Lab-Developed Tests
LDTs are a specific type of IVD. An IVD is a medical device regulated by the U.S. Food and Drug Administration (FDA) that takes samples from the human body. In essence, LDTs are diagnostic tests that are developed, validated, and used within one single laboratory. They are not commercially distributed to other laboratories for use. LDTs can be used for any number of reasons, such as identifying blood counts, genetic and molecular tests to detect heart disease, or cancer, to testing for drug substances in the body.
While the laboratories themselves that develop these LDTs are regulated by the Clinical Laboratory Improvement Amendments (CLIA) program, the LDTs are regulated by the FDA. Since the implementation of the Medical Device Amendments of 1976 (MDA), the FDA had exercised enforcement discretion with respect to LDTs. Specifically, in the preamble to the Final Rule, the FDA stated that
[I]n implementing the MDA since 1976, FDA has exercised enforcement discretion such that it generally has not enforced applicable legal requirements with respect to most LDTs. This means that, for most LDTs, FDA generally has not enforced requirements related to registration and listing, reporting adverse events to FDA, current good manufacturing practices (CGMPs), or premarket review of an IVD by FDA prior to use of the LDT in patient care, among other requirements.
Accordingly, laboratories that developed LDTs enjoyed enforcement discretion from the FDA for a long time. The FDA continued to note that:
The rationale for this approach was that, at the time of passage of the MDA, LDTs were mostly manufactured in small volumes by laboratories that served their local communities. They were typically intended for use in diagnosing rare diseases or for other uses to meet the needs of a local patient population, or were generally similar to well-characterized, standard IVDs (Refs. 2 and 3). They also tended to employ manual techniques (and did not use automation) and were performed by laboratory personnel with specialized expertise; to be used and interpreted by physicians or pathologists in a single institution responsible for the patient (and who were actively involved in patient care); and to be manufactured using components legally marketed for clinical use, such as general purpose reagents or immunohistochemical stains marketed in compliance with FDA requirements. Due to these and other factors, FDA exercised enforcement discretion such that it generally has not enforced applicable requirements for most LDTs.
The preamble explains that the “risks associated with most LDTs today are therefore much greater than they were . . . and most LDTs today are similar to other IVDs that have not been under FDA’s general enforcement discretion approach.” In the Proposed Rule, FDA further explained that LDTs are indeed “marketed to the same patients, sometimes on a national scale.” FDA also noted concern that firms were offering IVDs as “LDTs” when they are not LDTs as defined on the FDA’s website.
The FDA also was concerned about the potential for cybersecurity vulnerabilities:
Many LDTs are connected to Laboratory Information Management Systems and other IT infrastructure, making them a potential conduit for those looking to access information in such systems. This may include patient genetic information, among other things, which could have national security implications. Further, it has been demonstrated that hackers can modify medical test results. Through premarket review, FDA works with manufacturers to ensure cybersecurity is appropriately considered, mitigating the potential for future problems. Through medical device reporting (MDR) and correction and removal reporting requirements, FDA helps to ensure that any problems are appropriately addressed.
Key Provisions in FDA’s final rule
The definition of an IVD now also includes “when the manufacturer of these products is a laboratory.” The simple addition of this phrase to the definition of an IVD has the effect of FDA oversight over LDTs.
The Final Rule employs the following four-year phaseout period for FDA’s enforcement discretion of LDTs:
- Stage 1: Beginning one year after May 6, 2024, FDA will expect compliance with MDR requirements, correction and removal reporting requirements, and quality system (QS) requirements.
- Stage 2: Beginning two years after May 6, 2024, FDA will expect compliance with registration and listing requirements, labeling requirements, and investigational use requirements.
- Stage 3: Beginning three years after May 6, 2024, FDA will expect compliance with QS requirements under part 820 (21 C.F.R. Part 820);
- Stage 4: Beginning 3½ years after May 6, 2024, 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 FDA intends to continue to exercise enforcement discretion for the pendency of its review; and
- Stage 5: Beginning four years after May 6, 2024, 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 FDA intends to continue to exercise enforcement discretion for the pendency of its review.
The FDA identified certain categories of LDTs for which it intends to continue its enforcement discretion to varying degrees.
Specifically, FDA intends to continue the general enforcement discretion approach and generally not enforce any applicable requirements for the following LDTs:
- 1976-type LDTs.
- Human Leukocyte Antigen (HLA) tests that are designed, manufactured, and used within 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.
- Tests intended solely for forensic (law enforcement) purposes.
- LDTs manufactured and performed within the Department of Defense (DOD) and Veterans Health Administration (VHA) that are used for patients being tested and treated within the DOD or VHA.
FDA also generally intends to exercise enforcement discretion with respect to premarket review requirements for the following tests:
- LDTs approved by the New York State Department of Health Clinical Laboratory Evaluation Program in connection with premarket review requirements.
Finally, FDA also intends to exercise enforcement discretion and generally not enforce premarket review and most QS requirements for three categories of IVDs:
- LDTs manufactured and performed by a laboratory integrated within a health care system to meet an unmet need of patients receiving care within the same health care system. For these LDTs, FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records)). FDA considers an LDT to be for an unmet need when there is no available FDA-authorized IVD that meets the patient’s needs. This may be because (1) there is no FDA-authorized IVD for the disease or condition (for example, because it is a rare disease or condition); (2) there is an FDA-authorized IVD for the disease or condition, but it is not indicated for use on the patient, or a unique attribute needs to be added to the LDT to meet the patient’s needs; or (3) there is an FDA-authorized IVD, but it is not available to the patient.
- LDTs that were first marketed prior to the date of issuance of this rule (hereinafter, “currently marketed IVDs offered as LDTs”). FDA intends for this policy to apply to currently marketed IVDs offered as LDTs as long as they are not modified following the issuance of this Final Rule, or are modified but only in certain limited ways. Under this policy, FDA generally expects compliance with premarket review and QS requirements for currently marketed IVDs offered as LDTs when a laboratory’s modifications (individually or in aggregate): (1) change the indications for use of the IVD; (2) alter the operating principle of the IVD (e.g., changes in critical reaction components); (3) include 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 (4) adversely change the performance or safety specifications of the IVD.
FDA also will request that laboratories offering currently marketed IVDs offered as LDTs submit labeling, including IVD performance information and a summary of supporting validation. FDA will analyze this information and take action where claims are not adequately substantiated.
- 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.
FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records)) for these LDTs.
Challenges to Final Rule
The Final Rule has been met with judicial challenges. In the wake of the Final Rule, laboratory trade associations filed two lawsuits against the FDA. Both lawsuits named the same four defendants (FDA, FDA commissioner, HHS, and HHS secretary), alleged the same causes of action under the Administrative Procedure Act (APA) against the Final Rule (unlawful agency action and arbitrary and capricious agency action), and sought the same relief—declaratory relief with respect to the Final Rule and an order that vacates the Final Rule and enjoins defendants from enforcing it.
Specifically, on May 29, 2024, the American Clinical Laboratory Association (ACLA), a trade association representing clinical laboratories, and its member company HealthTrackRX filed a lawsuit against the FDA in the U.S. District Court for the Eastern District of Texas.
Shortly thereafter, on August 19, 2024, the Association for Molecular Pathology (AMP), a laboratory medicine trade association, and Dr. Michael Laposta, a medical doctor and clinical pathologist, filed their action in the U.S. District Court for the Southern District of Texas, which was transferred to the Eastern District. Since that time, the AMP plaintiffs have filed a motion for summary judgment.
Both lawsuits alleged that the FDA has not been granted authority to regulate LDTs. In the AMP complaint, plaintiffs cited the Final Rule’s own concession that there is a “lack of language in the [FFDCA] specifically mentioning . . . LDTs.” The plaintiffs assert that the FFDCA’s surrounding provisions reinforce the conclusion that only tangible goods fall within the definition of a device—not intangible medical services or procedures. In addition, the plaintiffs argued LDTs have been properly and comprehensively regulated under CLIA by CMS.
Both sets of plaintiffs also allege that FDA has acted arbitrarily and capriciously. As asserted in the ACLA complaint, the “FDA has not acted consistent with the requirements of reasoned decision-making, because it has not adequately responded to objections, provided a reasoned justification for its rule, or reasonably explained its sweeping assertion of new regulatory authority.”
The ACLA and AMP plaintiffs have filed their opening briefs (each are forty-page summary judgment motions) on September 3, 2024, and September 27, 2024, respectively.
Implications of Final Rule
In the wake of the Final Rule, laboratories must assess each individual LDT offering to identify what requirements must be met under the Final Rule and the corresponding timeline for compliance, notwithstanding the potential for judicial intervention.
Notably, laboratories should assess the time, effort, and financial investment that are required to meet applicable FDA rules. Compliance with the target dates noted in the Final Rule will require a substantial amount of planning.