Thin Lizzy famously declared in their 1976 hit, “The Boys are Back in Town.” The same is true almost 50 years later, as the U.S. Food and Drug Administration has announced its plan to phase out its general enforcement discretion approach of laboratory developed tests (“LDTs”) and bring the boys back for enforcement. On May 6, 2024, FDA published its Final Rule, clarifying that in vitro diagnostic products (“IVDs”) are medical devices under the Federal Food, Drug, and Cosmetic Act (“FD&C Act”), including when the manufacturer of the IVD is a laboratory.¹ As such, LDTs will no longer be under FDA’s previous enforcement discretion policy, with certain exceptions and subject to the phase-out policy outlined in this Bulletin.

Last month, FDA published a draft guidance document, “Laboratory Developed Tests: Small Entity Compliance Guide.”² In this Bulletin, we will provide a brief summary of FDA’s previous enforcement approach and a high-level overview of the phase-out policy as provided in the draft guidance. We will not discuss the Final Rule in detail here, which is already the subject of litigation.

Background

• Since 1976, FDA has chosen to exercise enforcement discretion over LDTs concerning requirements, such as establishment registration and product listing, medical device reporting to FDA, current good manufacturing practices (“GMPs”), and premarket review.
• IVDs are reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.³
• LDTs are IVDs that are intended for clinical use and are designed, manufactured, and used within a single clinical laboratory that meets certain laboratory requirements.⁴
• In the past, LDTs were mostly designed, manufactured, and used in small volumes by laboratories serving local communities and mostly interpreted by a single team of physicians and pathologists for a patient. These LDTs typically employed manual techniques in their development and usage.
• With innovation, LDTs now increasingly rely on high-tech instrumentation and software, and are often connected to IT infrastructure and laboratory information management systems. This creates substantial personal and national security risks regarding patient privacy.
• Recognizing the need for increased regulation in this new landscape, FDA announced a five-part, four-year phaseout policy of FDA’s general enforcement discretion (please see Table 1 below for an outline of this phaseout plan and compliance expectations).
• The phaseout is intended to ensure safety and effectiveness of IVDs offered as LDTs while also increasing patient access and reliance.

Overview and Scope

• The four-year phaseout plan shall begin on May 6, 2025, but this policy does not encompass all LDTs, as described below.
• In the draft guidance, FDA provides further detail regarding its compliance expectations for certain categories of IVDs (please see Table 2 below for an outline of the compliance expectations by phase for different product types).
• FDA intends to continue its enforcement discretion regarding different aspects of LDTs as follows:
  • FDA intends to continue the general enforcement discretion approach and generally not enforce any applicable requirements for the following categories of tests:
    • 1976-Type LDTs
    • Certain Human Leukocyte Antigen (“HLA”) Tests for Transplantation
    • Forensic Tests
    • Department of Defense (“DoD”) and Veterans Health Administration (“VHA”) LDTs
  • FDA generally intends to maintain enforcement discretion regarding premarket review requirements for:
    • LDTs approved by New York State Department of Health’s Clinical Laboratory Evaluation Program (“CLEP”)⁵
      • This discretion only applies to the approved version of the test.
    • Modified versions of another manufacturer’s 510(k) cleared or de novo authorized test
      • This discretion only applies to modifications following design controls and other quality system requirements (QSRs) for which FDA already expects compliance in a manner that does not significantly alter the safety, effectiveness, or intended use of the product, and where the test is being performed in the laboratory making the modification.
      • Premarket review submissions are expected when the change is significant such that it is no longer substantially equivalent to the original IVD, or where FDA would expect the original manufacturer to submit the change for premarket review.
  • FDA generally intends to maintain enforcement discretion regarding premarket review and QSRs for:
    • LDTs for unmet needs
      • Specifically, this refers to LDTs manufactured and performed in laboratories integrated within a healthcare system to meet an unmet need of patients receiving care within that healthcare system.
    • Currently marketed IVDs offered as LDTs
      • This discretion applies to IVDs first marketed prior to May 6, 2024 (the date of the LDT Final Rule publication), and not modified after that date or only modified in limited ways.
      • Modifications that change the indication for use of the IVD, alter the operating principle IVD, include significantly different technology in the IVD, or adversely change the performance of safety specifications of the IVD will be expected to comply with premarket review and QSR control requirements.
    • Non-molecular antisera LDTs for rare red blood cell (“RBC”) antigens for transfusion compatibility
      • This discretion only applies when such tests are manufactured and performed by blood establishments, including transfusion services and immunohematology labs, when no alternative IVD is available to meet the patient’s need for compatible blood transfusion.
      • This discretion does not apply to genotyping RBC antigen molecular tests.
  • The guidance document offers additional resources to help small entities comply with applicable FDA requirements regarding:
    • Complaints, Medical Device Reports, and Correction and Removal Reports Requirements
      • This includes items such as documentation of investigations of any complaints that the device manufacturer receives about its medical devices, and Medical Device Reports of reportable events.
    • Registration and Listing Requirements
      • This includes annual registration with FDA.
    • Device Labeling Requirements
      • This includes general labeling requirements, including formatting and substantive requirements.
    • Investigational Use Requirements
      • This refers to requirements relating to an approved investigational device exemption, which allows an investigational device to be shipped for clinical investigation purposes, to collect safety and effectiveness data without complying with other requirements of the FD&C Act.
    • Quality System Requirements
      • This includes GMPs for the medical devices, found as 21 C.F.R. part 820.
    • Premarket Review Requirements
      • This includes 510(k), de novo, and PMA submissions for pre-market approval or clearance.
    • General Information
      • FDA provides further resources regarding LDTs, IVDs, and devices generally, including guidance on Q-submissions.

AGG Observations

• FDA adopted its previous enforcement discretion policy with a different technological landscape in mind. The need to enforce standards of safety and efficacy grew with technological innovation.
• The phaseout policy is long-awaited, and FDA appears to have considered many of industry’s concerns regarding the implementation of the policy, as it was first announced.
  • FDA will still exercise certain discretion where it views its past policy as consistent with its goals of ensuring safety and efficacy for the public health.
• The policy reflects the agency’s ongoing commitment to ensuring that the products it regulates are safe and effective for their intended use. As technology advances, FDA may shift its focus to products that it sees as offering more risk to the public health. We can expect that, as technology continues to advance, it will continue to evaluate its enforcement priorities.
• It looks like FDA is “back in town” with a new enforcement policy, but with the litigation, it is not clear how long it can stay.

Table 1 – Stages of Final Phaseout Policy

Table 2 – FDA Compliance Expectations

* Because these tests are LDTs, FDA generally will not expect compliance with 21 C.F.R. part 820 (QSRs), except for design controls, purchasing controls, acceptance activities, corrective and preventative action (“CAPA”) activities, and records requirements.

** For tests that are LDTs, FDA generally will not expect compliance with 21 C.F.R. part 820 (QSRs), except for design controls, purchasing controls, acceptance activities, CAPA activities, and records requirements.

The authors would like to thank AGG summer associate Vanessa Okojie for her contributions to this Bulletin.

[1] 89 Fed. Reg 37286.

[2] The draft guidance is available here: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/laboratory-developed-tests-small-entity-compliance-guide. Comments can be reviewed or provided at docket FDA-2023-N-2177 here: https://www.regulations.gov/docket/FDA-2023-N-2177.

[3] 21 C.F.R. § 809.3.

[4] See e.g., https://bit.ly/4cZ8tfD

[5] NYS CLEP seeks to ensure the accuracy and reliability of test results in clinical laboratories located in or accepting specimens from New York. For an LDT to meet CLEP standards, it is put through a more rigorous validation measure and review than other LDTs.

[6] FDA does not explain what “generally” means for the purposes of this enforcement guidance, but we understand that the agency’s continued discretion is based on its determination that these device-types are unlikely to pose significant risks or are conducted in circumstances that themselves will mitigate the risks. This use of “generally” provides FDA flexibility to step in, if it determines that there is a higher-than-expected risk in a given circumstance.