The Question: Are FDA and IVDR Becoming More Aligned—or Less?
FDA vs IVDR companion diagnostics regulation is becoming a critical topic for sponsors developing oncology CDx for global markets. With FDA’s newly published proposal to reclassify many NAAT/NGS-based oncology companion diagnostics into Class II with special controls, the U.S. pathway is shifting in ways that differ sharply from Europe’s IVDR Class C + EMA consultation model.
On paper, both frameworks demand strong analytical and clinical performance, robust quality systems and explicit drug–test linkage. In practice, however, the workload and timelines for sponsors are diverging.
This comparison focuses on what CDx sponsors and their pharma partners will actually feel as they move a test through both systems.
How EU IVDR Regulates Companion Diagnostics Today
Under Regulation (EU) 2017/746 (IVDR), IVDs are classified into Classes A, B, C and D. Companion diagnostics sit squarely in the higher‑risk space:
- CDx are defined in the IVDR as devices essential for the safe and effective use of a corresponding medicinal product (Article 2).
- They are specifically captured by Rule 3 of Annex VIII, which places these devices in Class C (unless they meet even higher‑risk criteria under Rules 1 or 2).
Class C status has direct consequences:
- Notified Body involvement is mandatory: Class C IVDs must undergo third‑party conformity assessment; manufacturers cannot self‑certify.
- EMA or national authority consultation is required for CDx: Article 48(3)–(4) IVDR requires the Notified Body to seek a scientific opinion from the EMA or a national competent authority on the suitability of the CDx for the medicinal product. The opinion considers scientific validity and the analytical and clinical performance of the CDx in relation to the target medicine.
- Consultation timelines add complexity: EMA guidance indicates a nominal assessment time of 60 days, with the possibility of extending by another 60 days and additional time for follow‑up consultations.
- Multiple actors; fragmented responsibilities: EFPIA and MedTech Europe have highlighted that CDx development often involves uncoordinated interactions between EMA (or NCAs), Notified Bodies and device competent authorities, which can delay co‑development and misalign drug and device timelines.
The result is a high‑friction pathway:
- Sponsors must build full technical documentation (performance evaluation, QMS, risk management, labelling) for a Class C IVD.
- A Notified Body performs a detailed technical and QMS review.
- EMA or a national authority then reviews the drug–test linkage.
From a sponsor’s perspective, IVDR CDx compliance is demanding, multi‑step and heavily dependent on Notified Body capacity and cross‑agency coordination.
How FDA Has Historically Regulated Oncology CDx
Under U.S. law, post‑amendment high‑risk IVDs, including oncology companion diagnostics, default to Class III and require Premarket Approval (PMA) unless reclassified.
For over a decade, oncology NAAT/NGS CDx lived in that Class III world:
- FDA approved 35 PMAs and 403 supplements for oncology therapeutic nucleic acid‑based test systems between 2011 and 2025, across product codes OWD, PJG, PQP and SFL.
- Submissions typically combined extensive analytical validation, bridging to drug‑side clinical trials and detailed manufacturing and software documentation.
The PMA pathway is both deep and expensive:
- In FY 2025, the standard user fee for a PMA‑type application is $540,783, while a 510(k) fee is $24,335.
- Review clocks for PMA are longer and more iterative than for 510(k), especially for first‑in‑class CDx.
As long as FDA kept oncology CDx in Class III, sponsors could reasonably say that the U.S. and EU were comparably “heavy”, even if the mechanics (PMA vs NB+EMA) were different.
What Changes Under FDA’s Proposed 21 CFR 866.6075
The new proposal fundamentally changes that balance for nucleic acid‑based oncology test systems indicated for use with an approved oncology therapeutic product:
- FDA would reclassify these devices from Class III (PMA) to Class II (special controls) and route them to 510(k).
- The new device type includes both essential CDx and CDx‑adjacent tests, provided they use NAAT and/or sequencing technologies and are linked to an approved oncology therapy.
Special controls require:
- Analytical performance data (precision, accuracy, sensitivity, specificity, stability, genomic coverage)
- Clinical performance data using specimens representative of the intended‑use population
- Validation of specimen handling and biomarker classification (including bioinformatics)
- Labeling that clearly describes biomarkers, algorithms, performance and limitations
- Labeling statements about drug use that are consistent with the corresponding drug labeling (for both essential and non‑essential tests).
FDA explicitly notes that 510(k) is less burdensome and more cost‑effective than PMA and typically involves shorter review timelines, and that reclassification should increase patient access by enabling more manufacturers to enter this space.
In other words:
For qualifying oncology NAAT/NGS CDx, the U.S. pathway moves from PMA‑level intensity to a structured, special‑controls‑based 510(k).
Head‑to‑Head: Where FDA and IVDR Still Look Alike
Despite the structural differences, the scientific expectations remain broadly aligned:
Strong analytical performance: Both regimes expect validated precision, accuracy, sensitivity, specificity and robust understanding of detection limits and interferences.
Clinical performance and scientific validity: CDx must demonstrate that they reliably identify the biomarker–drug relationships claimed in the labeling, whether via clinical trial enrollment assays, bridging studies or other appropriate data.
Drug–test linkage: In the EU, EMA or NCAs opine on the suitability of the CDx for the medicinal product during consultation. In the U.S., FDA’s special controls require that CDx labeling about benefit or risk be consistent with the approved drug labeling.
Risk‑based classification logic: IVDR assigns CDx to Class C based on their importance for therapy decisions. FDA now treats oncology NAAT/NGS CDx as a specific Class II device type, having concluded that special controls can manage the risk.
From a scientific and clinical perspective, a well‑run CDx program will look similar on both sides of the Atlantic: rigorous analytical studies, an integrated evidence package with the drug, and careful labeling.
Where the Workload Now Diverges
The divergence appears in operational burden, not scientific content.
United States – After Reclassification
For an oncology NAAT/NGS test that fits 866.6075:
- Submission type: 510(k) with special controls, not PMA.
- User fees: 510(k) fees are a small fraction of PMA fees (FY 2025: $24,335 vs $540,783).
- Review focus: substantial equivalence plus conformity to special controls, within the 510(k) framework.
- Change control: clearer potential to use PCCPs for future modifications, reducing repeated submissions.
European Union – Under IVDR
For the same test in Europe:
- Classification: CDx remain Class C under Rule 3.
- Notified Body: full technical documentation and QMS assessment are mandatory.
- Consultation: NB must seek EMA/NCA opinion on suitability; the consultation adds distinct review steps and timelines (nominally 60 days, extendable).
- Governance: EFPIA and MedTech Europe highlight that fragmented responsibilities and capacity constraints can create delays and uncertainty for CDx developers.
The net effect is that for follow‑on and technology‑mature NAAT/NGS oncology CDx, FDA is moving to a lighter, more standardised pathway than IVDR currently offers.
What Happens to “Harmonisation”?
Before this proposed rule, sponsors could argue that:
- FDA PMA and IVDR Class C + EMA consultation were comparably demanding overall; both required high investment, long lead times and deep clinical packages.
After reclassification, assuming the rule is finalised:
Scientific harmonisation persists:
- Both systems still want strong analytical and clinical evidence, clear linkage to drug benefit/risk and transparent labeling.
Regulatory workload de‑harmonises:
- The U.S. pathway for oncology NAAT/NGS CDx becomes Class II / 510(k)‑based, with lower fees and shorter, more standardised reviews.
- EU CDx remain Class C with NB + EMA consultation, dependent on Notified Body capacity and multi‑agency coordination.
From a global‑development perspective, that means:
Evidence standards are converging; process burden is not. FDA’s move makes the U.S. relatively more attractive for mature oncology CDx than the IVDR can currently match.
Strategic Implications for Sponsors
For CDx sponsors and pharma partners planning global programmes, this shift should trigger several adjustments:
Re‑balance jurisdictional sequencing.
- Consider whether to prioritise U.S. 510(k) filings under 866.6075 for mature biomarkers, while planning parallel but longer‑horizon IVDR CDx submissions.
Design “one evidence set, two pathways.”
- Build analytical and clinical validation plans that explicitly map to FDA’s special controls and to IVDR performance evaluation requirements (scientific validity, analytical and clinical performance).
Plan for EMA consultation early.
- Ensure timelines for NB review and EMA/NCA consultation are integrated into overall launch planning, especially where drug and CDx approvals must stay synchronised.
Manage the labeling alignment constraint on both sides.
- In the EU, the medicinal product’s SmPC and the CDx IFU must remain aligned.
- In the U.S., FDA’s special controls require that device labeling about benefits/risks mirror the oncology drug’s labeling.
- Practically, this means drug sponsors and CDx sponsors must coordinate evidence generation and labeling strategies from the outset.
How MDx CRO Bridges FDA and IVDR for Companion Diagnostics
MDx CRO is structured to support CDx sponsors through this evolving two‑speed world:
- We act as a full‑service IVD CRO, delivering clinical performance studies (including delegated sponsor models), ISO 20916‑compliant site management and monitoring, data management, biostatistics and IVDR‑compliant study reports.
- Our regulatory affairs team designs integrated IVDR–FDA roadmaps, covering classification, performance evaluation, technical documentation and submissions to both U.S. FDA and EU authorities.
- We support EU IVDR CDx EMA consultations and other IVDR high‑risk processes, giving sponsors a realistic view of timelines and expectations.
As FDA moves oncology NAAT/NGS CDx into a Class II / 510(k) framework, the sponsors who will win are those who:
- Exploit the lighter U.S. pathway without under‑estimating evidence needs
- Design global trials that serve both FDA special controls and IVDR performance evaluation
- Coordinate drug and diagnostic strategies so labeling can keep pace with the science
If you are planning or running CDx programmes across the U.S. and EU, reach out to MDx CRO to pressure‑test your strategy against this new regulatory landscape and to build a development plan that keeps your companion diagnostic—and your therapy—on the critical path to patients.
This article is for informational purposes only and does not constitute legal or regulatory advice.
