Tuesday, November 25, 2025

CDX USA vs EU and CHANGES

 

CDX USA vs EU and CHANGES

In practical terms, this move means that for a big slice of oncology CDx, the U.S. pathway is about to become materially lighter than the EU IVDR pathway, even though both systems still ask for broadly similar science.

Below is a sponsor-eye view: what you actually have to do, who you talk to, how long it tends to take, and how much pain is involved — “recent state” vs “future state”.

1. Recent reality (last few years): both sides are punishing, but in different ways

United States – CDx as full PMA

Until this reclassification, an oncology NAAT/NGS CDx tied to a drug almost always meant Class III + PMA:

  • Core submission: a full PMA, often co-developed with the drug. This bundles:

    • Large clinical bridging datasets aligning the assay readout with drug benefit (response or PFS/OS) in a registration trial or a carefully curated external dataset. FDA Access Data+1

    • Full analytical performance (LoD, precision, reproducibility, interference, etc.).

    • Software validation, bioinformatics pipeline verification, manufacturing and QC detail.

  • FDA interactions: multiple pre-subs, then a PMA review with panel risk for novel mechanisms, plus supplements for label changes, indications, biomarkers, platforms, etc.

  • Time and money (order-of-magnitude, not a formal rule):

    • User fees: FY 2025 standard PMA fee is about $541k, versus about $24k for a 510(k). Federal Register+1

    • Timelines: statutory PMA review clock is 180 days, but with at least one major “AI” cycle, the practical window is often 12–24 months from first serious interaction to approval for a complex oncology CDx.

    • Internal cost: large multi-year teams; it’s credible when sponsors complain of “multi-year, multi-tens-of-millions” PMA CDx programs.

In other words, U.S. CDx PMA has been the archetypal “four-year, 100,000-page” ordeal.

European Union – IVDR CDx: Notified Body plus EMA

With IVDR fully in force for new CDx:

  • Risk class is fixed at Class C for all CDx. EFPIA

  • What the sponsor actually does:

    • Builds full technical documentation (performance evaluation = scientific validity + analytical + clinical performance) and full QMS dossier for a Notified Body (NB). EFPIA+1

    • The NB must seek a scientific opinion from EMA or a national competent authority on the suitability of the CDx for the medicinal product (Art. 48(3)–(4) IVDR). European Medicines Agency (EMA)+1

  • Consultation mechanics:

    • EMA consultation is officially 60 days, extendable to 120 days, with no clock stops once the consultation has begun. TÜV SÜD

    • In practice, the total NB + EMA cycle is heavily impacted by NB capacity; sponsors widely report 12–24+ month journeys, especially during the transition bulge for IVDR. Lindus Health+1

  • Costs:

    • EMA charges a specific CDx consultation fee, and NBs charge substantial fees for QMS and technical doc review. European Medicines Agency (EMA)+1

    • MedTech Europe’s 2025 burden analysis suggests that re-certification of one IVD QMS certificate averages ~€168k in NB fees alone, and technical doc reviews for Class C devices are in the tens-of-thousands per product, not counting internal costs. MedTech Europe

So under IVDR, Europe has moved from relatively light IVDD treatment to a system that is robustly heavy for CDx: NB + EMA, structured performance evaluation, and expensive, slow capacity-constrained conformity assessment.

Practical comparison recently (pre-reclassification)

For a sponsor with a new oncology CDx tied to a novel drug:

  • FDA PMA was usually the single heaviest, deepest submission – especially for first-in-class indications.

  • IVDR CDx was no longer “easy Europe”: similar demands on evidence, plus a more bureaucratic route (device authorities and EMA; NB scarcity; separate fees).

A reasonable practical view the last couple of years has been:

“Both FDA and IVDR are painful for CDx. The U.S. PMA is more intense document-by-document; IVDR is more structurally clunky and slower because of NB/EMA logistics.”

2. Future state for oncology NAAT/NGS CDx under the new FDA rule

The proposed FDA rule says: for “Nucleic Acid-Based Test Systems for Use with a Corresponding Approved Oncology Therapeutic Product”, FDA will:

  • Create a new Class II regulation with special controls, and

  • Allow future devices of this type to follow the 510(k) pathway instead of PMA. Federal Register+1

What changes in practice for a sponsor?

(a) Type of submission and depth of fight

  • Instead of a bespoke PMA, the sponsor builds a 510(k) referencing a well-defined device type and special controls:

    • Robust analytical validation (on par with what PMA CDx already showed).

    • Clinical support can lean heavily on:

      • Prior PMA CDx in the same biomarker/drug space, and/or

      • Literature and drug-side data, as long as the sponsor shows the test is “equivalent enough” analytically to an established assay.

  • FDA’s debate space shifts from “Is this entire benefit–risk story acceptable?” to “Have you demonstrated substantial equivalence under these special controls?” – typically fewer cycles and narrower arguments.

(b) Timelines and predictability

  • 510(k) statutory review goal is 90 days; oncology CDx will still have intense review, but under a framework that’s built for shorter, more standardized cycles than PMA.

  • There will still be tough questions on cut-offs, bioinformatics, and labeling, but they’re asked against a template; they are less likely to become multi-year open-ended negotiations.

(c) Fees and internal cost

  • User fee drops from PMA-scale (about $541k) to 510(k)-scale (about $24k in FY 2025). Federal Register+1

  • Internal sponsor costs should also compress because:

    • You no longer design a full PMA program every time.

    • You can reuse well-understood validation architectures and study designs that map directly to the codified special controls.

(d) Change control

  • Changes that previously demanded PMA supplements (platform changes, panel extensions, cut-off refinements) may, in many cases, be handled via:

    • 510(k)s for significant changes, or

    • Letter-to-file / internal documentation for smaller changes that don’t affect intended use or core performance claims.

  • By contrast, IVDR’s current guidance keeps many CDx changes inside formal NB + EMA re-review tracks, with new certificate supplements and defined triggers. Pure Global+1

3. Practical head-to-head: “What would a sponsor feel?”

Scenario: Follow-on EGFR or MSI NAAT CDx for oncology

In the U.S. – after reclassification:

  • Sponsor prepares:

    • Full analytical package per special controls.

    • Focused clinical comparability to an existing FDA-accepted assay / prior PMA CDx.

    • 510(k) dossier structured directly against the new regulation’s special controls.

  • Pays a 510(k) fee, targets a ~90-day review, maybe one substantial AI cycle.

  • Negotiates labeling within an existing labeling paradigm (“for selection of patients for X”).

In the EU – under IVDR:

  • Sponsor still:

    • Builds full Class C technical doc.

    • undergoes NB review, plus:

    • NB triggers EMA or NCA consultation to confirm suitability with the medicinal product.

  • Faces:

    • EMA timeline of up to 60–120 days once consultation starts TÜV SÜD

    • NB queues and iteration that often push overall duration well past a year.

  • Pays:

Net practical comparison, future state:

  • For mature oncology CDx technologies in the FDA’s new category, the U.S. will now be the faster, cheaper, and more standardized route for new entrants and follow-ons.

  • Europe remains structurally “high friction” for CDx under IVDR: NB + EMA, capacity constraints, and relatively rigid change-control signals.

4. Bottom line: what happens to “harmonization” in the real world?

  • Previously (PMA vs IVDR CDx), both sides were heavy; one could argue the systems were practically comparable in overall burden, albeit in very different ways.

  • After this FDA reclassification for oncology NAAT/NGS CDx, the situation changes:

    • Scientific expectations remain broadly aligned (good analytical and clinical validation; strong drug–test linkage).

    • Operational burden diverges:

      • U.S. becomes a Class II / 510(k) regime with codified special controls, shorter timelines, lower fees, and more flexible change management for this family of CDx. Federal Register+1

      • EU CDx under IVDR stays Class C with NB + EMA consultation, higher external fees, and structurally slower certification and recertification. EFPIA+2TÜV SÜD+2

For a policy-savvy reader, the practical takeaway is:

In scientific terms, FDA and IVDR are speaking the same language about what CDx should prove. In operational terms, this FDA move makes the U.S. pathway materially lighter than Europe’s for oncology NAAT/NGS CDx — effectively de-harmonizing the workload, even as the evidentiary ideals converge.

You said:
OK that's great. Can you also summarize this more concisely which makes it a little easier for the reader to absorb in one reading. Keep key facts but more in paragraph format and not so long as you just did. i will use both, in different places.
ChatGPT said:

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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