Academy of Diagnostics & Laboratory Medicine - Scientific Short

Laboratory developed tests: How will FDA regulation affect us?

Patricia M. Jones

Laboratory developed tests (LDTs) used to be referred to as home-brew tests or in-house tests. These are assays that are developed in one’s own laboratory, and they include a wide range of tests. LDTs can be as simple as colorimetric tests like the old Apt-Downey test for fetal hemoglobin, all the way up to very sophisticated molecular tests using techniques like the polymerase chain reaction (PCR) tests for viral DNA or genetic polymorphisms for drug metabolism. They also include most of the tests currently being used for newborn screening and the confirmatory diagnosis of inborn errors of metabolism, as well as all the immunohistochemical markers used in the histological diagnosis of many diseases.

CLIA has been regulating LDTs since CLIA’s inception. 42 CFR 493.1253(2) clearly states under what conditions a LDT must be established and validated. The list of validation criteria is extensive and thorough, and includes determining method accuracy, precision, analytical sensitivity, analytical specificity, reportable range, reference intervals and any other specifications necessary for a specific methodology. Along with CLIA, the College of American Pathologists (CAP) has additional requirements for assessing and monitoring quality performance in specific test systems. Laboratories which are accredited by these agencies develop and perform assays that currently meet stringent requirements.

The Food and Drug Administration (FDA) has long maintained the right to regulate LDTs, however until recently they have chosen to exercise ‘discretion’ and have left this to the individual labs and the laboratory regulatory agencies, such as CLIA, CAP and CMS. Due to many emerging factors, the FDA now wishes to take a more active role in regulation of LDTs.The FDA’s concern is twofold: patient safety and appropriate clinical use of LDTs. The FDA appears concerned that the accrediting agencies are focused on test analytical validity, and not the clinical validity of the tests.

The College of American Pathologists (CAP) has proposed a tiered approach to regulating LDTs, based on their level of risk to the patient. Low-risk LDTs would require the lab’s accrediting agency to verify assay validation and that the lab complies with accreditation standards. Moderate-risk LDTs would require approval by the accrediting agency before being offered clinically and high-risk LDTs would require full FDA review.

Currently there is significant disagreement about the FDA’s and the accrediting agencies roles in regulating LDTs. Given that a section of my own lab is composed entirely of LDTs, I am naturally concerned for how this will fall out and wish to be involved in the decisions that are made. How will the FDA go about this regulation? Will all LDTs, no matter how long they have been in existence, be required to fall under this regulation, or will assays be grandfathered? Will the amount of paperwork the FDA requires, and the amount of time they will need to “approve” a new in-house test, cause labs to stop developing in-house tests, or to drop tests that are currently being performed?

And ultimately, if regulation by the FDA is determined to be necessary for appropriate oversight of LDTs, how can we be involved to ensure that the processes are not so onerous that we cannot operate under them? Having recently read “The Immortal Life of Henrietta Lacks”, I am reminded that back in 1966, scientists thought that requiring IRB review would put an end to scientific inquiry and research. Change is hard, but doesn’t have to be a bad thing. As laboratorians, we should be involved in every step of the coming processes to ensure they are reasonable, realistic, and that they don’t stifle innovation or make it impossible for labs to develop and utilize new tests.

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Academy of Diagnostics & Laboratory Medicine Designation

Fellows of the Academy use the designation of FADLM. This designation is equivalent to FACB and FAACC, the previous designations used by fellows of the National Academy of Clinical Biochemistry and AACC Academy. Those groups were rebranded as Academy of Diagnostics & Laboratory Medicine in 2023.