Overview of FDA Laboratory Developed Test Final Rule

ASCP Hosts May 21 Town Hall briefing on the Rule

The U.S. Food and Drug Administration (FDA) has released its long-awaited Final Rule claiming regulatory authority over Laboratory Developed Tests, or LDTs. Once fully implemented, the FDA generally will expect all IVDs—including LDTs—to meet FDA regulatory controls. As anticipated, the 528-page rule—officially published in the Federal Register on May 6—follows the same timeline as the proposed rule. ASCP hosted a free Town Hall on May 21 to inform ASCP members and the laboratory medicine community about the ramifications of the Final Rule. To view the Town Hall, click here. 

Under the Final Rule, laboratories with new LDTs should expect a far more laborious, time consuming, and expensive FDA-approval process. Indeed, the FDA’s Final Rule has been criticized for this by several influential members of Congress, including Senator Bill Cassidy, MD, ranking member of the Senate Committee on Health, Education, Labor, and Pensions, House of Representatives Energy and Commerce Committee Chair Cathy McMorris Rodgers, and others. “This rule will undermine access to essential laboratory tests, increase health care costs, and ultimately harm patients. During the pandemic, we saw how too much government interference and red tape delays lifesaving care to Americans,” said Dr. Cassidy. FDA received approximately 6,500 comments on its proposed rule, many of them—including ASCP’s—were critical of the proposal.

Overview of the Final Rule
The Final Rule amends the FDA’s regulations to make explicit that in vitro diagnostic products (IVDs) are devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act), including when the manufacturer of the IVD is a laboratory. In conjunction with this change, the FDA is phasing out its general “enforcement discretion” approach for LDTs such that IVDs “manufactured” by a laboratory would generally fall under the same enforcement approach as other IVDs, though some LDTs may benefit from a new, more targeted form of enforcement discretion. Laboratories should be aware that the Final Rule allows the FDA to modify or withdraw its enforcement discretion policy at any time. The FDA will implement its new regulatory scheme in five stages over a four-year period.

The FDA is generally defining an LDT as an in vitro diagnostic (IVD) that is “intended for clinical use and that is designed, manufactured, and used within a single laboratory that is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and meets the regulatory requirements under CLIA to perform high complexity testing.” This definition would give the FDA sweeping authority over LDTs. FDA’s new oversight scheme will require laboratories to establish clinical as well as analytical validity for new LDTs.

Enforcement Discretion
Previously, the FDA’s general enforcement discretion policy provided extensive regulatory relief for LDTs. Under the Final Rule, the agency will substantially pare back how this policy will be applied. The FDA plans to provide three levels of enforcement discretion: Full enforcement discretion and two levels of partial enforcement discretion. Tests not benefiting from enforcement discretion will be subject to premarket review and other FDA regulatory controls. LDTs classified as high risk will be subject to premarket application/submission requirements whereas low and moderate risk tests will be subject to premarket review requirements.  It should be noted that FDA will be reviewing information submitted by laboratories as part of their compliance requirements.  The FDA maintains it may subject tests covered by enforcement discretion to undergo additional regulatory controls if it believes this is warranted.

Full Enforcement Discretion: The FDA will provide full enforcement discretion, meaning these tests will not be subject to FDA regulatory controls, such as medical device reporting requirements, for the following kinds of tests: “1976-type” LDTs, Human leukocyte antigen tests used for transplant, forensic tests, and LDTs manufactured and performed by Veterans Health Administration and Department of Defense laboratories.

The FDA will maintain enforcement discretion for “1976-type LDTs,” which it has defined as those LDTs that use “manual techniques (without automation) performed by laboratory personnel with specialized expertise; use of components legally marketed for clinical use; and design, manufacture, and use within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing.” LDTs that involve automated preparation or interpretation, as well as lateral flow tests, are not covered.

The FDA is also maintaining full enforcement discretion for human leukocyte antigen (HLA) tests—provided they are "designed, manufactured, and used in a single laboratory certified under CLIA that meets the requirements to perform high-complexity histocompatibility testing when used in connection with organ, stem cell, and tissue transplantation to perform HLA allele typing, for HLA antibody screening and monitoring, or for conducting real and 'virtual' HLA crossmatch tests."

In addition, FDA will be providing full enforcement discretion to LDTs used by law enforcement authorities solely for forensic purposes and LDTs manufactured and performed within Veterans Health Administration and Department of Defense laboratories.

Partial Enforcement Discretion: FDA will provide two levels of partial enforcement discretion, one covering premarket review only and the other covering premarket review and most quality systems requirements. FDA will not require LDTs to undergo premarket review and most Quality System (QS) requirements (compliance with FDA records requirements is required) for the following two types of tests:

1. “LDTs that were being marketed before May 6, 2024” (this enforcement discretion policy is often referred as “grandfathering,” however this term is a misnomer as FDA will be imposing regulatory controls for these tests and the Agency maintains it may subject these tests to additional regulation if it believes this is necessary)
2. “LDTs manufactured and performed by a laboratory integrated within (owned by) a healthcare system to meet an unmet need of patients” in that system only
3. “Non-molecular antisera LDTs for rare red blood cell (RBC) antigens where such tests are manufactured and performed in blood establishments, including transfusion services and immunohematology laboratories and where there is no alternative available to meet the patient’s need for a compatible blood transfusion.”

The least robust of the enforcement discretion policies provides relief from premarket review only. This level of enforcement discretion is reserved for LDTs that have been approved by the New York State Clinical Laboratory Evaluation Program.

The FDA expects laboratories with LDTs that benefit from enforcement discretion to comply with other applicable requirements, such as quality systems requirements, registration and listing, labeling, medical device report requirements, etc. Moreover, the FDA states in the rule that it may require any test—including those that have benefitted from enforcement discretion—to undergo premarket review if it believes such steps are warranted.

Modifications of “Grandfathered” LDTs
As outlined in its Final Rule, the FDA “generally expects compliance with premarket review and QS requirements for currently marketed IVDs offered as LDTs” when a laboratory modifies the test in any of the following ways:

• changes the indications for use of the IVD;

• alters the operating principle of the IVD (e.g., changes in critical reaction components);

• includes significantly different technology in the IVD (e.g., 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 changes the performance or safety specifications of the IVD.

Modifications of FDA-Approved tests
FDA is also “adopting a policy under which it generally does not intend to enforce premarket review requirements for certain laboratory changes to another manufacturer’s lawfully marketed test. In particular, this policy applies when a laboratory certified under CLIA and meeting the regulatory requirements under CLIA to perform high complexity testing modifies another manufacturer’s 510(k) cleared or De Novo authorized test, following design controls and other quality system requirements for which FDA expects compliance…If a laboratory’s modification is so significant that the IVD is no longer substantially equivalent to the original IVD and requires a PMA, FDA expects the PMA to be submitted either by stage 4 or before the modified test is marketed, whichever comes later.”  Modifications of another manufacturer’s high-risk test would require stage 5 premarket approval.

Implementation Schedule
The FDA’s policy for oversight of LDTs will involve a five-stage implementation process over four years. Except for those LDTs covered by full enforcement discretion, all LDTs must comply with all applicable controls outlined below:

• Stage 1 (May 6, 2025 – 1 year from Final Rule publication): FDA will end the general enforcement discretion approach with respect to medical device reporting (MDR) requirements, correction and removal reporting requirements, and complaint file requirements.
• Stage 2 (May 6, 2026 – 2 years from Final Rule publication): End the general enforcement discretion approach with respect to requirements other than MDR, correction and removal reporting, QS, and premarket review requirements (i.e., registration, listing, labeling, and investigational device requirements).
• Stage 3 (May 6, 2027 – 3 years from Final Rule publication): End the general enforcement discretion approach with respect to applicable QS requirements (i.e., design controls, purchasing controls, acceptance activities, corrective and preventative actions, and records requirements not already in effect).
• Stage 4 (November 6, 2027 – 3.5 years from Final Rule publication): End the general enforcement discretion approach with respect to premarket review requirements for high-risk IVDs.
• Stage 5 (May 6, 2028 – 4 years from Final Rule publication): End the general enforcement discretion approach with respect to premarket review requirements for moderate risk and low risk IVDs (that require premarket submissions).

ASCP’s Perspective
Even though the final rule includes several important changes, ASCP is still strongly opposed to it. ASCP is concerned that the FDA’s Final Rule will make it difficult, if not impossible, for many laboratories to ensure patient access to quality testing services.  The limited nature of the FDA’s new enforcement discretion policies will result in substantial regulatory burden and costs for laboratories with currently marketed LDTs. Moreover, the compliance systems that laboratories have in place to meet CLIA requirements are significantly different from those needed to satisfy the FDA manufacturing requirements. As a result, ASCP is working with other laboratory organizations to advocate for alternative oversight schemes that can ensure patient access to quality testing.

Upcoming ASCP Town Hall
To help our members and the laboratory community better understand how this important Final Rule will affect their work and laboratory, ASCP urges members and non-members to register for our free Town Hall on May 21 at 1:00PM ET. A panel of ASCP experts will be on hand to provide an overview and answer questions about the Final Rule’s requirements, deadlines, enforcement discretion policies, and what this all means for laboratories and staff. A recording of the Town Hall will be available for viewing after the event. Register here.

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