The Food and Drug Administration (FDA) released the final regulation on the oversight of laboratory-developed tests (LDTs) with some changes advocated for by the CAP. The CAP had opposed the regulation as written and called for several improvements that would ensure patient access to testing and allow for the continued innovation of new tests.

CAP President Donald Karcher, MD, FCAP, recently testified before the House Energy and Commerce Subcommittee on Health to firmly state the CAP’s opposition to the FDA’s oversight plan and advocate for policy solutions that target full regulation on only the highest-risk LDTs.

Dr. Karcher issued the following statement after the final rule’s release on April 29:

“The CAP remains concerned that the FDA is moving forward with its regulatory oversight plan for LDTs without making the additional changes needed to ensure both patient safety and access to accurate and innovative testing. While we recognize that the FDA adopted the CAP’s recommendation to allow LDTs offered prior to the rulemaking going into effect to remain under its enforcement discretion policy, the FDA must do more to recognize the realities of clinical laboratory testing and pathology practice in the 21st century.

“LDTs have been critical for the advancement of medicine and contributed to the evolution of modern scientifically-based health care services. Today, LDTs continue to have a critical role in scientifically-based diagnostics and clinical care for patients. While full FDA oversight of the small number of LDTs posing the highest risk to patients (tests using unconventional methods and/or non-transparent algorithms, with no opportunity for external verification of accuracy) may be warranted, many pathologists and laboratories will be forced to soon decide whether they will continue to offer lower-risk, well-validated and high-quality LDTs given the great cost and regulatory burden of the FDA’s new rules.

“We urge the FDA to reconsider the CAP’s prior feedback in light of the real-world effect its strict regulation will have on pathologists and laboratories meeting the needs of a diverse patient population across the United States. Importantly, FDA must conduct a massive outreach and education campaign on how laboratories can meet these regulatory requirements and still care for patients as the new rules are implemented.”

Initial Analysis of FDA Regulation

The final regulation retained the FDA three-tiered, risk-based structure and leverages third-party reviewers with the five-year phased out of enforcement discretion. The FDA will allow for tests developed prior to the rule’s issuance to remain under enforcement discretion, which is a change the CAP strongly advocated for in its comments to the FDA. For those LDTs developed prior to the rule’s engagement and under enforcement discretion, if modified the LDTs individually or in aggregate would require a premarket review when modifications:

• changed the indications for use of the in vitro diagnostic (IVD);
• altered the operating principle of the IVD (eg, changes in critical reaction components);
• included significantly different technology in the IVD (eg, addition of artificial intelligence or machine learning to the test algorithm, a change from targeted sequencing to whole genome sequencing, a change from immunoassay to mass spectrometry, or a change from manual to automated procedures); or
• adversely changed the performance or safety specifications of the IVD.

The phaseout policy contains the following five stages:

• Stage 1: beginning on May 6, 2025, the FDA will expect compliance with medical device reporting (MDR) requirements, correction and removal reporting requirements, and quality system requirements regarding complaint files.
• Stage 2: beginning on May 6, 2026, the FDA will expect compliance with requirements not covered during other stages of the phaseout policy, including registration and listing requirements, labeling requirements, and investigational use requirements.
• Stage 3: beginning on May 6, 2027, the FDA will expect compliance with quality system requirements.
• Stage 4: beginning on November 6, 2027, the FDA will expect compliance with premarket review requirements for high-risk IVDs offered as LDTs (IVDs that may be classified into class III or that are subject to licensure under section 351 of the Public Health Service Act), unless a premarket submission has been received by the beginning of this stage in which case the FDA intends to continue to exercise enforcement discretion for the pendency of its review.
• Stage 5: beginning on May 6, 2028, the FDA will expect compliance with premarket review requirements for moderate-risk and low-risk IVDs offered as LDTs (that require premarket submissions), unless a premarket submission has been received by the beginning of this stage in which case the FDA intends to continue to exercise enforcement discretion for the pendency of its review.

The rule does provide exemptions as initially proposed, such as for human leukocyte antigen (HLA), forensic, and manual tests. For manual tests, the FDA has determined that the risks are sufficiently low such that the FDA’s general enforcement discretion approach for LDTs should continue to apply. These tests might include, for example, immunohistochemistry tests that involve no automated preparation or interpretation, but would not include, for example, lateral flow tests; however, the agency has indicated that it will release additional guidance in the future to clarify.

Other changes include narrowing the quality system requirements outside of those stated in the phased-out approach to only design control and records, allowing laboratories leveraging New York State Department of Health (NYSDOH) LDT program to be exempt from premarket requirements, continued enforcement discretion for exempt categories, and enforcement discretion for LDTs developed in health care systems for certain unmet needs. The rule does provide enforcement discretion for those tests developed prior the rule’s issuance.

The CAP will provide additional updates on the regulation as new information becomes available.