Article

Navigating FDA’s Final Rule on Laboratory Developed Tests

6 Strategies to Help You Meet FDA Requirements and Maintain Market Access

Karin Hughes, Ph.D., SVP Global Regulatory and Quality
Authored by: Karin Hughes, Ph.D.
SVP Global Regulatory and Quality

On April 29, 2024, the US Food and Drug Administration (FDA) issued a long-anticipated final rule asserting its authority to regulate laboratory-developed tests (LDTs) as medical devices (“Medical Devices; Laboratory Developed Tests” (89 FR 37286) (“LDT Final Rule”)). This rule, effective May 6, 2024, marks a significant shift from the FDA’s previous enforcement discretion for LDTs, impacting stakeholders across the diagnostics industry.

Below are key highlights of the final rule and how laboratories offering LDTs may begin preparing to meet the new requirements and timelines.

Redefining LDTs as In Vitro Diagnostic (IVD) Medical Devices

The FDA’s final rule makes explicit that in vitro diagnostic products are medical devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act; 21 CFR § 809.3) “including when the manufacturer of the IVD is a laboratory”. While the laboratory community views LDTs as laboratory testing services, FDA defines LDTs as IVDs that are intended for clinical use and that are designed, manufactured, and used within a single laboratory that is certified under the CLIA and meets the regulatory requirements under CLIA to perform high complexity testing.

Phaseout of Enforcement Discretion

Over the next four years, the FDA will phase out its enforcement discretion for most LDTs. By May 6, 2028, all IVDs offered as LDTs must comply with FDA regulations akin to those for other FDA-regulated medical devices.  This includes implementing robust quality management systems, adhering to rigorous reporting practices, fulfilling establishment registration and device listing obligations, and undergoing FDA premarket review where applicable.  The phased approach aims to provide laboratories with time to adjust to the new regulatory landscape while ensuring patient safety and maintaining access to accurate diagnostic testing.

Phaseout of LDT Enforcement Discretion

The phaseout policy applies to “IVDs offered as LDTs” defined by the FDA as IVDs that are manufactured and offered as LDTs by laboratories that are certified to perform high complexity testing under CLIA, and used within such 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.

Implementation Stages and Requirements

STAGE 1: Medical Device Reporting Requirements

Beginning on May 6, 2025, which is 1 year after the publication date of the final LDT rule, laboratories offering IVDs as LDTs must comply with Stage 1 requirements, which include medical device reporting requirements (21 CFR part 803), corrections and removals (21 CFR part 806), and quality system (QS) requirements for establishing and maintaining complaint files (21 CFR 820.198).

These requirements will be new to laboratories because they are distinct from those under Clinical Laboratory Improvement Amendments (CLIA) (42 CFR Part 493). While CLIA mandates procedures for managing complaints related to the quality of laboratory testing services, the FDA’s requirements under 21 CFR 820.198 specifically pertain to managing complaints related to medical devices. This includes establishing and maintaining procedures to receive, review, and evaluate complaints alleging device deficiencies.

STAGE 2: Registration and Listing, Labeling, and Investigational Device Exemption Requirements

Beginning on May 6, 2026, laboratories offering IVDs as LDTs must comply with Stage 2 requirements.  These encompass establishment registration and device listing obligations (510 of the FD&C Act, 21 CFR part 607, and 21 CFR part 807 (excluding subpart E)), labeling requirements (section 502 of the FD&C Act and 21 CFR parts 801 and 809, subpart B); and investigational device exemption requirements (section 520(g) of the FD&C Act and 21 CFR part 812).

Compliance will demand understanding and adherence to FDA specifications for labeling, including formatting and content stipulations under 21 CFR parts 801 and 809, as well as ensuring the inclusion of Unique Device Identifiers (UDIs) on labels for traceability throughout the device lifecycle. Establishing a relationship with a UDI issuing agency is necessary to obtain UDIs and assign them to each device model or version, ensuring that the identifier contains essential information such as device identifier, production identifier, and, where applicable, lot or serial number.

Laboratories must also adhere to FDA’s regulatory framework for investigational use of medical devices, when IVDs offered as LDTs are used in clinical investigations. This will include determining the appropriate IVD risk (significant, non-significant, or IDE exempt), obtaining necessary study approvals, and ensuring ongoing compliance throughout the investigation.

STAGE 3: Quality System Regulations (QSR) Implementation

Beginning on May 6, 2027, laboratories offering IVDs as LDTs must comply with Stage 3 requirements, which encompass specific QSR requirements outlined in 21 CFR 820.  These include implementing design controls, purchasing controls, and corrective and preventive actions (CAPA).

On February 2, 2024, FDA issued a final rule amending the device QS regulation, 21 CFR part 820, to align more closely with international consensus standards for devices (89 FR 7496, available at https://www.federalregister.gov/d/2024-01709).When the final rule takes effect, FDA will also update the references to provisions in 21 CFR part 820 in this guidance to be consistent with that rule.

Key Components of Design Controls: Central to QSR compliance are Design Controls, a structured approach to product development that ensures devices meet specified requirements and are safe and effective for their intended use. Laboratories developing IVDs as LDTs must establish and maintain processes and procedures that encompass the following key components:

STAGE 4: Premarket Review for High Risk IVDs Offered as LDTs

Beginning on November 6, 2027, laboratories offering Class III IVDs as LDTs must comply with Stage 4 requirements, requiring FDA premarket approval (PMA) before marketing.  This entails comprehensive analytical and clinical evaluations to demonstrate device safety and effectiveness, aligning with stringent FDA review standards under 21 CFR 814.20.  The PMA application must include all elements required under 21 CFR 814.20, unless omissions can be justified by the applicant.

Separately, the FDA’s Center for Devices and Radiological Health (CDRH) intends to initiate the reclassification process for certain IVDs currently classified as Class III (high-risk devices) to Class II (moderate-risk devices). This reclassification would potentially enable these tests to undergo review through the less burdensome premarket notification (510(k)) pathway instead of the premarket approval (PMA) pathway, the most stringent type of FDA medical device review. 

However, the FDA will only consider reclassification for Class III devices if the agency has sufficient information (i.e., experience) to establish special controls that, together with general controls, provide a reasonable assurance of safety and effectiveness for these tests.  As a result, only those Class III IVDs for which the FDA can establish appropriate special controls will be eligible for down classification to Class II. 

STAGE 5: Premarket Review for Moderate and Low Risk IVDs Offered as LDTs

Beginning on May 6, 2028, laboratories offering Class II moderate-risk and Class I low-risk IVDs as LDTs must submit a 510(k) premarket notification demonstrating substantial equivalence to legally marketed devices, unless exempt. This stage also allows for alternative pathways like De Novo classification requests for devices lacking predicate devices but deemed safe and effective under general or special controls.

Additionally, certain other premarket submissions, such as Humanitarian Device Exemption applications or Biologics License Applications (BLAs), may also be appropriate depending on the specific circumstances of the IVD offered as an LDT.

Of note, for IVDs that rely on or otherwise incorporate software (including off-the-shelf software) or that meet the definition of a “cyber device” (Section 524B(c) of the FD&C Act), premarket submissions will need to be inclusive of documentation for FDA’s review and evaluation. For IVDs offered as LDTs already on the market, if a premarket submission has been received by the beginning of Stage 4 or Stage 5 (as applicable), the FDA intends to exercise enforcement discretion during the review period to ensure continued patient access to these devices without interruption.

The agency’s phaseout transition aims to enhance FDA oversight and ensure the safety and effectiveness of LDTs, by aligning expectations for regulatory compliance with that of commercially distributed medical devices. This phased approach is intended to allow laboratories time to comply with the new regulatory framework while continuing to meet the needs of patients and healthcare providers for accurate diagnostic testing.

Notably the amended regulation and phaseout policy do not change other requirements for laboratories, including requirements under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), which are separate from requirements under the FD&C Act.

Continued General Enforcement Discretion Approach for Certain IVDs

The FDA’s LDT Final Rule, in comparison to its proposed rule, broadens the scope of LDTs for which the agency intends to continue exercising general enforcement discretion. This means that the FDA will generally not enforce any applicable requirements for the following:

Tests manufactured and offered for use exclusively for public health surveillance are also not affected by the phaseout policy.

Targeted Enforcement Discretion Approach for Other IVDs   

Additionally, the FDA has outlined a targeted enforcement discretion approach for certain other categories of LDTs. Under this approach, the FDA intends not to enforce certain applicable requirements for these IVDs. This decision is based on the FDA’s assessment that tests in these categories are unlikely to pose significant risks, or they are conducted under circumstances that inherently mitigate potential risks. These IVDs offered as LDTs include:

The table below provides a high-level summary of the key categories of LDTs under FDA enforcement discretion and the regulatory requirements to which compliance is expected in Stages 1 through 5 of the agency’s phaseout policy.

LDT Enforcement Discretion
(click image to enlarge)

Importantly, there are additional limitations to the agency’s enforcement discretion policies. For example, for LDTs that are modified versions of another manufacturer’s 510(k) cleared or De Novo authorized test, the FDA’s enforcement discretion policy exempting premarket review only applies when the modification was made following design control and other quality system requirements and in a manner that could not “significantly affect the safety or effectiveness of the test and does not constitute a major change or modification in intended use, and where the modified test is performed only in the laboratory making the modification”. Otherwise, FDA expects premarket submissions from laboratories modifying a third party’s 510(k) cleared or De Novo authorized test for the same types of changes for which FDA would expect a premarket submission from the original manufacturer making changes to its own IVD.

Similarly, any “significant modifications” to an LDT marketed before May 6, 2024 will require meeting compliance expectations that align with the phaseout policy. And, for LDTs for unmet needs manufactured and performed by laboratories in an integrated healthcare system, enforcement discretion would end when an FDA-authorized test that addresses the unmet need becomes available.

Moreover, as with any enforcement discretion policy, FDA may update any of these policies as circumstances warrant or if the circumstances that inform these policies change, consistent with FDA’s good guidance practices (section 701(h) of the FD&C Act, 21 CFR 10.115).  Additionally, regardless of the phaseout timeline and enforcement discretion policies for certain IVDs, FDA retains discretion to pursue enforcement action for violations of the FD&C Act at any time.

Laboratories will need to determine the FDA’s applicable regulations and enforcement discretion policies that apply to each of their LDTs.  This will guide decisions on compliance pathways and documentation requirements and help in determining needed resources.

6 Strategies to Help You Get Started

  1. Stay Informed
    • Stay abreast of legislative developments and regulatory changes that may impact LDT regulation.
    • This includes proposed legislation, and changes in enforcement policies as well as FDA announcements, guidance documents, webinars, and other resources.
  2. Understand FDA Requirements
    • Become familiar with FDA definitions, requirements, and expectations for LDTs.
    • This includes understanding the differences between LDTs and FDA-cleared/approved tests and knowing when FDA regulation applies.
  3. Know your Test Status
    • Determine the FDA’s applicable regulations and enforcement discretion policies that apply to each type of LDT.
    • This will guide decisions on compliance pathways and documentation requirements and help in determining needed resources.
  4. Quality System Compliance
    • Evaluate your laboratory’s CLIA Quality Management System (QMS) against FDA’s Quality System Regulations (QSR) to identify gaps.
    • Begin planning necessary changes to align with FDA requirements, ensuring documentation and processes meet regulatory standards.
  5. Document Decisions and Rationale
    • Document decisions related to regulatory compliance, including rationale for enforcement discretion or alternative compliance strategies based on FDA policies.
    • Document compliance with FDA’s conditions for enforcement discretion, if applicable.
  6. Plan for FDA Submissions
    • Assess whether FDA premarket submissions are necessary for your LDTs based on FDA requirements, the tests intended use and classification according to the FD&C Act necessary to reasonably assure safety and effectiveness.
    • Develop timelines and strategies for compiling necessary documentation and data to support submissions, if applicable.

How Beaufort Can Help

The phased approach aims to enhance FDA oversight while allowing laboratories time to adapt to new regulatory standards. However, laboratories should proactively prepare for compliance to ensure continued market access for their LDTs.

Our team of regulatory, quality, and clinical experts can help laboratories navigate the new regulatory landscape and ensure readiness for upcoming compliance milestones. We offers comprehensive support including:

Contact us to learn more about our services and how we can assist in meeting FDA requirements and maintaining market access for your LDTs.

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