For readers outside of the U.S., this content can be used as a case study resource.
Understanding the regulatory environment is critical for the successful creation and launch of diagnostic tests—both in-vitro diagnostics (IVDs) and laboratory developed tests (LDTs). The latest educational paper published by the Arizona State University College of Health Solutions describes the regulatory landscape for laboratories establishing an LDT in the U.S., and how to navigate requirements set forth by the Food and Drug Administration (FDA) and Centers for Medicare & Medicaid Services (CMS). Let’s take a closer look at the key takeaways from this paper.
How does the FDA distinguish between IVDs and LDTs?
Laboratories that design and implement diagnostic tests must first understand how the FDA distinguishes between IVDs and LDTs (Table 1). FDA regulation of IVDs and LDTs has fueled an ongoing, two-decade debate. IVD tests manufactured for use in multiple laboratories, including clinical assays, are subject to FDA regulation such as premarket notification, approval or clearance. On the other hand, LDTs, based on in-house protocols and used at a single site, are exempt from such oversight.
Table 1. Differences between IVD tests registered with the U.S. FDA and LDTs.
|IVD test with FDA approval||LDT|
|Developed for sale to diagnostic laboratories, health clinics, or consumers||Developed by individual laboratories; not transferred, licensed, or sold|
|Standardized instrument qualification procedures and training required||Instrument qualification and training requirements established by individual laboratories|
|Must be pre-validated with a data analysis and bioinformatics report||Often developed in-house by necessity—no standard assay available|
|Must be clinically validated||Must be clinically verified and can be implemented quickly for emergency use*|
*Must comply with the Clinical Laboratory Improvement Amendments (CLIA) of the U.S. Centers for Medicare and Medicaid Services.
What does the FDA say about RUOs, IUOs, and EUAs?It’s important to note that the FDA permits use of non-approved assays for research use only (RUO) or investigational use only (IUO) if they are not part of any clinical diagnostic procedures. It is illegal to make a clinical diagnosis with RUO or IUO tests because they lack comprehensive performance characterization, quality system conformity and cGMP manufacturing compliance. During a declared public health emergency, the FDA may grant Emergency Use Authorization (EUA) for unapproved medical products (including diagnostic tests). EUAs compress the development time (validation and clinical testing) required by manufacturers to provide comprehensive evidence of safety and effectiveness, compared to conventional approval. Following the EUA path is risky, and so it’s necessary to have a plan in place for market approval when the health emergency is over.How are LDTs regulated at clinical laboratories?While the FDA maintains authority over manufacturers in a device-centric manner, CMS uses a process-centric focus towards laboratories where the tests are performed. Unlike the FDA, the Clinical Laboratory Improvement Amendments (CLIA) program through CMS focuses on laboratory quality and competence, rather than the assays themselves. Any facility that performs diagnostic tests on human specimens must obtain the appropriate CLIA certificate from CMS. Analytical validation studies are required at each location to ensure assays perform as intended. CLIA-certified clinical laboratories must obtain certification for each type of assay they perform, which is assigned a complexity level by the FDA. By definition, LDTs are highly complex and must meet the most stringent criteria.Arizona State University College of Health Solutions is dedicated to translating scientific health research and discovery into practical interventions. Be sure to read ASU’s educational paper for more information on regulatory guidance for laboratories that design and implement tests for clinical use.In case you missed it, check out these related and informative resources:
- An introduction to diagnostic testing in laboratories
- Preparing for and implementing a laboratory-developed test
- Reimbursement for laboratory-developed and in vitro diagnostic tests
- The Simple, Sensible, Salient & Still Spell-Binding Seven Questions About Laboratory-Developed Tests
- Challenges of Establishing Laboratory-Developed Tests
|FDA||United States Food and Drug Administration||FDA has oversight of biomedical products sold across state lines in the USA.|
|IVD||in vitro Diagnostic||Diagnostic tests must be approved as a medical device by FDA if it is manufactured for use in multiple laboratories.|
|LDT||Laboratory-developed test||LDTs are based on in-house protocols, and are exempt from premarket review and manufacturing oversight from FDA, as long as the test is manufactured and used at a single site.|
|RUO||Research Use Only||A non-IVD product in the laboratory research phase of development that cannot be used in diagnostic procedures.|
|IUO||Investigational Use Only||A product being shipped or delivered for product testing and process evaluation, but not yet commercialized.|
|EUA||Emergency Use Authorization||A type of FDA authorization for unapproved medical products, including IVDs, during a declared public health emergency.|
|CMS||Centers for Medicare & Medicaid Services||A government organization that provides health coverage. Clinical labs must obtain a certificate of compliance in order to bill the CMS for their services.|
|CLIA||Clinical Laboratory Improvement Amendments||The CMS regulates all laboratory testing (except research) performed on humans in the U.S. through the Clinical Laboratory Improvement Amendments (CLIA).|
- 21 CFR 809.3
- 42 CFR Part 493