Last year, when FDA was sparring with stakeholders and courts over its LDT regulations, FDA promised to downclassify many types of diagnostics from Class III to Class II. They went radio-silent from April to November, but now, the regulation is in print.
This is big news because it changes the landscape of how hard it is to get an FDA label as a companion diagnostic. It also means that new ranges of tests will qualify for Medicare benefits. NCD 90.2, for NGS testing in cancer, automatically covers NGS tests that are "cleared or approved" as CDx. And sole-source tests (run from one lab) are eligible for ADLT pricing rules if they are "cleared or approved." Now the range of "cleared" tests will be larger.
See an early essay at Linked In by Karin Hughes PhD here.
See the Fed Reg regulation proposal here. Comment in 60 days until January 26, 2026.
The rule runs 14 pages and covers many considerations and details. The regulation for 510K aka Class II CDx will be at 21 CFR 866.6075, as “Nucleic Acid-Based Test Systems for Use with a Corresponding Approved Oncology Therapeutic Product.” Within the 14-page publication, the actual regulation at 21 CFR will be about 680 words long (two full columns of the Federal Register).
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FDA Down-Classifies Key Oncology Companion Diagnostics:A Policy-Level Summary
In a significant regulatory shift, FDA has proposed reclassifying a cluster of oncology companion diagnostics (CDx) and CDx-adjacent molecular tests—from Class III (PMA) to Class II with special controls. The 14-page notice marks FDA’s first broad structural change to CDx oversight in more than a decade and reflects the agency’s conclusion that these technologies are now mature, well-characterized, and manageable within the 510(k) framework.
Rationale for Reclassification
FDA’s justification rests on two main pillars:
1. A Large, Stable PMA Evidence Base
FDA points to 17 prior PMA approvals and a panel-track supplement covering tests such as NGS panels, PCR hotspot assays, MSI/LOH signatures, and gene-specific mutation assays. Across these submissions, the agency notes:
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Highly consistent technology (PCR and NGS platforms with known performance boundaries).
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Longstanding and predictable risk modes.
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No unique or recurring post-market safety events.
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Extensive analytic validation data accumulated over more than a decade.
In effect, FDA signals that this body of PMA experience now functions as the predicate scientific foundation for safe 510(k) benchmarking.
2. Technological Maturity and Standardized Methods
The agency emphasizes that these oncology molecular devices no longer present the novelty or uncertainty that once justified PMA status. Their design, specimen types, analytic characteristics, and error profiles are sufficiently well understood that FDA can now define the controls needed to mitigate risks without PMA-level scrutiny.
The agency also implicitly acknowledges that analytic performance expectations for CDx have converged across platforms, making differentiated regulatory treatment (PMA vs. 510(k)) less scientifically justified than it once appeared.
Special Controls Framework
FDA proposes a structured set of special controls that anchor the new Class II classification. These include:
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Analytic validity requirements: Defined performance characteristics for accuracy, precision, LoD, reportable range, reference materials, and quality system parameters.
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Clinical validity expectations: A requirement that sponsors demonstrate the test’s ability to identify the biomarker for which the associated therapeutic product is indicated.
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Design and labeling requirements: Clear statements on intended use, limitations, specimen types, cutoff justification, and the relationship between biomarker detection and associated therapies.
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Quality system-oriented controls: Ensuring calibration, reagent stability, and software verification meet standards previously demonstrated in PMAs.
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Post-market controls where appropriate, although FDA explicitly states that historical PMA experience shows minimal adverse trends.
Importantly, these special controls are structured such that substantial equivalence to a well-characterized archetype is possible, eliminating the need for clinical trials for each new test if analytic comparability is demonstrated.
FDA’s Regulatory Method: A Retrospective Meta-Analysis of PMAs
The agency’s method is unusually transparent: it explicitly “looks back” across the entire set of oncology CDx PMAs, extracts shared risk profiles, and evaluates the sufficiency of accumulated scientific knowledge. This retrospective analysis provides the risk-benefit justification required under the statute’s reclassification provisions (including the six-year rule for PMA vintage).
In short, FDA is codifying what many regulators have long concluded informally—that these tests behave like a well-bounded technological family, and that PMA is no longer proportionate to risk.
Summary of the Actual Regulatory Text (Final Pages)
In the final codified section, FDA formally:
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Amends the classification regulations to place these oncology CDx molecular assays into Class II.
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Defines the device type as tests intended to detect specified genetic alterations for the purpose of selecting patients for targeted therapies.
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Lists the special controls, which function as binding performance, design, labeling, and verification requirements necessary for reasonable assurance of safety and effectiveness.
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Establishes that future devices in this category will follow the 510(k) pathway, provided they meet the special controls and demonstrate substantial equivalence.
This codified amendment is concise—essentially a legal wrapper around the analytic and risk-based reasoning laid out in the earlier narrative. But its practical impact is substantial: it opens a 510(k) pathway for a major class of oncology molecular diagnostics that, until now, were locked into PMA.
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With this change, how does this future FDA rule and method for CDx compare to the current recently revised European union rule and method for CDx? Would you say this change brings the two regimes into closer alignment, or would you say the alignment WAS close, and now the FDA is pulling away? Asking because of the harmonization thing.
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Here is a more concise, paragraph-style summary that preserves the key policy and practical points.
Concise Practical Comparison: FDA’s New CDx Pathway vs. IVDR
Under the EU IVDR, all companion diagnostics are locked into Class C, requiring a full technical file, Notified Body review, and a mandatory EMA (or national authority) consultation on the drug–test linkage. In practice, this produces long, multi-step reviews often running 12–24 months, driven partly by Notified Body capacity constraints. Costs are substantial: NB technical-file reviews, EMA consultation fees, and heavy internal preparation. Change control also remains strict; many modifications trigger new formal reviews. IVDR has therefore become a high-friction, high-burden system for CDx, even when the underlying assay technology is mature.
Historically, the FDA PMA pathway for oncology CDx was similarly burdensome: sponsors routinely submitted massive analytic and clinical datasets, endured multi-year PMA cycles, and managed ongoing PMA supplement obligations. The process could be exacting and expensive, with user fees in the hundreds of thousands of dollars and multi-year internal program costs.
The new FDA proposal fundamentally changes this equation for nucleic-acid based oncology CDx. After reviewing 17 PMAs and a decade of experience, FDA concludes that these technologies are now well understood, with risks fully characterizable through special controls. As a result, these CDx will move from Class III (PMA) to Class II (510(k)). The required evidence—robust analytical validation and a clear demonstration of clinical relevance—remains rigorous, but the submission is now structured against a defined regulatory template with narrower debates than PMA. User fees fall dramatically, and review timelines align with the 90-day 510(k) process, even if oncology CDx will receive close scrutiny.
Practically, this means that for follow-on EGFR, BRAF, MSI, LOH, or similar oncology NAAT/NGS CDx, the U.S. will become materially faster, cheaper, and more predictable than Europe. The scientific expectations of FDA and IVDR remain broadly aligned—both still require strong analytical and clinical performance, drug-test linkage, and clear labeling—but the operational burden diverges sharply. IVDR continues to function as a high-cost, multi-agency process; FDA is reclassifying mature CDx technology into a streamlined, mid-tier regulatory track.
The net effect is that scientific harmonization persists, but regulatory workload is no longer harmonized. FDA’s move aligns the evidence standards but pulls away from Europe in efficiency, creating a lighter U.S. pathway for many oncology CDx than the IVDR can presently offer.
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See a deep-dive sidebar about EU vs FDA
https://brucedocumentblog.blogspot.com/2025/11/cdx-usa-vs-eu-and-changes.html
