO 13485, and will work to have that in place before stage three begins. If the LDT will be considered a class III device, meeting the QS requirements in this stage is needed for the required premarket approval (PMA).
- Stage Four - At three and half years the FDA will end enforcement discretion around premarket approvals for high-risk IVDs as part of stage four. Class III IVDs that require a PMA will fall into this stage (see 21 USC 360e and 21 CFR 814 for PMA review requirements). Interestingly, if a premarket submission is submitted to the FDA by the beginning of this stage for a high-risk IVD, the FDA intends to continue exercising enforcement discretion, thereby helping to allow the LDT to remain on the market and available to patients, while under review.
- Finally, there is Stage Five which begins four years after the final rule is published. In this stage, the FDA will end enforcement discretion on moderate and low-risk IVDs (i.e., Class I and II IVDs) and expect compliance with premarket review requirements such as 510(k) submissions (21 USC 360(k), 360c(i) and 21 CFR 807, subpart E) and De Novo requests (21 USC 360c(f)(2) and 21 CFR 860, subpart D). As in stage four, if lab developers submit a premarket application by the beginning of this stage, the FDA intends to continue exercising enforcement discretion for moderate or low-risk LDTs while under review to help avoid any interruptions to patient access. The 510(k) Third-Party Review Program (3P510k) is also an option for many LDTs falling into these classes.
How Could This Impact the IVD Industry ?
The end of the enforcement discretion on LDTs by the FDA may catch laboratory
manufacturers by surprise. It has been anticipated for some time, but labs may
not have familiarity with the FDA’s regulatory pathways, data requirements, and
submissions. As a result, TE Connectivity’s (TE) IVD Solutions team would like
to offer a few recommendations on what LDT developers could consider when
deciding their next steps:
- Make sure you understand the device classification of your
LDT(s). This will help determine your compliance timeframe with the final rule.
- Does the clinical data currently available meet the FDA’s expectations on the data required to support design verification and clinical validation? The FDA’s requirements for analytical and clinical data are very different from the requirements imposed by CMS under CLIA.
- Do you have a Quality System that is compliant with the quality system regulation [21 CFR 820]?
Need Help?
The IVD Solutions team at TE is experienced in helping IVD manufacturers achieve
FDA clearance/approval for IVDs with a variety of intended uses. Should you
need assistance navigating the latest FDA oversight, the IVD Solutions team at TE can assist.
For Informational Purposes Only. Individual circumstances vary. This information is provided for promotional or general informational purposes only and is not to be relied upon as a professional opinion or advice. No reader should act or refrain from acting on the basis of this information without first seeking advice from a qualified professional.
