On September 29, 2023, the Food and Drug Administration (“FDA”) announced the issuance of a Notice of Proposed Rulemaking (the “Proposed Rule”) to expand the FDA’s regulatory scope over in vitro diagnostics products (“IVDs”) to specifically address Laboratory Developed Tests (“LDTs”). Traditionally, the FDA exercised enforcement discretion over LDTs, meaning that the FDA has not enforced applicable requirements regarding most LDTs, recognizing their limited scope in diagnosing rare diseases and their use in controlled clinical settings. However, the evolution of LDTs, including their increased complexity and broader application, has caused the FDA to “become increasingly concerned that some LDTs may not provide accurate test results or perform as well as FDA-authorized tests or other complying with FDA requirements,” according to an FDA news release.

The Proposed Rule, a long time in the making, outlines a phased approach to bring LDTs under similar regulatory scrutiny as other IVDs. The FDA does not propose to “grandfather” any LDTs currently on the market, although it is seeking comments on this aspect, which will significantly impact clinical laboratories, hospitals and other stakeholders involved in the development and use of IVDs across the entire health care system. Given the potentially significant impact of the Proposed Rule, it is crucial for the industry to closely review these proposed changes and understand their implications.

Key Provisions of the Proposed Rule

  1. Regulatory Redefinition: The Proposed Rule explicitly categorizes all IVDs, including LDTs, as medical devices under the Food Drug and Cosmetic Act. Specifically, the definition of IVD in 21 C.F.R. § 809.3(a) would be modified to add the words “including when the manufacturer of these products is a laboratory.” This modification means that all IVDs, including LDTs, will be required to comply fully with FDA’s medical device regulatory requirements, including registration and listing, premarket review, post-market reporting requirements and compliance with the FDA’s Quality System Regulation (21 C.F.R. Part 820), unless they fall under an exemption.
  2. Phased Enforcement Strategy: The FDA delineates a detailed five-stage plan to transition from a policy of enforcement discretion to full regulation of LDTs as medical devices by 2028. At the end of this four-year period, most LDTs will be subject to all applicable medical device regulations.
  3. Limited Exemptions: The FDA is proposing to continue to exercise enforcement discretion with regard to a limited number of categories of LDTs: “1976-Type LDTs,” which the FDA describes as those tests that have the following characteristics common to LDTs offered in 1976: use of manual techniques (without automation) performed by laboratory personnel with specialized expertise; use of components legally marketed for clinical use; design, manufacture and use within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing; Human Leukocyte Antigen tests used in high complexity laboratories; LDTs intended for forensic use (law enforcement); and LDTs used exclusively for public health surveillance and where: (1) they are intended solely for use on systemically collected samples for analysis and interpretation of health data in connection with disease prevention and control, and (2) tests results are not reported to patients or their health care providers.

The FDA’s five-stage plan includes:

Stage 1: Within one year of finalizing the rule, the FDA will enforce medical device reporting (“MDR”) requirements (21 C.F.R. Part 803), along with the requirements for notices of correction per 21 C.F.R. Part 806. This stage aims to enhance the FDA’s capacity to monitor and respond to adverse events related to LDTs.

Stage 2: Two years post-finalization, the FDA will broaden its regulatory scope beyond MDR to encompass additional requirements. This includes registration and listing (21 C.F.R. Part 807), device labeling requirements (21 C.F.R. Part 801) and investigational device exemption requirements (21 C.F.R. Part 812), establishing a more comprehensive regulatory environment.

Stage 3: Three years after finalization, LDT manufacturers will need to align with Current Good Manufacturing Practice requirements (21 C.F.R. Part 820). This stage introduces rigorous quality system standards, ensuring consistency in manufacturing processes and product quality.

Stage 4: At three and a half years (but no earlier than October 1, 2027), the focus shifts to high‑risk IVDs (i.e., Class III). Premarket review requirements for these IVDs will be implemented, ensuring critical devices undergo rigorous assessment before market entry by submitting an application for Premarket Approval (“PMA”) to the FDA.

Stage 5: By the fourth year (but no earlier than April 1, 2028), moderate and low-risk IVDs (Class I or II) will also be subject to premarket review and be required to submit a 510(k) premarket notification unless exempted. This final stage solidifies the FDA’s regulatory oversight across all risk categories of IVDs, establishing a uniform standard for the safety and efficacy of IVDs.

Request for Comments

In the Proposed Rule, the FDA is requesting comments on a variety of topics. Specifically, the FDA is seeking to obtain feedback on the following, as outlined in the Proposed Rule:

  • Should the FDA continue the general enforcement discretion approach with respect to any requirements, such as premarket review requirements, for tests manufactured by Academic Medical Center laboratories?
  • Is there a public health rationale for having a longer phaseout period for IVDs offered as LDTs by laboratories with annual receipts below a certain threshold (e.g., $150,000)? If so, please provide relevant data and comments, specifically on an alternative recommended timeline.
  • FDA is also interested in comments on leveraging other public health programs (e.g., the NYS Department of Health Clinical Laboratory Evaluation Program) to allow the FDA to continue the general enforcement discretion approach in certain circumstances. If so, the FDA is seeking a rationale and any data to support any suggestions on how these outside programs could be leveraged.
  • To the extent that entities suggest that the FDA continue to maintain the current general enforcement discretion approach, the agency requests information to support that approach including the following:
    • Given the information in the “Need for the Rule” section of the [Proposed Rule], what would be the public health rationale for generally exercising enforcement discretion with respect to premarket review and some or all QS requirements, for LDTs that are being offered as of the date of issuance of this proposed rule and are not changed with respect to indications for use or performance after that date? Please provide data to support such an approach. Also, if you think there are steps that might help support such an approach, including ideas that might help to address the public health concerns discussed in the “Need for the Rule” section, please describe them, and include a rationale and any supporting evidence.

Practical Takeaways

  1. Prepare for Enhanced Oversight: Entities involved in LDT development and use should begin preparing for the increased regulatory oversight. While the FDA’s timeline is extremely ambitious given how long it has taken the FDA to implement other initiatives, the Proposed Rule offers at least a good starting point to allow laboratories to begin building out their quality systems to comply with the QSR and other applicable medical device regulations.
  2. Review and Update of Internal Processes and Procedures: Entities should review and, where necessary, update or implement internal processes and procedures to begin operating as an FDA-regulated entity. This involves assessing the Proposed Rule’s applicability on all LDTs, especially high-risk ones that may require PMAs, and beginning to prepare for starting conversations with the FDA about a potential regulatory submission.
  3. Consider the Proposed Exemptions: Entities should closely review the Proposed Rule’s exemptions, which exclude certain tests like forensic and human leukocyte antigen tests, from the new enhanced oversight. It is crucial to assess whether any of their LDTs fit these categories, especially in light of the FDA’s decision not to “grandfather” existing LDTs.

Comments on the Proposed Rule must be submitted by December 4, 2023. Unfortunately, the FDA has declined to extend the comment period despite several requests for an extension. In response to a request, the FDA stated, “[a]fter considering the requests and other factors, including the extensive background of public comment on this topic and the public health benefits of proceeding expeditiously, FDA has determined to proceed with the standard 60-day comment period.” Comments may be submitted electronically to the docket here.