The Discussion Paper on Laboratory Developed Tests, released by the Food and Drug Administration (FDA), describes a possible approach to expanding FDA oversight of laboratory developed tests (LDTs). An LDT is a type of in vitro diagnostic (IVD). Specifically, it is a clinical test that is designed, manufactured, and used in a single CLIA-certified laboratory, as opposed to a commercially distributed IVD, which is manufactured and sold for use by many laboratories. The FDA has the authority to regulate all IVDs as devices, but has generally limited its oversight on LDTs, exercising enforcement discretion. However, as LDTs have grown in complexity, number, and reach, the FDA is considering expanding its LDT oversight.
The LDT discussion paper provides an overview of extensive comments received from clinical stakeholders, patients, government agencies, and Congress in response to an LDT draft guidance policy issued by the FDA in 2014. Like the draft guidance, the discussion paper proposes a risk-based approach that the FDA might take on LDT oversight. However, in response to stakeholder feedback, the discussion paper significantly scaled back the scope of the draft guidance's proposed oversight.
Key proposals in the FDA’s 2017 discussion paper include:
- Focused Oversight: The FDA would focus oversight on new and significantly modified LDTs of high or moderate risk. Risk would be assessed based on the potential consequences for patients if the LDT were to fail. Previously marketed LDTs would be largely exempt from oversight, although the FDA would retain enforcement discretion for all LDTs.
- Risk-Based, Phased-in Oversight: the FDA proposes a four year phased-in approach for premarket review of new and significantly modified LDTs, as opposed to the nine years the 2014 draft guidance. The FDA suggests the following phased-in timeline:
- Year 1: Serious adverse event and malfunction reporting for all LDTs except: traditional LDTs, LDTs intended solely for public health surveillance, certain stem cell/tissue/organ transplantation LDTs, and LDTs intended solely for forensic use.
- Year 2: Premarket review for new/modified LDTs with the same intended use as an in vitro diagnostic (IVD) approved under a premarket approval (i.e., tests that have already been identified as high-risk by the FDA).
- Year 3: Premarket review for new/modified LDTs with the same intended use as a Class II device type subject to 510(k) clearance (i.e., tests that have already been identified as moderate risk by the FDA).
- Year 4: Premarket review for new/modified LDTs that do not fall into the above categories.
- Evidence Standards: the FDA asserts that its clinical and analytical validation and evidence requirements would complement the Centers for Medicare and Medicaid Services (CMS)’s requirements for clinical oversight. “CMS’s oversight through the Clinical Laboratory Improvement Amendments (CLIA) program is designed to confirm that a lab assesses analytical validity, but does not confirm whether it had results from an analytical validity assessment that were sufficient to support the claimed intended use of the test.” However, “laboratories that already conduct proper validation should not experience new costs for validating their test to support marketing authorization.” This document shows how CLIA enforces regulatory oversight over all LDTs.
- Third-party Review: the FDA proposes that eligible LDTs could participate in its third-party premarket review program.
- Clinical Collaboratives: the FDA proposes to expand its collaborative work with various stakeholders to develop standards for analytical and clinical validity of LDTs.
- Transparency: the FDA plans to make analytical and clinical validity reviews of all LDTs publicly available so that the public can understand the test performance and results.
- Modifications: the FDA suggests that laboratories include change protocols (plans for anticipated postmarket changes to LDTs) in their premarket submissions. Once approved, such change protocol would allow the relevant test modifications to be implemented without the need for a new premarket submission.
- CMS/CLIA Quality System (QS) Requirements: the FDA plans to supplement CLIA QS requirements for LDTs with three requirements:
- Design controls (21 CFR 820.30)
- Acceptance activities (i.e., mechanisms to ensure product meets specifications throughout testing) (21 CFR 820.80)
- Procedures for corrective and preventive actions (CAPAs) (21 CFR 820.100).
- Postmarket Surveillance: the FDA proposes postmarket surveillance for LDTs to monitor postmarket modifications and serious adverse events.
The paper does not address conventional IVD kits, which are submitted to more stringent oversight.
The LDT discussion paper is not enforceable, does not represent the formal position of the FDA, and is not a substitute for a final FDA guidance. It synthesizes the regulatory dialogue that the FDA and stakeholders have had since 2010 and outlines future regulatory possibilities for LDTs.
Extensive stakeholder feedback on the 2014 draft guidance highlighted the importance of balancing healthcare access to LDTs with a reasonable assurance that such tests are analytically and clinically valid. The paper is meant to “advance the public discussion” by providing “a possible approach to spur further dialogue.”