On May 6, 2024, the Food and Drug Administration (FDA) released a final rule on regulation of laboratory-developed tests (LDTs) as medical devices. The FDA received more than 6,500 comments on the proposed rule. The final regulatory text itself is just 10 words, adding to the provision defining an in vitro diagnostic (IVD) as a “medical device” the following clause: “including when the manufacturer of the IVD is a laboratory.” The FDA devotes the remainder of the 160-page publication to an explanation of its legal authority and how it intends to regulate LDTs as medical devices and cataloging comments on the proposed rule and its responses.
In response to comments about the potentially adverse impacts of the proposed rule’s policies on patient access to currently offered LDTs, and perhaps in recognition of its own resource constraints, the FDA has included in the final rule a significant number of carveouts and policies of “enforcement discretion” for various types of tests, including LDTs approved by the New York State Clinical Laboratory Evaluation Program (CLEP), LDTs for “unmet needs” offered within a health system, currently marketed LDTs, and FDA-cleared tests that have been modified in certain ways by high-complexity laboratories certified by the Clinical Laboratory Improvement Amendments Program (CLIA). Nevertheless, most LDTs will be subject to many aspects of medical device regulation beginning one year after issuance of the final rule, regardless of whether they are subject to a carveout or enforcement discretion.
General Timeline for Regulation of LDTs as Medical Devices
The phaseout of the FDA’s traditional policy of enforcement discretion for LDTs is largely unchanged from the proposed rule. The various aspects of the phase-out policy apply in full only to LDTs that are not subject to any carveouts or continuing enforcement discretion. Other LDTs subject to a carveout or enforcement discretion may be subject to some, but not all, of the medical device regulatory provisions (for example, an LDT may be exempt from premarket review but subject to labeling requirements). The phaseout consists of five stages over four years.
Stage 1 (one year after publication): Compliance with medical device reporting, correction and removal reporting requirements, and complaint files
The FDA “seeks to obtain information about potentially harmful IVDs offered as LDTs as soon as feasible.” A medical device report (MDR) will be required by a laboratory running an LDT when it becomes aware of an event that reasonably suggests that an LDT has, or may have, caused or contributed to death or serious injury or when it becomes aware that the LDT has malfunctioned and, were the malfunction to recur, it would be reasonably likely to cause death or serious injury. The LDT failure need not be the sole cause of the injury or death, and the LDT could have caused the injury or death due to its failure, malfunction, improper or inadequate design, manufacture, labeling, or user error. If the cause is solely due to user error (and not because the user error was caused, at least in part, by a failure of the LDT (including its labeling)), an MDR need not be filed, though the supporting information should be retained. This means that when user error like losing or mislabeling a sample that has nothing to do with the actual test is the cause of the serious injury or death, no MDR must be filed.
A report of correction and removal will be required if an LDT is removed from the market or otherwise corrected to reduce a risk to health or remedy a violation of the Federal Food, Drug, and Cosmetic Act that may present a risk to health. Reporting of corrections and removals occurs for some but not all recalls, as well as in some non-recall circumstances.
Complaints are defined by the FDA to be “any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution.” Laboratories offering LDTs have to have systems in place to review and investigate complaints. The FDA expects corrective actions in response to the root causes of the underlying issues identified during the investigation. If the investigation results in a conclusion that the product has or may have caused or contributed to serious injury or death, an MDR must be filed.
The FDA has recordkeeping requirements for MDRs, reports of corrections and removals, and complaints. Records related to MDRs must be retained for the latter of two years from the date of the event or the shelf life of the test. Records related to reports of corrections or removals must be maintained for at least two years beyond the shelf life of the test. Complaint files must be maintained for the longer of shelf life or two years from release and distribution of the test.
Stage 2 (2 years after publication): Compliance with registration and listing, labeling, and investigation device exemption requirements
The FDA seeks to obtain registration and listing information to give it a better understanding of the universe of LDTs and to facilitate premarket review of LDTs in the future. Registration and listing are largely administrative in nature with a requirement to provide basic identifying information. Labeling requirements for tests include both the label (including unique device identification to aid in tracking product) and a package insert that describes, among other things, the test method and the data upon which the specific performance characteristics are based. The FDA recognizes that guidance and additional resources on labeling requirements for LDTs would be helpful for laboratories, and it intends to issue targeted guidance for labeling requirements before Stage 2 of the phase-out period.
Stage 3 (3 years after publication): Compliance with quality system requirements
For what the FDA considers “traditional” LDTs (“designed, manufactured, and used within a single laboratory that is certified under [CLIA] and meets the regulatory requirements under CLIA to perform high complexity testing”), these requirements are limited to design controls, purchasing controls, acceptance activities, correction and preventive actions, and records. These are in line with the new Quality Management System Regulation (QMSR), which will be effective February 2, 2026. The QMSR is an update to the existing Quality System Regulation (QSR), which has provisions related to these topics.
The FDA notes that conformity with quality system requirements is a prerequisite to approval of a premarket approval (PMA) application, but anyone subject to quality system requirements may petition for an exemption or variance from any quality system requirement.
Stage 4 (3 ½ years after publication): Submission of PMA application for high-risk (Class III) tests
An LDT for which a PMA submission has been made by the beginning of Stage 4 may continue to be offered while the application is under review. If a PMA submission has not been made by this time, the test may not be offered until the offeror receives authorization from the FDA to market the test.
Stage 5 (4 years after publication): Submission of premarket notification (510(k)) and de novo submissions for low- and moderate-risk tests
An LDT for which a 510(k) or de novo submission has been made may continue to be offered while the submission is under review. If a 510(k) or de novo submission has not been made by this time, the test may not be offered until the offeror receives authorization from the FDA to market the test.
The FDA maintains that “the phaseout policy does not in any way alter the fact that it is illegal to offer IVDs without complying with applicable requirements. Regardless of the phaseout timeline and enforcement discretion policies for certain IVDs …, FDA retains discretion to pursue enforcement action for violations of the [Federal Food, Drug, and Cosmetic Act] at any time, and intends to do so when appropriate.” Thus, laboratories offering LDTs are still subject to the FDA enforcement action, should the agency decide such action is warranted.
Carveouts and Enforcement Discretion for Certain Categories of LDTs
Certain LDTs will remain subject to general enforcement discretion for compliance with any medical device regulations, while others will be subject to some aspects of medical device regulation but not others.
Enforcement discretion for all medical device regulations
A few types of LDTs will remain subject to the FDA’s enforcement discretion for any medical device regulations:
- “1976-type LDTs,” characterized by manual techniques performed by laboratory personnel, use of components legally marketed for clinical use, and performance within a single CLIA-certified high-complexity laboratory.
- HLA tests performed within a single CLIA-certified high-complexity histocompatibility laboratory when used in connection with organ, stem cell, and tissue transplantation to perform HLA allele typing.
- LDTs intended solely for forensic (law enforcement) purposes.
- LDTs performed within Department of Defense or Veterans Health Administration facilities.
LDTs approved by CLEP
The FDA does not intend to enforce premarket review requirements for LDTs that are approved by New York State CLEP, but the FDA intends to phase out enforcement discretion after one year for MDR requirements, correction and removal reporting, and complaint files; after two years for registration and listing and labeling requirements; and after three years for quality system requirements. This policy applies only to the CLEP-approved version of the LDT. It would apply whether a patient specimen comes from New York State or elsewhere. The enforcement discretion is not only for LDTs that are CLEP-approved as of the issuance of the final rule but also will apply both to current CLEP-approved LDTs and to LDTs approved by CLEP in the future.
The FDA believes that CLEP’s approval process “help[s] reduce the risk of harm from inaccurate and unreliable LDTs.” The FDA’s enforcement discretion policy will apply once LDTs have received full and conditional CLEP approval. High-risk LDTs require full technical review and approval before testing on specimens. Moderate-risk LDTs require full technical review and may be granted conditional approval if a laboratory holds a permit in the appropriate category.
The FDA said:
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Exercising enforcement discretion with respect to the premarket review requirements for LDTs approved by NYS CLEP will facilitate more efficient use of FDA resources. The resources that FDA would otherwise spend on premarket review of such LDTs can instead be focused on premarket review of other IVDs offered as LDTs and enforcement of other applicable requirements. … With respect to concerns regarding potentially overwhelming NYS CLEP, the likelihood of this result is unclear. … Should experience with this policy indicate that changes are warranted, FDA would consider appropriate policy changes through guidance in accordance with good guidance practices. |
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LDTs for unmet needs within a health care system
The FDA intends to exercise enforcement discretion and generally not enforce premarket review and most of the QSR for LDTs for unmet needs offered within a health care system. Examples of LDTs for unmet needs are:
- An LDT for a disease or condition there is no FDA-authorized test for.
- An LDT to accommodate an alternative specimen type when the specimen type required for an FDA-authorized test is not, and cannot be made, available.
- An LDT for use on pediatric patients when FDA-authorized tests are indicated for use on adults only.
- An LDT that generates results in a significantly shorter period (e.g., hours versus days) than an FDA-authorized test with the same indications when the shorter time period is critical for clinical decision-making.
- An LDT for the same indication as an FDA-authorized test that is offered only in another health care system that is not accessible to the patient and the developing laboratory will not make the test available outside its system.
- An LDT for an emerging pathogen for which there is no FDA-authorized test and for which the FDA has not identified an emergent situation.
The FDA does not intend for this policy “to serve as an alternative ‘pathway’ to market for LDTs for unmet needs,” and it intends to issue additional guidance on this enforcement discretion policy.
The FDA sought input in the proposed rule on whether it should have a different enforcement policy for LDTs offered by academic medical center (AMC) laboratories. While some LDTs offered by AMCs likely are encompassed within the policy of enforcement discretion for LDTs for unmet needs within health care systems, the final policy is both broader and narrower than an AMC-specific policy.
It is broader because it applies to LDTs that are ordered by a health care practitioner or on the staff or with credentials and privileges at a facility owned and operated by the same health care system performing the LDT. This gives the FDA “greater confidence that ordering physicians will communicate any questions about LDTs or concerns regarding the safety and effectiveness of the LDT … to a laboratory given the built-in communication mechanisms present.” It is narrower because it applies only to those LDTs for an unmet need rather than any LDT offered by an AMC for its patients.
LDTs first offered and marketed before the final rule
The FDA intends to exercise enforcement discretion and generally not enforce premarket review and quality system requirements (except for record-keeping requirements under 21 C.F.R. Part 820) for “currently marketed IVDs offered as LDTs”1 that were first marketed before this rule was issued as long as they are not modified following the issuance of the final rule or are modified only in certain limited ways. For these tests, the FDA intends to phase out enforcement discretion after one year for MDR requirements, correction and removal reporting, and complaint files, and after two years for registration and listing and labeling requirements.
Whereas LDTs under the CLEP enforcement discretion policy will still be subject to quality system requirements under 21 C.F.R. Part 820, currently marketed LDTs under this policy will not have to comply with them (except for records requirements for activities that occur after the final rule is issued). This is because the FDA has concluded that an expectation of compliance with premarket review and quality system requirements may prompt many laboratories to stop offering tests, given the costs. The FDA determined that compliance with CLEP’s clinical laboratory standards generally could satisfy most subparts of the quality system requirements, and it does not anticipate significant additional burden on clients with quality system requirements for laboratories offering CLEP-approved LDTs.
The FDA intends to take “targeted steps” to address problematic LDTs. It will request that laboratories offering these tests submit labeling to the FDA, including performance information and a summary of supporting validation to “help FDA more closely monitor currently marketed IVDs offered as LDTs and identify those that may lack analytical validity, clinical validity, or safety. … FDA also intends to look closely at claims of superior performance and whether those claims are adequately substantiated.” It will enforce records requirements, which it says will enable it to understand the validation bases and processes underlying the LDTs. It also expects that other laboratories will alert the FDA about potential problems with competitors’ LDTs, which will help direct the FDA’s attention to problematic tests.
Changes to Existing LDTs and IVDs
The FDA intends to exercise enforcement discretion when a currently marketed LDT is changed in certain ways. The agency recognizes that a laboratory might make a change to integrate a test into its overall operations, accommodate storage conditions, or address supply shortages. However, the FDA expects compliance with premarket review and quality system requirements for currently marketed LDTs when a laboratory’s modifications: (1) change the indications for use of the test; (2) alter the operating principle of the test (e.g., changes in critical reaction components); (3) include significantly different technology (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, a change from manual to automated procedures); or (4) adversely change the performance or safety specifications of the test. Such a test would no longer be subject to the FDA’s exercise of enforcement discretion for premarket review and QSR.
The FDA does not intend to enforce premarket review requirements for certain laboratory changes to another manufacturer’s 510(k)-cleared or de novo authorized IVD (following design controls and other quality system requirements) in a manner that could not significantly affect the safety and effectiveness of the test and does not constitute a major change or modification in intended use, and when the modified test is performed only in the laboratory making the modification.2 However, a laboratory may not alter an IVD with a PMA without premarket review by the agency.
It is possible to obtain an FDA IVD approval that includes a predetermined change control plan (PCCP). The purpose of a PCCP is to allow changes to the test without a new premarket review. One reason to consider a PCCP is to accommodate artificial intelligence and machine learning in the tests—as the technology changes, the test can change accordingly. Currently, a PCCP is not available outside the context of the FDA premarket review.
Conclusion
Unless Congress steps in or the rule is modified or enjoined by the courts, regulatory requirements will begin for many tests very soon. Much of the diagnostic testing industry has not previously complied with the FDA requirements for medical device reporting, corrections and removals, and complaint files. It will take time to establish the systems required to comply with these and other regulatory provisions. Laboratories should consider starting to review their operations and establishing FDA-compliant systems as soon as possible to ensure they are compliant as the existing enforcement discretion is phased out.
2 The types of changes for which the FDA would expect a premarket submission for a modified 510(k) or de novo authorized test are in 21 C.F.R. § 807.81(a)(3) and in “Deciding When to Submit a 510(k) for a Change to an Existing Device.”
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