An In-depth Look at the FDA’s Final Rule Regarding Laboratory-Developed Tests

On April 29, 2024, the FDA announced a Final Rule to ensure the safety and efficacy of laboratory-developed tests (LDTs). The final rule was released to regulate LDTs and to address the difference between in-vitro diagnostics (IVDs) that are sold outside the laboratories and LDTs that are created and utilized in a single lab. Under the Federal Food, Drug, and Cosmetic Act (FD&C), in-vitro diagnostic products (IVDs) are considered devices. Still, LDTs have faced less stringent FDA regulations in the past, which led to a regulatory gap. Now, the Final Rule has closed this gap by applying the same rules and regulations for the safety and effectiveness of LDTs, similar to the IVDs in healthcare settings.

Laboratory-developed tests (LDTs)

Laboratory-developed tests, or LDTs, are diagnostic tests that are designed, conducted, and validated in a single laboratory and are not commercially distributed to other laboratories. As LDTs are used in a single laboratory, the lab is certified under CLIA (Clinical Laboratory Improvement Amendments of 1988) and ensures it meets the regulatory requirements of CLIA to conduct testing. LDTs have been considered by the FDA as IVDs under 21 CFR §809 and, as such, “devices” under FD&C Act §201. The Final rule defines that IVDs, including those that are manufactured in laboratories, are devices under the FD&C Act by amending the definition of IVDs at CFR §809. So, IVDs that act like LDTs will undergo FDA regulation as medical devices.

Like any other IVD, LDTs could be used to identify a wide range of molecules or analytes in a body, including glucose, proteins, cholesterol, and DNA. It provides data on a patient’s health, such as how to diagnose, monitor, or suggest treatment for certain diseases. An increasing number of healthcare decisions include LDTs that are offered as IVDs, and the concerns related to the safety and effectiveness of these LDTs have been raised for many years

LDT Regulation

Over the years, the FDA has discussed the increased monitoring of LDTs, such as organizing a workshop in 2010, drafting a guidance document proposal in 2014, a discussion paper in 2017, and associating with industry and congressional stakeholders. The FDA's concerns arose regarding LDTs due to the proliferation and evolution of LDTs and their increased outcomes regarding their safety and efficacy, so the need for proper regulation for LDTs became necessary. On October 3, 2023, the FDA proposed a rule that aimed to ensure the safety and effectiveness of these LDTs, and in April 2024, the FDA finalized the rule-making, which is known as the “Final Rule." The FDA seeks the Final Rule as "correcting the imbalance in its oversight between non-laboratory and laboratory IVD manufacturers—an imbalance that harms American patients."

Phase out Policy

The FDA has finalized a structured “phaseout policy” under which it will give insights into IVDs that act like LDTs by “phaseout” of enforcement discretion for LDTs over four years. During this period, the FDA will “phase-in” requirements for regulatory compliance for IVDs offered as LDTs in five stages. This approach developed by the FDA is important for the assurance of a manageable shift for labs to regulatory compliance and the pre-market and post-market standards.

Phase out Policy Stages:

Stage 1

Starting one year after the publication date of the final LDT rule, the FDA will expect compliance with Medical Device Reporting (MDR) requirements under ? 21 C.F.R. Part 803 and Quality System Requirements (QSR) under 21 C.F.R. § 820.198. MDR requirements are the removal and correction of the reporting criteria, and QS requirements include complaint files.

Stage 2

Within 2 years after the publication date of the final LDT rule, the FDA will expect compliance with registration and listing requirements under 21 C.F.R. Parts 607 and 807, labeling demands under 21 C.F.R. Parts 801 and 809, and investigational use standards under 21 C.F.R. Part 812, as these are the requirements not covered during other stages of the phaseout policy.

Stage 3

Beginning 3 years after the publication date of the Final LDT rule, FDA expects compliance with full QS requirements under 21 C.F.R. Part 820 (other than the QS requirements already addressed in stage 1).

Stage 4

Within 3 and a half years after the publication of the Final LDT rule, compliance with pre-market review standards is expected for high-risk LDTs (that were offered as IVDs) classified as Class III devices. If a pre-market review is submitted by the companies at the beginning of this stage, it will benefit from the FDA’s enforcement discretion during the review procedure.

Stage 5

Following 4 years after the publication date of the Final LDT rule, the FDA expects compliance with the requirements of pre-market review for intermediate-risk and low-risk IVDs (Class 1 and Class 2 devices) that act like LDTs. The FDA’s intention is to continue the enforcement discretion during the review phase, and this stage remains consistent with the proposed rule.

Targeted Enforcement Discretion Policies—"Carve-Outs"

The “phase-out” policy of the Final Rule also involves Targeted Enforcement Discretion Policies—"Carve-Outs" for specific IVDs offered as LDTs by a laboratory. These Carve-Outs will indicate if the FDA wants to exercise enforcement discretion and not enforce all of the regulatory requirements for certain categories of LDTs.

Continued Enforcement Discretion applies to;

1. 1976-Type LDTs Such tests are similar to those accessible in 1976, designed, manufactured, and conducted in a single CLIA-certified laboratory, including manual procedures and legally authorized constituents.
2. Human Leukocyte Antigen (HLA) Tests These tests are developed and used in a single CLIA-certified laboratory for organ, stem-cell, and tissue transplantation.
3. Non-Molecular Antisera Tests Tests for rare red blood cell antigens, including transfusion services and immunohematology labs, and when a patient needs a compatible blood transfusion but a suitable alternative test is not available.
4. ?Forensic tests These tests are only developed and used for law enforcement purposes
5. Tests for the Department of Veteran Health Administration LDTs are manufactured and conducted within the Department of Defense and Veteran Health Administration.

Major Carve-outs

• Currently marketed LDTs

LDTs that were marketed before the release of the Final Rule will not undergo enforcement of pre-market review or QSR (Quality System Regulation) by the FDA. This exemption will help the currently marketed tests perform without the issue of strict new regulations. However, these LDTs must still comply with the Medical Device Reporting (MDR) requirements.

• Revisions to existing LDTs

The FDA will ask for a pre-market review and QSR if an existing LDT has undergone modifications impacting its use, performance, or technology.

• Tests addressing unmet demands

These tests are developed in a healthcare setting to fulfill the unmet needs of patients when there is no FDA-approved substitute. The FDA plans to offer guidance on this policy and has acknowledged over 100 comments.

• ?New York State Clinical Laboratory Evaluation Program (CLEP)

FDA pre-market value is not strictly necessary for the LDTS approved by NYS CLEP for high-risk and moderate-risk. However, post-market requirements are applicable for such LDTs.

Conclusion

The FDA’s Final Rule for LDTs is a major turning point in diagnostic testing regulation, which aims to ensure the safety and efficacy of LDTs. The FDA addresses the constant concerns about the regulatory gaps that could threaten patient safety by adjusting LDTs with the same requirements that regulate IVDs. The FDA ensures LDT reliability and patient safety by creating a clear regulatory framework.?

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