FDA’s New CDx Pathway vs EU IVDR: Harmonised Science, Diverging Workload

November 27, 2025

Carlos Galamba

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.

Written by:

Carlos Galamba

CEO & Head of IVD

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

Industry Insights & Regulatory Updates

FDA Proposes to Down‑Classify Key Oncology Companion Diagnostics to Class II: What CDx Sponsors Need to Know

Companion Diagnostics IVD Consultancy within the EMA Framework: Comprehensive Guidance

Scientific Validity Report (SVR) Under EU IVDR: From Literature Review to Defensible Scientific Argument

Navigating the IVDR CDx Certification Pathway

ISO 20916:2024 What You Need to Know for Clinical Performance Studies in 2026

FDA Proposes to Down‑Classify Key Oncology Companion Diagnostics to Class II: What CDx Sponsors Need to Know

November 27, 2025

Carlos Galamba

A Structural Shift in FDA Companion Diagnostic Policy

FDA has published a proposed order in the Federal Register to reclassify a major family of oncology companion diagnostics and related molecular tests—from post‑amendment Class III (PMA) devices to Class II with special controls, under a new regulation at 21 CFR 866.6075.

This proposal creates, for the first time, a unified Class II device type for “Nucleic Acid‑Based Test Systems for Use with a Corresponding Approved Oncology Therapeutic Product”. It would move many oncology nucleic‑acid tests (including core companion diagnostics) onto a 510(k) pathway—while maintaining stringent analytical and clinical expectations via special controls.

For CDx sponsors, pharma partners and oncology laboratories, this is more than a technical reclassification. It reshapes how you plan evidence, sequence FDA and EMA/IVDR strategies, budget user fees, and negotiate drug–test labeling.

As an IVD‑focused CRO with deep experience in IVD clinical studies services, IVDR performance studies, EMA CDx consultation and FDA submissions, MDx CRO is already working with sponsors to future‑proof pipelines against this new framework.

What Exactly Has FDA Proposed?

FDA’s proposed order would:

Create a new device type at 21 CFR 866.6075 titled “Nucleic Acid‑Based Test Systems for Use with a Corresponding Approved Oncology Therapeutic Product.”
Reclassify post‑amendment Class III devices in this category—currently approved under product codes OWD, PJG, PQP and SFL—into Class II (special controls), subject to 510(k).
Apply the new regulation to both currently approved devices and future devices that fit this definition.

Under the proposed identification, these devices are prescription IVDs that:

Detect specific genetic variants and/or other nucleic acid biomarkers in human clinical specimens
Use nucleic acid amplification (e.g., PCR) and/or sequencing technologies (e.g., NGS)
Provide information related to the use of a corresponding FDA‑approved oncology therapeutic product

Crucially, the device type covers two sub‑families:

1 – True companion diagnostics – tests essential for the safe and effective use of an oncology therapeutic product, with reciprocal references in both the device labeling and the drug labeling.

2 – “CDx‑adjacent” tests – tests that are not essential for use of the drug, but are referenced in the drug’s labeling because they provide information about known benefits and/or risks (for example, prognostic or response‑enrichment information).

FDA has opened a 60‑day public comment period following publication of the proposed order; if finalized, the new classification would take effect 30 days after the final order is published in the Federal Register.

Why Is FDA Comfortable Moving Oncology NAAT/NGS CDx to Class II?

FDA’s justification rests on a decade‑plus of real‑world experience with these technologies, framed through the statutory reclassification provisions in section 513(f)(3) of the FD&C Act.

1. Extensive PMA Experience

Since the first approval in 2011 (cobas 4800 BRAF V600 Mutation Test), FDA has approved 35 PMAs and 403 PMA supplements for oncology nucleic acid‑based test systems across four product codes (OWD, PJG, PQP, SFL).

For this proposed reclassification, FDA relied on data from 17 original PMAs and one panel‑track supplement, making use of the “six‑year rule” in section 520(h)(4) to draw on PMA datasets once they were sufficiently aged to be used for reclassification.

These submissions include PCR hotspot assays, NGS panels, BRCA and RAS panels, MSI signatures and other archetypal oncology CDx platforms.

2. Post‑market Safety and Recall Data

FDA analysed MDRs (MAUDE database) and recalls for these product codes:

147 MDRs across four product codes, with >80% related to false positives; >95% reported no clinical harm, and the fraction associated with serious health impact was low.
Four Class III recalls and 23 Class II recalls, with root causes concentrated in non‑specific molecular interactions, non‑conforming components, process deviations, labelling errors and off‑label use—not systemic failures of the technology itself.

The conclusion: risk modes are well understood and can be mitigated through defined special controls, rather than case‑by‑case PMA‑level scrutiny.

3. Technological Maturity

FDA explicitly characterises oncology nucleic acid‑based test systems as a well‑bounded technological family, with:

Similar purposes and intended uses
Common analytical principles (PCR and NGS)
Comparable bioinformatics pipelines
No unique, unmitigated risk patterns across product codes

On that basis, FDA finds that Class II with appropriate special controls can provide reasonable assurance of safety and effectiveness.

What Are the Proposed Special Controls?

The special controls in proposed 21 CFR 866.6075(b) fall into two main buckets: design verification/validation and labeling.

1. Design Verification and Validation

Sponsors must provide:

Analytical performance data

Precision, analytical accuracy, analytical sensitivity, analytical specificity
Sample and reagent stability
Evaluation for each gene/variant, or an FDA‑accepted representative strategy

Coverage and limitations

Data showing which genomic regions are targeted and detected
Disclosure of regions not covered or with limited detection

Clinical performance data

Generated using clinical specimens representative of the intended use population
Demonstrating appropriate clinical performance for the intended use (e.g., response‑predictive or risk‑informative claims)

Specimen handling validation

Validation of specimen types, pre‑analytical handling, extraction and preparation as described in the labeling

Biomarker classification / bioinformatics validation

Clear description of the classification pipeline and criteria
Documentation of the basis for biomarker interpretation, with appropriate references

Risk‑mitigation specifications

Controls, procedures and user‑training requirements designed to reduce false results and misinterpretation

In practice, this codifies what high‑quality oncology CDx sponsors already do under PMA—now packaged as device‑type‑level expectations rather than bespoke PMA negotiations.

2. Labeling Controls – Including the New Label‑Alignment Requirement

Labeling must include:

Device description (biomarkers detected, analysis algorithms, quality metrics, detection limitations)
A summary of analytical and clinical performance studies and their results

For essential CDx tests:

Language stating that the test is indicated for use with a specific FDA‑approved oncology therapeutic product, and
A requirement that device labeling be consistent with the corresponding drug’s FDA‑approved labeling.

For non‑essential but drug‑informative tests:

Language summarising known benefits and/or risks of the drug as informed by the test, which also must be consistent with the therapeutic product’s FDA‑approved labeling.

That last element—the requirement that test claims about drug benefit or risk “track” the drug label—is where the most interesting policy tension sits.

Why This Matters Operationally: PMA vs 510(k) for Oncology CDx

If finalized, reclassification would move this family of tests from PMA to 510(k), with important practical effects:

Less burdensome submission type. FDA itself notes that the 510(k) pathway is generally less burdensome and more cost‑effective than PMA, with shorter review timelines.
Lower user fees. In FY 2025, the standard user fee for a PMA‑type application is about $541k, while a 510(k) fee is about $24k—roughly a 20‑to‑1 difference, before small‑business reductions.
More predictable review questions. Instead of re‑litigating the entire benefit–risk story, sponsors will argue substantial equivalence and conformity to codified special controls.
More flexible change control. FDA explicitly points to predetermined change control plans (PCCPs) as a way to implement certain future modifications without a new 510(k) each time, if the change is covered by a cleared PCCP.

For oncology CDx sponsors, that means:

Faster and cheaper routes for follow‑on tests targeting established biomarkers (EGFR, BRAF, BRCA, MSI, etc.).
A clearer template for analytical and clinical evidence packages.
Easier lifecycle management for panel expansions, algorithm updates and bioinformatics refinements—subject to PCCP design.

The Built‑In Ceiling: Test Claims Cannot Outrun Drug Labeling

While the new Class II device type creates a more efficient pathway, it also codifies a strict rule about how far test labeling can go:

For tests essential to a drug’s safe and effective use, device labeling must be consistent with the corresponding drug label.

For tests that merely provide information about known benefits or risks (without being essential), the device can only summarise those benefits/risks in language that is, again, consistent with the drug label.

In practice, this means:

You cannot obtain CDx labeling for a novel biomarker–drug relationship unless the drug’s own labeling acknowledges that relationship.
Independent evidence generated by an IVD sponsor, academic group or cooperative trial cannot, on its own, support drug‑linked claims in device labeling if the corresponding therapeutic product label remains silent or disagrees.

This alignment rule is not new, it has long applied in the PMA CDx world, but the new regulation explicitly extends it to the broader family of “CDx‑adjacent” oncology NAAT/NGS tests.

From a sponsor’s perspective, that creates a structural stalemate scenario:

A test developer may generate high‑quality evidence showing that a biomarker predicts lack of benefit or heightened risk for a widely used oncology drug.
If the drug sponsor declines to pursue a label update, FDA cannot allow device labeling that effectively rewrites the drug’s benefit–risk profile.
The test might still be cleared as a purely analytical device, but it would not carry the clinically meaningful, drug‑linked claims that drive adoption and reimbursement.

For CDx developers, the implication is clear:

Regulatory strategy for these new Class II tests still hinges on drug‑sponsor alignment, not just assay science.

What Should Sponsors Do Now?

Even before the order is final, CDx and oncology test sponsors can act:

Map your pipeline against the new device type: Identify NAAT/NGS oncology tests tied to approved therapies that fall into the new 866.6075 definition.
Re‑think U.S. regulatory roadmaps: For qualifying tests, plan around a 510(k) with special controls instead of a PMA—while recognising that evidence expectations remain high.
Align CDx and drug strategies early: For new biomarkers, ensure drug‑side teams understand that therapeutically meaningful test claims will require corresponding drug‑label changes.
Design performance studies that satisfy both FDA and IVDR: Build analytical and clinical validation packages that can support 510(k) clearance and the IVDR Class C CDx pathway, including EMA consultation.
Leverage PCCPs thoughtfully: Consider where a PCCP can safely cover bioinformatics updates, new variants or refined cut‑offs—without triggering repeated submissions.

How MDx CRO Can Help

MDx CRO is built around IVD and CDx:

We deliver end‑to‑end IVD trial solutions, including delegated sponsor responsibilities, ISO 20916‑compliant clinical performance studies, biostatistics, data management, safety reporting and IVDR‑compliant study reports.
Our regulatory affairs team designs global strategies for IVDR and FDA, including device classification, performance evaluation, technical documentation and regulatory submissions.
We are already supporting IVDR CDx EMA consultation processes, making us well placed to harmonise evidence plans with FDA’s new Class II framework for oncology NAAT/NGS CDx.

If your portfolio includes oncology companion diagnostics, predictive biomarkers or NGS oncology panels, this proposed reclassification is an opportunity to:

Reduce time and cost to achieve an FDA label
Align U.S. and EU strategies more intelligently
Design performance studies that work once and serve both regimes

Contact MDx CRO to discuss how to stress‑test your CDx roadmap against the new 21 CFR 866.6075 framework and build a regulatory plan that works on both sides of the Atlantic.

This article is provided for general information only and does not constitute legal or regulatory advice. Sponsors should consult their own regulatory and legal counsel for device‑specific strategies.

Written by:

Carlos Galamba

CEO & Head of IVD

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

Industry Insights & Regulatory Updates

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

Scientific Validity Report (SVR) Under EU IVDR: From Literature Review to Defensible Scientific Argument

MDCG 2021-24 Rev.1: What Changed in EU MDR Device Classification (April 2026)

FDA Companion Diagnostics: A Complete Regulatory Guide to CDx Development, Approval, and Co-Development Strategy

Team-NB clarifies CDx changes under IVDR Annex IX 5.2

November 11, 2025

What the new Team-NB paper covers

Team-NB has adopted an updated position paper (Version 2, 22 Oct 2025) clarifying which changes to companion diagnostics (CDx) under IVDR Annex IX, section 5.2 must be reported to the Notified Body (NB) and when consultation with the medicinal products authority (EMA or relevant national authority) is required. Under Annex IX 5.2(f), manufacturers must inform their NB before making changes that affect performance, intended use, or suitability of the device in relation to the medicinal product. The NB then decides whether a new conformity assessment is needed or a supplement to the EU technical documentation certificate is sufficient, and whether consultation with the medicinal products authority is required.

The paper also notes that manufacturers are responsible for determining if a change requires consultation and must document and justify a decision not to consult; justifications must be available to competent authorities on request. In general, a change that requires consultation should be considered reportable to the NB.

Legacy CDx under Article 110(3)

For legacy CDx (per MDCG 2022-8), significant changes to design or intended purpose cause loss of legacy status (per MDCG 2022-6) and trigger a new IVDR conformity assessment involving a NB and a consultation with the medicinal products authority.

How Team-NB categorizes changes (with examples)

The annex introduces a practical flow that first asks: Does the anticipated change affect the CDx’s suitability for the medicinal product? Depending on the answer, changes fall into three groups.

1) No EMA/National authority consultation required

(“NO” path in the flow; changes out of scope of medicinal product authority consultation)
Examples:

Change in critical raw material or its supplier
Platform transfer (e.g., validation on a new NGS platform)
Extension of CDx shelf-life
New supplier for a reagent
New place of market in distant sales

2) Follow-up consultation (supplement) — change within the scope of the original consultation

Examples:

New limitation in use of the CDx (e.g., cross-reactivity)
Medicinal product restriction impacting the CDx claim
Large-panel NGS tumour profiling device: addition of tissue type for an existing INN
Changes to analytical parameters of the CDx
Change in reagent presentation (e.g., liquid vs lyophilized) that impacts the CDx claim

3) Initial consultation (new conformity assessment) — change outside the scope of the original consultation

Examples:

Medicinal product extension impacting the CDx claim
Addition of a new sample type that changes intended purpose
Addition of a new/expanded target patient population
Large-panel NGS tumour profiling device: additional INNs after initial certification
Addition of additional mutations with outcome data

Important: Team-NB stresses that the annex examples are illustrative, and final determinations are case-specific based on detailed evaluation.

Practical takeaways for CDx teams

Treat changes that likely affect design or intended purpose as reportable and assess them with supporting evidence.
Document your consultation decision (including rationale for no consultation) and keep it ready for competent authorities.
For legacy CDx, avoid significant changes to design/intended purpose unless you’re prepared for loss of legacy status and a new IVDR assessment with consultation.
Refer to the EMA homepage (or relevant EU/EEA medicinal product authority) for process details on consultations.

Why this matters

This Team-NB paper gives CDx manufacturers and their partners a shared interpretation baseline with Notified Bodies and medicinal product authorities, reducing ambiguity around when to notify the NB and when to seek EMA/national consultation after a change. The included flow and examples help teams pre-classify changes and plan evidence/consultation pathways efficiently.

Need a CDx-focused partner?

If you’re planning or assessing CDx changes under IVDR and want a clear pathway through NB reporting and EMA/national consultations, talk to MDx CRO—a consultancy dedicated to companion diagnostics strategy, clinical evidence, and regulatory execution.

Written by:

Carlos Galamba

CEO & Head of IVD

Senior regulatory leader and former BSI IVDR reviewer with deep experience in CE marking high-risk IVDs, companion diagnostics, and IVDR implementation.

Industry Insights & Regulatory Updates

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

MDCG 2021-24 Rev.1: What Changed in EU MDR Device Classification (April 2026)

FDA Companion Diagnostics: A Complete Regulatory Guide to CDx Development, Approval, and Co-Development Strategy

ISO 20417:2026 You May Have a Gap Today: What Medical Device Manufacturers Shall Do Now

Performance studies in gene therapy trials: from assay cut-offs to clinical impact

October 31, 2025

In gene therapy, your in-vitro diagnostic (IVD) doesn’t sit on the sidelines—it drives clinical decisions. If a result screens a participant in/out, times dosing, or informs safety management, you’re in IVDR performance study territory with ISO 20916 as the operational backbone. Treat the IVD like a product under evaluation, not a lab tool, and design a study that proves it’s fit for the exact decision your trial needs.

What actually triggers a performance study in gene therapy?

Use the simplest rule of thumb: does the assay influence patient management? If yes, plan for an IVDR Article 58 performance study in parallel with your clinical trial authorization. Typical triggers:

Eligibility/stratification: AAV neutralizing antibody (NAb) or total-antibody (ELISA) results that gate inclusion/exclusion or set a dosing window.
Patient monitoring: Assays that guide timing or continuation (e.g., changes in humoral markers relevant to vector readiness).
CDx trajectory: When the test is essential for safe and effective use, your evidence should be built to scale toward CDx—even if you’re not filing as CDx yet.

Treat these as combined trials (IMP + IVD). Align the performance study application with the drug CTA so approvals move together.

Build the right “assay stack” for AAV programs

Design your assay plan around the decisions your trial must make. In combined trials (IMP + IVD), that usually means separating screening, decision-making, and context/supporting activities—and documenting exactly which assay output drives which action in the CPSP and APR.

1) Screening assays

Purpose: Identify participants who may be eligible for dosing or further evaluation.
Typical methods: Total antibody (ELISA) and/or neutralizing antibody (NAb) assays.
Predefine: intended purpose, the output used for screening, cut-off, QC/controls, and invalid/repeat handling.
Regulatory note: If screening impacts enrollment/timing, it’s within IVDR performance study scope—reflect this in the protocol and dossier.

2) Decision-making assays

Purpose: Provide the result that directly guides patient management (e.g., eligibility for AAV dosing or readiness after a waiting/intervention period).
Typical method: Cell-based NAb assay when the decision depends on functional inhibition of transduction.
Predefine: a validated cut-off and how it’s applied at the decision point; acceptance criteria (controls/repeats), handling of invalid/borderline results, and any repeat-testing logic.

3) Context/supporting assays

Purpose: Provide supporting information (e.g., PCR/NGS for inclusion criteria or other exploratory markers) without driving patient management unless explicitly pre-specified.
Governance: These may be exploratory assays; do not let them influence decisions unless pre-declared.

Designing the CPSP: endpoints that matter (and survive small-N)

Tie endpoints to the decision you must defend. In rare diseases, power is constrained—precision and transparency carry weight.

Primary, decision-linked endpoints (illustrative):

Proportion below cut-off at the dosing/decision point.
Time-to-negativity (post-intervention or natural decline).
Duration of sustained negativity.
Change from baseline in NAb titers.

Key secondaries (analytical + feasibility + safety):

Analytical performance in operations: run-level QC pass rate, invalid/repeat rate, assay deficiencies/deviations.
Feasibility: turnaround time from collection to result, pre-analytical robustness (freeze–thaw, transport windows, matrix effects), stability.
Safety: AEs from sample collection/device use as per IVDR performance study reporting.

Correlative (pre-specified, descriptive):
Relate NAb kinetics to other humoral markers (e.g., total IgG, capsid-specific antibodies) where it clarifies the biology without over-claiming.

When your IVD sample size is constrained by the gene therapy protocol, say so. Set precision targets for agreement or proportions and specify how you’ll treat indeterminates/missing—regulators prefer realistic clarity over decorative p-values.

From LDT to IVDR: documentation that actually wins

Many gene therapy assays start as lab-developed tests or adapted RUO methods. Under IVDR you need an Analytical Performance Report (APR), not just a conventional validation report. The APR:

Maps analytics to intended purpose and clinical decision.
Uses a structured narrative per characteristic: Purpose → Study design → Statistics → Acceptance criteria → Results → Conclusion.
References applicable frameworks (IVDR, ISO, MDCG) and integrates ICH Q2(R2)/Q14 principles within the IVDR lens.
Justifies non-applicable GSPR requirements explicitly instead of hiding them.

What reviewers expect to “see on the page”

Analytical sensitivity: LoD/LoQ with methods, not just point estimates.
Analytical specificity: cross-reactivity, interference, matrix effects—demonstrated, not assumed.
Accuracy (trueness/bias): vs. reference materials/known concentrations across the measuring range.
Precision: repeatability, reproducibility and intermediate precision (operators, days, instruments).
Measuring interval/reportable range: tied to clinical decisions.
Robustness & stability: small-parameter changes; specimen/reagent stability across the actual logistics.
Traceability: metrological traceability to reference materials or SI units wherever feasible.

Bridging without back-tracking

If you migrate platforms or laboratories, pre-declare equivalence boundaries, commutable panels, and the statistical approach before you switch. Link the APR to the Design History File and ultimately to the Performance Evaluation Report to keep evidence audit-ready.

Operational blueprint: lab-centric, ISO 20916–aligned execution

Programs that run smoothly accept a basic truth: lab operations are clinical operations when an assay drives decisions.

Risk-based monitoring (ISO 20916): Prioritize calibration records, control runs, instrument logs, sample accountability, LIMS audit trails, and lab-critical SDV.
Clear RACI across stakeholders: pharma sponsor, diagnostic partner, central lab, CRO(s). Assign a single “owner of truth” for eligibility calls and a documented adjudication path for gray-zone results.
Sample governance: pre-analytical controls (shipping, temperature, freeze–thaw limits), redraw/retest SLAs, and chain-of-custody that survives inspection.
Safety integration: define device-side AE/device-deficiency flows and their handshakes with the IMP SAE process—who reports what, where, when—and hold joint drills before FPI.

Common pitfalls (and the fix)

Copy-pasting a validation report into IVDR—without showing how analytics support the clinical decision.

Fix: Rewrite into an APR aligned to the intended purpose; connect every analytic claim to the use case.

Pretending power exists in tiny cohorts.

Fix: Pre-specify precision not power; make QC-forward primary endpoints; keep clinical associations descriptive.

Letting exploratory assays creep into decision-making ad hoc.

Fix: Lock the assay stack and decision logic in the CPSP; label everything else exploratory.

Underplaying pre-analytical risk.

Fix: Measure it (transport windows, freeze–thaw), set acceptance criteria, and track at run-level.

Ambiguity in roles and safety.

Fix: Publish a RACI and an integrated safety matrix early; rehearse escalations.

Sponsor checklist

Decide early if the assay changes patient management → if yes, plan an IVDR performance study.
Lock claims, cut-offs, and gray zones; write the CPSP to those decisions.
Choose your study model (prospective/retrospective/bridging) to match real sample access and clinical trial needs.
Produce an APR with complete traceability and justified non-applicable requirements.
Stand up lab-centric monitoring (ISO 20916), eTMF rigor, and LIMS auditability.
Align device and drug safety reporting—on paper and in practice.
Embrace small-N: set precision goals, prioritize QC endpoints, and keep associations descriptive.
Think CDx-ready: structure today’s evidence so tomorrow’s filing doesn’t start from zero.

How MDx CRO accelerates combined gene therapy studies

We run the device side of your combined trial end-to-end: strategy, CPSP/APR/PER authorship, submissions, ISO 20916-aligned operations, lab-centric monitoring and SDV, data/biostats, and inspection-ready traceability. We design performance studies that mirror real clinical decisions, so approvals and operations move in lockstep.

Let’s co-design your performance study

Speak with our IVD & gene therapy team

Industry Insights & Regulatory Updates

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

ISO 10993-1:2025 From Checkbox Compliance to Risk-Based Biocompatibility

Making IVDR Work in Combined Studies: Scientific & Operational Lessons from 40+ Programs

ISO 14155:2026 What’s Changed and What It Means for Your Clinical Investigation

Portugal’s New Clinical Trials Law No. 9/2026: What Sponsors Need to Know

Spanish IVD Regulation 2025 – New Royal Decree Updates for IVD Manufacturers, Sponsors, and Labs

October 21, 2025

On 21 October 2025, the Council of Ministers approved Spain’s new Royal Decree for in vitro diagnostic devices. AEMPS confirmed the approval and explained that the decree complements IVDR (EU) 2017/746, strengthens patient protection, and adds national rules on language, in-house manufacturing, performance studies, and vigilance. This development anchors the Spanish IVD Regulation 2025 and sets clear obligations for manufacturers, sponsors, and laboratories. (Official announcement: AEMPS)

Spanish IVD Regulation 2025: What Changed and Why It Matters

The Spanish IVD Regulation 2025 replaces Royal Decree 1662/2000. It clarifies how IVDR applies in Spain and fills Member-State choices, including competent authority, language regime, Article 5(5) in-house devices, genetic testing and counseling, a national marketing register, performance study authorization, and vigilance and market control.

The regulation aims to raise quality, ensure traceability, and speed up corrective actions. It also improves access to certain self-tests through pharmacy channels.

Quick Guide for Busy Teams (Manufacturers, Sponsors, Labs)

Confirm what the Spanish IVD Regulation 2025 changes for your role.
Map licensing, registration, language, Article 5(5), ISO 15189, performance studies, and vigilance to owners and deadlines.
Prepare Spanish-language materials and set up traceability and incident reporting workflows.
Labs should plan ISO 15189 and Article 5(5) notifications to AEMPS.

Competent Authority and Language Rules under the Spanish IVD Regulation 2025

AEMPS is the competent authority for IVDs in Spain. Under the Spanish IVD Regulation 2025, user-facing materials for devices marketed in Spain must appear in Spanish. That includes labels, IFU, and safety notices. Regulatory submissions to AEMPS should include Spanish content. Co-official languages may be added, but Spanish is mandatory.

Action: Audit labeling, IFU, FSNs, PMS templates, and performance study files. Plan translations and version control.

Facility Licensing: Manufacturers, Sterilizers, and Importers

The Spanish IVD Regulation 2025 requires operating licenses for manufacturers, sterilizers, and importers before they place devices on the market. AEMPS evaluates facilities, personnel, and quality systems.

Each site must appoint a Technical Responsible Person (national role) and meet IVDR oversight led by a PRRC. One qualified person can cover both if they meet the criteria.

Transitional rule: Existing third-party manufacturers get up to one year from entry into force to secure the new license. Existing licenses remain valid until renewal or change, which then follow the new procedure.

Action: Confirm license status, designate the responsible person, and prepare for renewal under the new framework.

Marketing Register and Traceability

The decree creates a Spanish marketing register for devices placed on the market. Manufacturers, authorized representatives, and importers must notify product information to support traceability and market surveillance. The register complements EUDAMED and UDI.

Transitional rule: Spain will activate notifications when the register is operational. Until then, use existing national channels.

Action: Build a clean data set for device identifiers, certificates, and supply chains. Prepare to submit once AEMPS opens the register.

In-House Devices (Article 5(5) IVDR): What Labs Must Do Now

Scope and intent

The Spanish IVD Regulation 2025 regulates in-house IVDs made and used within the same health institution. Labs must justify need: a commercial CE-marked device cannot meet the specific clinical need. No industrial-scale production. No commercial supply to third parties.

Quality and documentation

In-house devices must meet IVDR GSPRs. Labs should keep a technical file (intended purpose, risk management, analytical and clinical performance, V&V, SOPs, and labeling for internal use).

ISO 15189 accreditation

Labs that manufacture in-house devices must obtain ISO 15189 accreditation for the manufacturing scope. Spain ties this to the transitional schedule.

Notification to AEMPS

Before starting in-house manufacture, labs must notify AEMPS and submit the Article 5(5) declaration. They must designate a responsible person for the in-house manufacturing process.

Action for labs: Launch ISO 15189 projects, finalize Article 5(5) templates, and prepare the AEMPS notification package.

Genetic Testing: Information and Counseling

The Spanish IVD Regulation 2025 requires clear information and appropriate counseling for genetic testing. Health professionals must explain limits, implications, and result interpretation. This duty applies before and after testing.

Health professionals and centers must obtain explicit informed consent from individuals before performing a genetic test. The patient must be made aware of the nature and purpose of the test and consent in writing (except where law may exempt certain public health screening). This goes beyond standard consent, recognizing the personal and familial implications of genetic data.

Before the test, patients should be informed about what the test can and cannot tell them, and after the test, a qualified professional should explain the results and any recommended follow-up. This requirement ensures genetic tests (such as those for hereditary disease risk) are not delivered without context or support, helping patients make informed decisions.

These obligations apply to genetic IVDs regardless of whether they are done in-house or as commercial tests. For example, a direct-to-consumer genetic test kit (if allowed on the market) would need to be accompanied by processes that ensure the purchaser gets necessary information and counseling. However, most genetic tests are administered in clinical settings; the decree effectively standardizes the practice of genetic counseling as part of testing.

Action: Update consent forms, patient information sheets, and SOPs for genetic counseling, including training for staff.

Performance Studies in Spain

All performance studies in Spain must first obtain a favorable opinion from an accredited Research Ethics Committee (REC) and authorization from the health center’s management where the study will be conducted. This applies to any study using human specimens or data for evaluating an IVD’s performance, ensuring ethical considerations (informed consent, data protection, etc.) are addressed early.

When you need authorization

Interventional clinical performance studies and other studies involving risks require AEMPS authorization before first participant. Ethics approval remains mandatory.

What sponsors must prepare

Spanish protocol (CPSP), Investigator’s Brochure, and informed consent.
Insurance/indemnity for participants and a clear liability framework. The decree explicitly requires compensation for damages and defines the liability regime for sponsors. Sponsors should budget for a clinical trial insurance policy and follow the decree’s rules on coverage minimums and conditions (similar to drug trial insurance requirements in Spain).
Monitoring, data management, and safety reporting plans aligned with IVDR. Upon study completion, results (whether positive, negative, or inconclusive) should be documented and may need to be reported in the public database or to AEMPS.

Studies with CE-marked devices

If the study adds invasive or burdensome procedures or goes outside intended use, sponsors should request authorization and notify AEMPS.

Action for sponsors: Build a Spain-ready dossier, confirm insurance, and align timelines with AEMPS and ethics reviews.

Vigilance and Market Control

The Spanish IVD Regulation 2025 reinforces vigilance. Manufacturers must report serious incidents and FSCAs to AEMPS. Healthcare professionals and institutions should also report incidents. Authorities will coordinate inspections and market control actions.

For instance, if an IVD test yields false results that lead to patient harm, the manufacturer has to notify AEMPS and submit a Spanish-language safety notice so that users in Spain can be adequately informed. This ensures critical safety information is effectively communicated and mitigated in the local context.

The decree emphasizes that healthcare professionals, health institutions, and even patients/users have a responsibility to report any suspected serious incidents to AEMPS. Spain is thus bolstering a culture of vigilance: a lab that encounters a device malfunction or a clinician who notices a pattern of erroneous results should alert the authorities. The more comprehensive the reporting, the better AEMPS can intervene to prevent harm.

Action: Maintain robust PMS plans, trend analysis, Spanish FSNs, and clear internal reporting lines. Hospitals should assign a vigilance lead and train teams.

Self-Test Access and Pharmacy Channels

Notably, the new rules remove the prescription requirement for at-home self-testing kits (e.g. self-tests for glucose, pregnancy, COVID-19, etc.), making them more accessible. However, even without needing a prescription, these self-diagnostic products can only be sold through pharmacies (in-store or via an official pharmacy website) to ensure proper guidance on use. High-risk tests or those used for critical decisions may still require a prescription or professional administration.

Action: Manufacturers should confirm packaging, leaflets, and e-commerce pharmacy guidance in Spanish.

Transitional Timelines You Should Track

Entry into force: The decree takes effect after BOE publication.
Licensing: Existing third-party manufacturers have up to one year to obtain the new operating license.
Marketing register: Notification duties start when the register goes live.
In-house devices: Spain applies the IVDR timelines. Labs must meet Article 5(5) conditions and ISO 15189 by the dates set in the transitional provisions and related guidance.
Legacy devices: Spain honors the IVDR transition for legacy IVDs and preserves specific old-rule processes until systems fully switch over.

Action: Put a dated compliance tracker in place for licensing, Article 5(5), ISO 15189, registry readiness, and vigilance.

Implications by Stakeholder

IVD manufacturers

Secure or update operating licenses.
Localize labels/IFU into Spanish.
Prepare marketing register data.
Strengthen PMS and vigilance interfaces with AEMPS.

Hospital and private labs

Confirm Article 5(5) eligibility and prepare technical documentation for the in-house test.
Achieve ISO 15189 for manufacturing scope.
Notify AEMPS and assign the in-house responsible person.
Update genetic testing consent and counseling SOPs.

How MDx CRO Helps You Execute

Regulatory strategy and submissions

We align IVDR with the Spanish IVD Regulation 2025 and prepare AEMPS submissions (licenses, notifications, marketing register onboarding when live).

ISO 15189 and Article 5(5)

We run gap assessments, build SOPs, and guide labs to ISO 15189 accreditation for in-house manufacture. We prepare the Article 5(5) declaration and AEMPS notification package.

Performance studies

We plan and manage interventional and risk-involving performance studies in Spain. We handle AEMPS authorization, ethics submissions, monitoring, and safety reporting. MDx can also act your IVD performance study legal representative in the EU.

Vigilance and PMS

We design Spanish-compliant PMS frameworks, incident workflows, and FSNs. We help you interface with AEMPS and prepare for inspections.

Contact MDx CRO

Written by:

David Tomé

President

Clinical research leader and MedTech entrepreneur with deep expertise in medical devices, IVDs & precision medicine, with global study experience.

Industry Insights & Regulatory Updates

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

Scientific Validity Report (SVR) Under EU IVDR: From Literature Review to Defensible Scientific Argument

ISO 10993-1:2025 From Checkbox Compliance to Risk-Based Biocompatibility

Making IVDR Work in Combined Studies: Scientific & Operational Lessons from 40+ Programs

ISO 14155:2026 What’s Changed and What It Means for Your Clinical Investigation

MDx CRO at MPP 2025: Aligning Companion Diagnostics and Drug Development under IVDR

October 20, 2025

Precision medicine needs alignment, not lighter rules

Europe’s precision medicine ecosystem advances when diagnostics and medicines move in lockstep. The real bottleneck is not regulation itself; it is the structural divergence between the Clinical Trials Regulation and the IVDR. In our work across oncology and rare disease programmes, we repeatedly see how separate clocks, committees, documentation and reporting streams create avoidable friction. Our message at MPP 2025 was simple: bring both tracks together from the start and design one plan that satisfies clinical utility and regulatory rigor at the same time.

CDx and drug trials: bridging IVDR and CTR

When a biomarker guides enrolment or treatment and the assay is not CE-marked for that purpose, Article 58 triggers a performance study alongside the medicinal trial. That study’s endpoints, analytical validation and risk–benefit narrative must be coherent with the drug protocol, because outcomes like PFS, OS and ORR depend on the test defining the right population. Misalignment costs time; EFPIA’s 2023 evidence shows many sponsors facing six to twelve-month delays linked to IVDR requirements, which ultimately pushes patient access further out.

What MDx CRO presented at MPP 2025 and how it will affect 2026

At the Medtech & Pharma Platform Annual Conference on 16 September 2025 at the Novartis Campus in Basel, Carlos Galamba, CEO at MDx CRO, joined the session “IVDs, CDx & Personalized Medicine: Moving from Compliance to Innovation,” chaired by Fatima Bennai-Sanfourche of Bayer and Andreas Emmendoerffer of Roche. The panel brought together Antonella Baron from the European Medicines Agency, Heike Möhlig-Zuttermeister of TÜV SÜD, and patient advocate David Haerry of Positive Council Switzerland, alongside MDx.

Carlos Galamba of MDx CRO presenting at MPP 2025 in Basel on aligning companion diagnostics with drug development under IVDR. — **Carlos Galamba, CEO at MDx CRO presenting at the MPP conference**

Evidence on delays and the impact on patients

The data are unambiguous: EFPIA’s survey indicates 43 percent of companies estimated six to twelve-month delays due to IVDR, with downstream consequences for trial starts and patient inclusion across major disease areas. Every month lost to mis-sequenced processes or unclear governance is a month patients wait for targeted therapies.

Signals from regulators, notified bodies, and patient advocates

The discussion reflected a clear appetite for convergence. EMA perspectives on embedding companion diagnostics under IVDR, TÜV SÜD’s insights on conformity assessment for CDx, and the patient community’s call for earlier access all point in the same direction: coordinated planning and earlier dialogue across agencies, notified bodies and sponsors.

Key insights for 2026 from the MPP panel and fellow presenters

Compliance versus innovation is the wrong debate. The practical path forward is compliance and innovation together: a single evidence plan, shared endpoints, and a unified risk–benefit narrative that treats the diagnostic and the drug as interdependent elements of one therapy journey. That is how companion diagnostics under IVDR accelerate, rather than delay, precision medicine.

How MDx CRO accelerates CDx from design to approval

MDx builds one cross-functional plan from day one, aligning clinical and device protocols, mapping Article 58 triggers, and sequencing submissions so site start-up and “first sample tested” are not held back by documentation gaps. Our teams scrutinise analytical validation, prepare CPSPs and Annex XIV packages aligned to ISO 20916, and train investigators on device-specific safety reporting and sample flows across multilingual EU sites. This integrated approach has delivered a consistent approval track record for CDx submissions.

Operational playbook for combined studies in Europe

Effective combined studies require clear governance between drug and device sponsors, modular and wave submissions across Member States, separate informed consents for the CDx component where appropriate, and proactive scientific advice with EMA or NCAs for borderline cases. With local regulatory intelligence and language capability across Europe, we coordinate roles and documentation so CTR and IVDR remain synchronised throughout the study lifecycle.

Acknowledgment to MPP and our co-presenters

Our thanks to the Medtech & Pharma Platform Association for convening this timely discussion and to the session chairs and speakers who brought regulatory, conformity assessment and patient perspectives to the same table: Fatima Bennai-Sanfourche, Andreas Emmendoerffer, Antonella Baron, Heike Möhlig-Zuttermeister and David Haerry.

Partner with MDx CRO to make CDx work under IVDR

If your programme depends on biomarker-driven enrolment or treatment decisions, partner with a team that speaks CTR and IVDR fluently. MDx CRO compresses timelines, de-risks submissions and delivers companion diagnostics that make precision medicine real for the patients who need it most

Contact MDx Today

Industry Insights & Regulatory Updates

Making IVDR Work in Combined Studies: Scientific & Operational Lessons from 40+ Programs

MDx CRO at ESMO 2025 (Berlin): Advancing IVDR Transitions & Combined Clinical Trials

MDx to Present ESMO 2025 Poster on IVDR CE Marking for Large Germline NGS Panels

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

MDx CRO at ESMO 2025 (Berlin): Advancing IVDR Transitions & Combined Clinical Trials

October 20, 2025

MDx CRO presented new evidence and hands‑on learnings at ESMO 2025 that reinforce our position as the partner of choice for IVDR transitions and combined clinical trials involving investigational IVDs. We were first author on a poster with Fulgent Genetics and contributors to a Servier poster—both centered on the operational and regulatory realities of bringing high‑impact oncology diagnostics into clinical practice under the EU IVDR.

Highlights from our ESMO 2025 posters

Fulgent Genetics & MDx CRO — MDx CRO first author

Title: IVDR Compliance Challenges in Certifying a Large‑Scale NGS Panel for Hereditary Cancer

What it covers:

Practical blueprint for transitioning a comprehensive, service‑based NGS hereditary cancer panel under IVDR.
Defining intended use and scientific validity across a large gene set; end‑to‑end technical documentation; bioinformatics validation aligned to IEC 62304/82304; and notified‑body engagement strategy.
Lessons on right‑sizing verification/validation and building a living evidence package to support CE‑marking.

Why it matters: Sponsors and lab developers gain an actionable path for moving complex NGS services to IVDR compliance—without slowing clinical programs.

MDx CRO at ESMO 2025 in Berlin presenting a poster on IVDR compliance for NGS large panels for germline disease testing with Fulgent Genetics — **Dr. Marketa Svobodova, Precision Medicine Director & Carlos Galamba, CEO at MDx – Poster presentation at ESMO 2025 in Berlin**

Servier & MDx CRO (CHONQUER study) — MDx CRO contributor

Title: Navigating Regulatory Complexity in Combined Studies under CTR and IVDR (CHONQUER)

What it covers:

How combined trials (drug + investigational IVD) trigger dual oversight under CTR and IVDR and the knock‑on effects for timelines, submissions, and site activation across EU member states.
Operational patterns that accelerate approvals: early CPS planning, consolidated documentation, and aligned ethics/competent authority strategies.

Why it matters: Oncology sponsors can de‑risk global programs by anticipating IVDR‑specific requirements—and partnering with an IVD CRO that has worked both sides of the fence.

MDx CRO presented a poster at ESMO 2025 (Berlin) on combined CTR + IVDR clinical studies with Servier. — **Dr. Marketa Svobodova, Precision Medicine Director at MDx – poster presentation at ESMO 2025 – CHONQUER study, a combined study under IVDR/CTR**

Key takeaways for sponsors

IVDR transitions—end to end. MDx CRO supports dossier strategy, clinical performance studies (ISO 20916), scientific validity, and notified‑body engagement for CE‑marking.
Combined trials, simplified. We design and run CPS and combined CTR + IVDR studies, harmonizing submissions across multi‑country portfolios.
Oncology‑ready operations. Deep experience with molecular prescreening, NGS workflows, and drug–device coordination for precision oncology.

Need a quick debrief? Contact our IVD CRO team for a walkthrough of how these findings translate to your IVDR transition or combined study plan.

FAQs

What does MDx CRO do for IVDR transitions?

We provide end‑to‑end support—from intended‑use definition and scientific validity to clinical performance studies, technical documentation, and notified‑body engagement.

How does MDx CRO support combined CTR + IVDR studies?

We plan and execute CPS and combined trials, consolidating submissions and aligning ethics/competent authority requirements to reduce delays.

Can MDx CRO help with NGS panel validation under IVDR?

Yes. We design right‑sized verification/validation programs and bioinformatics validation aligned with IEC 62304/82304.

Where can I get the ESMO 2025 posters?

Both PDFs are available at the ESMO platform; contact us for a guided readout.

Industry Insights & Regulatory Updates

MDx to Present ESMO 2025 Poster on IVDR CE Marking for Large Germline NGS Panels

Making IVDR Work in Combined Studies: Scientific & Operational Lessons from 40+ Programs

MDx CRO at MPP 2025: Aligning Companion Diagnostics and Drug Development under IVDR

FDA Human Factors Guidance 2026: What the Final Guidance Means for Your Submission

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

TGA guidance (Oct 2025): IVD Companion Diagnostics (CDx) Requirements in Australia

October 16, 2025

What’s new

TGA IVD companion diagnostics requirements are now clearly explained in the Therapeutic Goods Administration’s guidance on IVD companion diagnostics (CDx) in Australia (updated 16 October 2025). Their revised companion diagnostics framework, adds process diagrams, a companion testing plan concept for medicine/biological sponsors, clearer clinical performance expectations, and case studies showing how the pathway works in practice.

This blog post summarises the definition of a CDx, Class 3 IVD classification, ARTG inclusion, companion testing plans, and the TGA CDx List.

What is a CDx under Australian law?

A companion diagnostic is an IVD (commercial or in‑house) that provides information essential for the safe and effective use of a corresponding medicine or biological—for patient selection, risk of serious adverse reactions, or treatment monitoring. To qualify, the test must be referenced in the Product Information (PI) for the medicine or in the Instructions for Use (IFU) of the biological. Tests used only for cell/tissue compatibility are excluded from the CDx definition.

This definition underpins the TGA IVD companion diagnostics requirements for medicines and biologicals that rely on patient selection testing.

Note: The term “a particular medicine or biological” can also cover a class of products with a similar mechanism of action, not only a single named product.

When does an indication require CDx testing?

An indication requires CDx testing when both:

the medicine’s PI (or biological IFU) states that CDx testing is essential, and
the CDx claims it is intended for that testing to enable use of the medicine/biological.
This may apply to some (not all) indications of a medicine.

To aid transparency, the TGA recommends a PI “flag phrase” indicating that testing is essential and that clinical practice testing should be adequately comparable to the pivotal trial testing; the TGA also publishes a CDx List of approved tests.

How the TGA applies CDx requirements: Class 3 IVDs and ARTG inclusion

Classification: Under TGA IVD companion diagnostics requirements, all CDx—commercial and in-house—are Class 3 IVDs (including in‑house CDx).
Separate ARTG entries: Each CDx requires its own ARTG inclusion with a Unique Product Identifier (UPI) defined by the manufacturer.
Application audit: CDx applications are subject to a mandatory application audit unless supported by specified comparable overseas regulator documentation (e.g., EU IVDR, FDA PMA, PMDA, HSA, Health Canada).
Concurrent submissions: While encouraged, concurrent medicine/CDx submissions are not mandatory; however, a CDx application should only be submitted if the corresponding indication is approved or under concurrent review.

From companion testing plans to ARTG submissions, MDx CRO streamlines the end-to-end CDx pathway in Australia, aligning clinical, regulatory, and quality workstreams to the TGA’s expectations.

Request a CDx consultation

The companion testing plan (for medicine/biological sponsors)

Every new indication that requires CDx testing must include a companion testing plan (dated and version‑controlled) describing how Australian patients will access at least one adequate test. This is central to meeting TGA IVD companion diagnostics requirements. Four options are available:

Option 1: A commercial CDx ARTG application is planned/underway (provide device submission details and sponsor contact).
Option 2: An in‑house IVD CDx will be accredited under the National Pathology Accreditation Scheme (provide lab details, accreditation timeline, and quality/access reassurances).
Option 3: Standard Australian testing is expected to deliver comparable clinical outcomes to the pivotal trials (provide detailed justification).
Option 4: None of the above—TGA reviews full device data within the medicine dossier (appropriate when no onshore testing is expected).

If Option 4 is used, TGA may add a condition of registration requiring the sponsor to maintain and update the plan (e.g., in case of supply interruption, regulatory action, or material changes to test methodology). Approval of an indication can proceed even when no ARTG‑listed or accredited CDx is available, provided an adequate plan exists; however, a commercial CDx must be in the ARTG (or an in‑house CDx accredited) before supply in Australia.

Clinical trial assay evaluation & comparability

When an indication requires CDx testing, TGA evaluates the clinical trial assay used in the pivotal studies—reviewing scientific validity, analytical performance, clinical performance, and clinical utility. Subsequent CDx must show clinical comparability to the trial assay, typically via concordance and/or bridging studies (or other appropriate evidence) aligned to the trial assay’s core characteristics.

Responsibilities at a glance

Medicine/Biological sponsors must:

Use the TGA CDx identification guide to determine if CDx testing is essential.
Consider consequences of false positives/negatives, test failures or no result.
Include: (a) evidence to support evaluation of the clinical trial assay, and (b) a companion testing plan nominating at least one adequate test.
Note: The framework does not require a one‑to‑one link between an indication and a single proprietary CDx; it focuses on the core characteristics of testing.

Device sponsors must:

Submit an IVD medical device application for ARTG inclusion of the CDx (indicating the application is for a CDx and providing the UPI).
Demonstrate comparability to pivotal trial testing and meet Essential Principles; applications may undergo audit as above.
Ensure the corresponding indication is approved or under concurrent review.

In-house IVD CDx, NATA accreditation and NPAAC obligations

Pathology laboratories may develop/modify in‑house tests for use as CDx. Class 1–3 in‑house IVDs are not included in the ARTG, but require NATA accreditation, identification of CDx in the TGA notification test list, and compliance with the NPAAC standard. Under a NATA–TGA MoU, NATA can request TGA technical assistance during evaluation of in‑house CDx performance; TGA is not otherwise involved in the accreditation decision.

TGA CDx List

The TGA publishes a CDx List showing approved commercial CDx linked to corresponding indications (with in‑house CDx to be added). The list is informational (not a regulatory instrument) and may lag recent approvals by up to one month.

Transitional arrangements and change control

Transition: CDx previously included in the ARTG as Class 2 or 3 before 1 Feb 2020 (and certain in‑house IVDs) may continue supply until 31 Dec 2028; a new compliant application is required to continue supply thereafter.
Changes: Sponsors manage post‑market device changes via the TGA Device Change Request process.

Key takeaways (quick reference)

All CDx are Class 3 IVDs and require separate ARTG inclusion (commercial) or NATA accreditation (in‑house).
Every relevant medicine/biological indication must include a companion testing plan (Options 1–4).
TGA assesses the clinical trial assay and expects comparability evidence for subsequent CDx.
Approval can proceed without on‑shore CDx if a robust plan exists, but supply requires ARTG inclusion or in‑house accreditation.

FAQs

Are all CDx Class 3 IVDs in Australia?

Yes. The regulations specify all CDx (commercial and in‑house) are Class 3 IVDs.

Can an indication be approved if no Australian CDx is available yet?

Yes—if a suitable companion testing plan is in place; however, a commercial CDx must be in the ARTG (or an in‑house CDx accredited) before legal supply.

What goes into a companion testing plan?

Identify at least one adequate test and choose Option 1–4 with supporting details (e.g., ARTG application in progress, in‑house accreditation, justification that standard testing is adequate, or full device data reviewed within the medicine dossier).

Will the PI show that CDx testing is essential?

The TGA recommends a PI “flag phrase” indicating testing is essential and should be comparable to trial testing; approved tests appear on the TGA CDx List.

Written by:

Carlos Galamba

CEO & Head of IVD

Senior regulatory leader and advisor to top 10 global precision medicine companies with deep experience in high-risk IVDs including companion diagnostics.

Industry Insights & Regulatory Updates

FDA Regulation of In Vitro Diagnostic Devices: The Complete Guide for US Market Entry

Scientific Validity Report (SVR) Under EU IVDR: From Literature Review to Defensible Scientific Argument

ISO 10993-1:2025 From Checkbox Compliance to Risk-Based Biocompatibility

Making IVDR Work in Combined Studies: Scientific & Operational Lessons from 40+ Programs

ISO 14155:2026 What’s Changed and What It Means for Your Clinical Investigation

Companion Diagnostic Clinical Trial Case Study

October 8, 2025

Regulatory Turnaround for a Phase 3 Global CDx Clinical Trial (Annex XIV)

A global biopharma company faced a critical delay in a phase 3 clinical trial in oncology. The study required an NGS-based companion diagnostic (CDx) assay to detect a specific mutation and pre-screen patients for eligibility. Several EU authorities initially rejected or stalled the Clinical Performance Study (CPS/PSA) due to assay validation concerns and fragmented IVDR processes. MDx CRO mobilized a specialized cross-functional team, redesigned the documentation package, and re-submitted in six EU countries within three months, clearing all RFIs and enabling on-time trial initiation. This case study has been accepted for presentation at ESMO 2025 in Berlin.

The Challenge

Early rejection and major RFIs: EU bodies questioned assay validation and risk management, threatening the trial start.
Dual-regulation complexity: The trial combined CT and IVDR CPS submissions with different national portals, templates, and timelines.
Harmonization gaps: With EUDAMED not fully operational, CPS authorizations varied widely by Member State, creating long and unpredictable timelines.

What was at stake: lost recruitment windows, protocol amendments, cost escalation, and missed milestones tied to major scientific congresses.

MDx CRO Approach

1) Rapid diagnostic and plan

Completed a 48-hour gap analysis across the submission: CDx protocol, analytical performance package, CER/PER linkages, IFU, training, and risk files.
Mapped country-specific expectations (EC vs NCA) to pre-empt common RFIs: informed consent, site/PI suitability, device training, and performance datasets.

2) Targeted re-engineering

Revised the clinical performance study protocol (CPSP) for the CDx assay to clarify endpoints, eligibility flows, and pre-screening logistics.
Overhauled analytical performance evidence (accuracy, precision, LoD, reproducibility) and tightened traceability to risk controls.
Redeveloped risk management documentation to align hazards, mitigations, and verification with Annex I GSPRs.
Strengthened usability & training to address EC concerns on user competence and patient protection.

3) Country-by-country execution

Sequenced six EU CPS submissions to match national review modalities (combined, parallel, or sequential EC/NCA), reducing idle time between waves.
Built a rapid RFI response playbook so sponsors and sites could respond in days, not weeks.

Results & Impact

All RFIs resolved: Delivered clear, evidence-backed answers across EC and NCA questions, including consent, site suitability, training, and performance data.
Approvals secured quickly: The re-submission strategy compressed timelines and returned the program to the original start path despite EU-wide CPS delays.
Trial initiation preserved: Sites opened on schedule, enabling screening with the NGS CDx pre-screen.
Scientific visibility: Study learnings and regulatory insights are accepted for presentation at ESMO 2025, showcasing efficient navigation of combined CT/IVDR frameworks.

Why It Matters

The IVDR raised the bar for pre-market CDx and investigational IVDs used in drug trials. Sponsors now need diagnostic-grade evidence, strong risk-benefit narratives, and country-aware submission execution. MDx CRO bridges those gaps with integrated clinical, regulatory, and diagnostics expertise so drug–diagnostic programs stay on track.

What We Delivered

Regulatory rescue for a phase 3 global CDx trial in oncology (Annex XIV).
Six-country CPS re-submission under IVDR with country-specific strategies.
Protocol refinement for CDx use, analytical performance reinforcement, and risk-file re-mapping to GSPRs.
RFI playbook & rapid responses covering EC and NCA priorities (consent, training, site suitability; analytical/clinical evidence, CPS plan).
On-time site activation and screening with an NGS CDx assay.

Client Outcome

“MDx CRO restored regulatory confidence and protected our timelines. Their team aligned clinical, diagnostic, and regulatory workstreams and cleared every RFI with precision.”

Ready to Accelerate Your CDx Trial?

Running an EU drug–diagnostic study under IVDR? We can accelerate CPS authorizations, clear RFIs fast, and keep your trial on schedule.

Talk to MDx CRO

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