The U.S. Food and Drug Administration (FDA) Laboratory Developed Tests (LDTs) final has been released titled, “Medical Devices: Laboratory Developed Tests. The FDA LDTs final rule will take effect on July 5th according to a April 29th news release from the agency. The regulation 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. Along with this amendment, the FDA issued a policy to phase out, over the course of four years, its general enforcement discretion approach for LDTs. The agency also published targeted enforcement discretion policies for certain categories of IVDs manufactured by laboratories.”
America’s Blood Centers previously provided comments to FDA ahead of the LDTs final rule be issued. The ABC comments advocate that general enforcement discretion should be applied to all blood centers’ LDTs. Though the agency did not fully agree with all of ABC’s proposed recommendations, the FDA LDTs final rule does address some of the concerns raised by community blood centers with provisions outlining instances where enforcement discretion is allowed.
Specifically, FDA is grandfathering IVDs offered as LDTs under the final rule. The agency explained that, “FDA intends to exercise enforcement discretion…for currently marketed IVDs offered as LDTs that were first marketed prior to the date of issuance of this rule and that are not modified, or that are modified in certain limited ways.” However, FDA stated that it, “expects compliance with premarket review and quality system (QS) requirements for currently marketed IVDs offered as LDTs when a laboratory’s modifications:
- change the indications for use of the IVD;
- alter the operating principle of the IVD (e.g., changes in critical reaction components);
- 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
- adversely change the performance or safety specifications of the IVD.”
Furthermore in the FDA LDTs final rule, the agency specifies that it intends to address IVDs offered as LDT’s that are “problematic” by using available mechanisms to target manufacturers of inaccurate or poorly validated IVDs offered as LDTs. Such mechanisms include requesting labs to submit labeling to help FDA monitor these tests, “and identify those that may lack analytical validity, clinical validity, or safety.” Additionally, FDA will enforce records requirements to, “facilitate FDA’s review of these IVDs during inspections.” Finally, FDA “expects laboratories to comply with applicable requirements other than premarket review and most QS requirements, including Medical Device Report (MDR) requirements, corrections and removals reporting requirements, registration and listing requirements, and labeling requirements.”
The FDA LDTs final rule also noted that the agency will exercise enforcement discretion, “for 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. This policy does not apply to molecular tests used for genotyping RBC antigens.” The agency recognized, as noted in ABC’s comments, that, “non-molecular antisera LDTs within the scope of this policy share certain characteristics with ‘1976-Type LDTs,’ as they use manual techniques performed by laboratory personnel with specialized expertise. For such LDTs, in instances where there is no available alternative to ensure that a patient receives a compatible transfusion, FDA has determined it is in the best interest of public health to adopt this enforcement discretion policy.” The policy applies to premarket review and QS requirements. FDA will still expect compliance with records requirements for non-molecular antisera LDTs.
The FDA LDTs final rule also explains that FDA plans to exercise enforcement discretion and, “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…in a manner that could not significantly affect the safety or effectiveness of the test and does not constitute a major change or modification in intended use, and where the modified test is performed only in the laboratory making the modification.” The FDA stated that its resources to review such changes could be better spent elsewhere, taking into account the low risks associated with these minor changes.
FDA also finalized its proposal to continue to apply the current general enforcement discretion approach to 1976-Type LDTs, and provided specific examples of tests that would be included under this enforcement discretion policy, including: “adsorbing warm-reactive autoantibodies using allogeneic or autologous red blood cells, the Donath-Landsteiner test for aiding in the diagnosis of paroxysmal cold hemoglobinuria, Ham’s test to aid in the diagnosis of paroxysmal nocturnal hemoglobinuria, tests to evaluate drug-induced hemolysis or interference in compatibility testing, monocyte-monolayer test to assess possible clinical significance of RBC alloantibodies, modified Kleihauer-Betke, and SDa antigen neutralization with urine.”
The agency has published several resources regarding the FDA LDTs final rule on its website including FAQs. FDA is hosting a May 14th webinar to go over the final rule. The webinar will:
- “[p]rovide an overview of the final rule amending the FDA’s regulations to make it explicit that in vitro diagnostic products (IVDs) are devices under the Federal Food, Drug, and Cosmetic Act including when the manufacturer of the IVD is a laboratory; and
- [d]escribe the phaseout of the FDA’s general enforcement discretion approach to laboratory developed tests (LDTs).”
ABC also previously submitted comments in response to the request for information (RFI) for reforms to diagnostics regulation from Sen. Bill Cassidy, MD (R-La.), ranking member of the Senate Committee on Health, Education, Labor, and Pensions that advocated for Congress to allow a blood center LDTs exemption in LDTs regulations. he blood center LDTs exemption comment letter from ABC urged that an exemption for laboratory developed tests (LDTs) used by blood centers should exist to exclude such LDTs, “from any reforms to diagnostics regulation since these tests do not fall within the categories of laboratory services and diagnostic products that Congress and FDA are looking to regulate.”
Questions for potential discussion on the webinar can be emailed to the agency by May 7th. ABC will continue to provide updates on its advocacy efforts as they become available.