Significance of Issuing a Discussion Paper
The LDT discussion paper is not enforceable and does not represent the formal position of the FDA, nor does it constitute a final version of the draft guidance. Rather, issuing the paper allows FDA to publicize, gauge and build support for its proposals on a controversial topic while avoiding the requirement that FDA provide notice to Congress 60 days before issuing any final or draft guidance on LDTs.
Although FDA’s issuance of a discussion paper on LDTs is unexpected, the move is not unprecedented. For example, FDA first vetted its potential policy approach to next generation sequencing (NGS) with a preliminary discussion paper in 2014. FDA then published additional discussion papers and held public workshops to gather stakeholder input before releasing two draft guidance documents in July 2016. The proposals announced in the NGS draft guidance documents tracked certain key provisions that were advanced in the discussion papers.
Highlights of FDA’s Proposal
FDA’s proposal for regulatory oversight over LDTs reflects a risk-based, phased-in approach but backs away from many provisions of the draft guidance.
Key provisions in FDA’s proposal include:
- Prospective oversight – The proposed framework focuses on new and significantly modified high and moderate-risk products and exempts “grandfathered” products from most FDA regulatory controls.
- Grandfathered products – The prospective oversight approach means that products already on the market would not have to comply with FDA regulatory requirements, including premarket review, Quality System Regulation (QSR) or registration and listing requirements (although FDA would retain the ability to enforce these requirements under certain circumstances). “Grandfathered” products would, however, be subject to serious adverse event and malfunction reporting.
- Traditional, low-risk and other LDTs – Certain new or significantly modified LDTs — including low-risk LDTs and LDTs for rare diseases — also would be subject to serious adverse event and malfunction reporting, but would not be subject to other regulatory requirements.
- Premarket evidence – FDA would review clinical and analytical data in premarket submissions and expand its third-party premarket review program.
- LDT modifications – FDA would have limited pre-market review of changes to cleared LDTs.
- Quality System requirements – FDA would leverage Clinical Laboratory Improvement Amendments (CLIA) certification requirements and only focus on three Quality System requirements: (1) design controls (21 C.F.R. § 820.30); (2) acceptance activities (i.e., mechanisms to ensure product meets specifications throughout testing) (21 C.F.R. § 820.80); and (3) procedures for corrective and preventive actions (CAPAs) (21 C.F.R. § 820.100).
- Conventional IVD kits – The paper addresses only LDTs that are designed, manufactured and used in a CLIA-certified lab and does not apply to conventional IVD kits, which would require premarket review.
Notable differences from the proposal outlined in the 2014 draft guidance:
- Instead of being phased in, currently marketed high and moderate-risk LDTs would not be subject to premarket review unless necessary to protect public health.
- The phased-in review of new and significantly modified LDTs could be accomplished over a shorter period (four years rather than the nine years proposed in the draft guidance) because of the high number of grandfathered products, and would begin with the tests that could pose the greatest risk to patients in the event of a false result.
- FDA would take measures to expedite the premarket review process by (1) collaborating with healthcare professionals, industry and other stakeholder groups to leverage accepted reference and review standards for analytical validity; (2) expanding its third-party premarket review program to include LDTs that are eligible under existing programs (such as New York State’s Clinical Laboratory Evaluation Program and programs run by CLIA-accrediting organizations); and (3) permitting clinical validity to be established by sources, such as literature and “well-curated” databases, that meet the valid scientific evidence standard.
- The term “traditional” LDTs – which under the discussion paper, as according to the draft guidance, would be grandfathered – is defined differently than it was in the 2014 draft guidance to mean “tests that use components that are legally marketed for clinical use and whose output is the result of manual interpretation by a qualified laboratory professional,” which excludes tests that use automated instrumentation or software to interpret the results. The intent of the new definition seems to be to exclude tests that use research use only (RUO) components as well as multi-analyte algorithm-based assays (MAAA) tests from grandfathering.
- The discussion paper proposal broadened the category of LDTs for unmet needs so that it is no longer limited to tests that are manufactured and used by a healthcare system laboratory for patients treated within that facility’s healthcare system. Rather than exercising enforcement discretion for premarket review and quality systems requirements, the new approach would require LDTs that address unmet needs to send a “premarket submission” to FDA or to a third-party reviewer within 90 days after entering the market, and the LDT would be permitted to remain on the market during the review.
If history serves as a guide, FDA likely will solicit further stakeholder participation regarding the new proposals outlined in the discussion paper, possibly by holding a public workshop. Industry should carefully consider the proposals made in the discussion paper and be prepared to provide meaningful input.
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