IVDR Companion Diagnostic Consultation File: NB-EMA/NCA Package Guide
Prepare an IVDR companion diagnostic consultation file for NB submission, covering EMA/NCA review, contents, performance evidence, drug label alignment, timing, and deficiency risks.
What This Article Covers
This article explains how to prepare the consultation file that a Notified Body (NB) submits to the European Medicines Agency (EMA) or a national competent authority (NCA) when assessing a companion diagnostic (CDx) under IVDR Article 48 and Annex IX Section 5.2. It covers the consultation trigger, package contents, timing, analytical and clinical performance evidence requirements, drug label alignment, deficiency patterns, and the Team-NB V2 (October 2025) decision flowchart for significant changes.
This article covers:
When and why the NB must consult a medicinal product authority for CDx devices
Which authority (EMA vs. NCA) the NB must consult, and when
The complete consultation file: contents, structure, and evidence requirements
Analytical performance evidence the consultation file must contain
Clinical performance evidence and how it links to the drug label
Timing of the consultation relative to the drug's marketing authorisation
The Team-NB V2 flowchart for significant changes to CDx devices
Common deficiency patterns in the consultation process
RACI for CDx consultation preparation
Bridging study requirements for clinical trial assay-to-commercial CDx comparability
This article does NOT cover:
Companion diagnostics regulatory overview (see the companion diagnostics guide)
General IVDR classification or conformity assessment procedures
IVDR performance evaluation methodology for non-CDx IVDs
FDA companion diagnostic co-development pathways
Drug marketing authorisation procedures at EMA
When the NB Must Consult a Medicinal Product Authority
Regulatory Trigger
Under IVDR Article 48(3), when the conformity assessment of a CDx is conducted under Annex IX (full quality assurance and technical documentation assessment), the NB must seek a scientific opinion on the suitability of the CDx in relation to the corresponding medicinal product. The NB shall give due consideration to the scientific opinion and must not issue a certificate if the opinion is unfavourable.
Which Authority: EMA vs. NCA
Table 1: Consultation Authority Determination
| Scenario | Consultation Authority | Legal Basis |
|---|---|---|
| Medicinal product falls exclusively within the scope of the centralized procedure | EMA | IVDR Article 48(3) |
| Medicinal product is already authorized through the centralized procedure | EMA | IVDR Article 48(3) |
| A marketing authorisation application (MAA) for the medicinal product has been submitted through the centralized procedure | EMA | IVDR Article 48(3) |
| Medicinal product authorized through national or mutual recognition / decentralized procedure | National competent authority OR EMA (NB's choice) | IVDR Article 48(4) |
The CDx Definition Test
Not every biomarker-detecting IVD is a CDx. Per IVDR Article 2(7), a CDx is a device essential for the safe and effective use of a corresponding medicinal product to:
Identify patients who are most likely to benefit from the medicinal product, OR
Identify patients likely to be at increased risk of serious adverse reactions from the medicinal product
Per Recital 12 IVDR, devices used for monitoring treatment to ensure concentrations stay within a therapeutic window are NOT companion diagnostics. MDCG 2020-16 Annex II provides a flowchart to determine CDx status.
Table 2: CDx Classification and Consultation Requirements
| IVDR Classification | Rule | Consultation Required | Conformity Assessment Route |
|---|---|---|---|
| Class C | Annex VIII, Rule 3f (all CDx are Class C) | Yes — mandatory | Annex IX (full QMS + TD assessment) or Annex X (TD assessment) + Annex XI (product QA) |
Consultation File Package Contents
The consultation file is submitted by the NB (not the manufacturer directly) to EMA or the NCA. However, the manufacturer must prepare and provide all supporting documentation to the NB. The package must contain:
Table 3: CDx Consultation File — Complete Package Contents
| # | Document / Section | Content Requirements | Owner / Preparer |
|---|---|---|---|
| 1 | NB application form | EMA's standard application form for initial consultation on a CDx (available on EMA website, ~128 KB DOCX) | NB (with manufacturer input) |
| 2 | Device description and intended purpose | CDx name, biomarker detected, specimen type, platform/technology, intended use population, corresponding medicinal product(s) | Manufacturer |
| 3 | Intended use and CDx–drug pairing rationale | Why the biomarker identification is essential for safe/effective use of the medicinal product; clinical context | Manufacturer + Drug Sponsor/MAH |
| 4 | Analytical performance data | Scientific validity, analytical sensitivity, analytical specificity, accuracy, precision, measurand trueness, cut-off determination, interference, cross-reactivity | Manufacturer |
| 5 | Clinical performance data | Diagnostic sensitivity, diagnostic specificity, positive/negative predictive values, clinical concordance with therapeutic outcome | Manufacturer |
| 6 | Bridging study data (if applicable) | Concordance between clinical trial assay (CTA) and commercial CDx; sample overlap; statistical comparison | Manufacturer |
| 7 | Corresponding medicinal product information | Drug name, INN, MA status, relevant section of SmPC relating to biomarker-guided treatment | Drug Sponsor/MAH |
| 8 | Drug label alignment | Mapping of CDx intended use claims to specific sections of the drug's Summary of Product Characteristics (SmPC) | Manufacturer + Drug Sponsor/MAH |
| 9 | Risk management file (summary) | Residual risks, benefit-risk determination, risk-benefit of the CDx–drug pairing | Manufacturer |
| 10 | Performance evaluation report (relevant sections) | PER sections covering scientific validity, analytical performance, and clinical performance | Manufacturer |
| 11 | IFU (draft or final) | Instructions for use of the CDx device | Manufacturer |
| 12 | Proposed CDx labeling claims | All claims the manufacturer intends to make about the CDx–drug relationship | Manufacturer + Drug Sponsor/MAH |
Analytical Performance Evidence
The consultation file must demonstrate that the CDx accurately and reliably detects the biomarker it claims to detect. The analytical performance section of the file must address:
Table 4: Analytical Performance Data Requirements for CDx Consultation
| Parameter | What to Document | Typical Acceptance Approach |
|---|---|---|
| Scientific validity | Peer-reviewed literature establishing the biomarker's relevance to the disease/therapy | Systematic literature review; referenced in PER |
| Analytical sensitivity | Limit of detection (LoD), limit of quantification (LoQ) for the biomarker | LoD established per CLSI EP17 or equivalent |
| Analytical specificity | Cross-reactivity with related biomarkers; interference from common substances | Cross-reactivity panel; interference study per CLSI EP07 |
| Accuracy | Agreement with reference method or orthogonal assay | Overall percent agreement (OPA) with 95% CI |
| Precision | Repeatability (within-run), intermediate precision (between-run, between-lot, between-site) | Per CLSI EP05; results per run, per lot, per site |
| Cut-off determination | How the diagnostic cut-off was established and validated | ROC curve analysis; clinical decision point justification |
| Sample types | Evidence that the CDx performs as specified with all claimed specimen types (FFPE tissue, fresh frozen, liquid biopsy, etc.) | Validation in each claimed specimen type |
| Stability | Specimen stability, reagent stability, onboard stability | Per IVDR Annex I Section 9.4 |
Clinical Performance Evidence
Clinical performance is the most extensively discussed topic during EMA consultations (per Frontiers in Medicine analysis of 20 centralized procedures). The consultation file must demonstrate that the CDx identifies the correct patient population for the corresponding medicinal product.
Table 5: Clinical Performance Data Requirements for CDx Consultation
| Parameter | What to Document | Evidence Source |
|---|---|---|
| Diagnostic sensitivity | Proportion of biomarker-positive patients correctly identified by the CDx | Clinical performance study; bridging study |
| Diagnostic specificity | Proportion of biomarker-negative patients correctly identified as negative | Clinical performance study; bridging study |
| Positive predictive value (PPV) | Proportion of CDx-positive patients who truly have the biomarker | Clinical study or real-world data |
| Negative predictive value (NPV) | Proportion of CDx-negative patients who truly lack the biomarker | Clinical study or real-world data |
| Clinical concordance with therapeutic outcome | Does biomarker status (as determined by CDx) predict treatment response? | Pivotal drug clinical trial data (CDx arm or bridging) |
| Prevalence context | Biomarker prevalence in the intended use population | Literature; screening data; drug clinical trial screening data |
Bridging Studies: Clinical Trial Assay to Commercial CDx
In most CDx programs, the assay used during the pivotal drug clinical trial (the Clinical Trial Assay, CTA) is different from the final commercial CDx. A bridging study demonstrates that the commercial CDx produces results concordant with the CTA.
Table 6: Bridging Study Design Framework
| Element | Requirement |
|---|---|
| Objective | Demonstrate concordance between CTA and commercial CDx |
| Sample selection | Retained clinical trial samples (positive and negative for biomarker); must span the range of biomarker expression |
| Minimum sample size | Typically 100–300 samples depending on biomarker prevalence; must be justified statistically |
| Statistical method | Positive percent agreement (PPA), negative percent agreement (NPA) with 95% CI; Cohen's kappa |
| Acceptance criteria | Pre-specified concordance thresholds (typically PPA and NPA ≥ 90% with lower CI bound ≥ 85%) |
| Discordant sample resolution | Orthogonal testing of discordant results; clinical outcome review |
| Documentation | Bridging study report included in consultation file (Table 3, Item 6) |
Timing the Consultation
Coordination with Drug Marketing Authorisation
The EMA Q&A document on CDx consultation procedures states that the CDx consultation should ideally be submitted during the final evaluation phase of the associated medicinal product's marketing authorisation application (MAA). The NB and device manufacturer must coordinate closely with the drug applicant/MAH.
Table 7: CDx Consultation Timeline
| Milestone | Timing | Responsible | Notes |
|---|---|---|---|
| Letter of intent to EMA | ≥ 3 months before expected NB application submission | NB (with manufacturer coordination) | Submitted via EMA Service Desk: Business Services → Human Regulatory → Pre-Submission Phase – Human → Companion Diagnostics Request |
| NB application to EMA | When CDx technical documentation is complete | NB | EMA procedural timetable provides specific submission dates |
| EMA scientific opinion | ~60–90 days from acceptance of application | EMA CDx Expert Group | Timetable available on EMA website |
| NB decision on certification | After receiving EMA scientific opinion | NB | NB must give due consideration; cannot issue certificate if opinion is unfavourable |
Letter of Intent
The letter of intent is mandatory. Per RegDesk analysis of the EMA Q&A, applicants (the NB on behalf of the manufacturer) must submit it at least three months before the expected application date. This enables EMA resource planning and allocation of the CDx Expert Group.
Team-NB V2 Decision Flowchart for Significant Changes
Team-NB published Version 2 of its position paper on CDx significant changes under IVDR Annex IX Section 5.2 on October 29, 2025. The key decision point:
Does the anticipated change to a CDx affect the suitability of the device in relation to the medicinal product concerned?
Table 8: Team-NB V2 Change Classification
| Change Type | Examples | NB Action | EMA/NCA Consultation Required? |
|---|---|---|---|
| Changes requiring initial consultation (new conformity assessment) | New biomarker target; new indication (additional cancer type); change in companion medicinal product; new drug–CDx pairing | Full new conformity assessment | Yes — EMA or NCA |
| Changes requiring follow-up consultation (certificate supplement) | Additional mutation within same biomarker with outcome data; change in cut-off that affects patient selection; new specimen type | Certificate supplement | Possibly — NB determines based on flowchart |
| Changes not requiring consultation | Change in critical raw material/supplier (no performance impact); platform transfer (validated, same performance); shelf-life extension; new reagent supplier; new place of manufacture (no performance change) | NB notification; may require assessment | No |
The Team-NB V2 flowchart should be applied for every planned change to a CDx to determine the correct regulatory pathway.
Common Deficiency Patterns
Based on analysis of EMA assessment reports and Frontiers in Medicine research on CDx evaluation across 20 centralized procedures:
Table 9: Common CDx Consultation Deficiency Patterns
| Deficiency Area | Frequency | Description | How to Prevent |
|---|---|---|---|
| Clinical performance evidence | Most common | Insufficient data demonstrating that CDx-identified patients actually respond differently to the drug vs. non-identified patients | Include pivotal trial stratification data; provide biomarker-by-outcome interaction analysis |
| Analytical performance gaps | Very common | Missing cross-reactivity data for related biomarker variants; cut-off not clinically validated | Complete analytical panel per Table 4; clinically justify cut-off |
| Bridging study design | Common | Inadequate sample size; samples not representative of intended use population; no discordant resolution | Design bridging study early; use clinical trial samples spanning biomarker range; pre-specify concordance criteria |
| Drug label misalignment | Common | CDx intended use does not precisely match SmPC language about biomarker-guided treatment | Map every CDx claim to specific SmPC text (Table 10); coordinate with drug MAH |
| Sample handling issues | Less common but critical | Discordant results due to different sample fixation/processing between CTA and CDx | Validate CDx on same sample types used in pivotal trial; document sample handling SOPs |
| Missing interchangeability data | Less common | No data on whether the CDx can be interchanged with alternative assays for the same biomarker | Include concordance data with established reference assays if applicable |
Drug Label Alignment Matrix
Table 10: CDx–SmPC Alignment Matrix
| CDx Claim / Intended Use Statement | Corresponding SmPC Section | SmPC Text (illustrative) | Aligned? | Evidence Reference |
|---|---|---|---|---|
| "The CDx identifies EGFR exon 19 deletions and exon 21 L858R substitution mutations in NSCLC patients eligible for treatment with [Drug X]" | Section 4.1 (Therapeutic indications) | "[Drug X] is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC harboring activating EGFR mutations (exon 19 deletions or exon 21 L858R)" | Yes | PER Section 5.3; Bridging study report |
| "The CDx is intended for use with FFPE tumor tissue specimens" | Section 4.2 (Posology and method of administration) | "Treatment with [Drug X] should be initiated by a physician experienced in the administration of anticancer therapies. Patients must have EGFR mutation-positive NSCLC as detected by a validated test using FFPE tumor tissue" | Yes | Analytical validation report, Section 3.2 |
| "Patients negative for EGFR activating mutations should not receive [Drug X]" | Section 4.4 (Special warnings and precautions) | "Patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 L858R have not been studied. [Drug X] should not be used in these patients" | Partially — CDx must detect all specified mutations | Clinical performance data for all claimed mutations |
RACI for CDx Consultation Preparation
Table 11: CDx Consultation RACI
| Activity | Responsible | Accountable | Consulted | Informed |
|---|---|---|---|---|
| Determine CDx classification (confirm Class C) | Regulatory Affairs (IVD) | Regulatory Affairs Director | Clinical, Quality | Management |
| Identify corresponding medicinal product and MA status | Regulatory Affairs (IVD) + Drug Regulatory Affairs | Regulatory Affairs Director | Drug Sponsor/MAH | Management |
| Determine consultation authority (EMA vs. NCA) | NB + Regulatory Affairs | NB | Drug Sponsor/MAH | Manufacturer |
| Prepare analytical performance dossier | R&D / Assay Development | Regulatory Affairs (IVD) | Clinical, Statistics | Quality |
| Prepare clinical performance dossier | Clinical Affairs | Regulatory Affairs (IVD) | Drug Sponsor/MAH, Statistics | Quality |
| Design and execute bridging study | Clinical Operations + R&D | Clinical Affairs Director | Statistics, Drug Sponsor | Regulatory Affairs, Quality |
| Prepare drug label alignment matrix | Regulatory Affairs (IVD) + Drug Regulatory Affairs | Regulatory Affairs Director | Drug Sponsor/MAH, Clinical | Management |
| Submit letter of intent to EMA | NB | NB Program Manager | Manufacturer Regulatory Affairs | Manufacturer Management |
| Compile consultation file for NB | Regulatory Affairs (IVD) | Regulatory Affairs Director | All contributors | Quality, Management |
| NB submits application to EMA/NCA | NB | NB Assessment Manager | Manufacturer | Manufacturer Regulatory Affairs |
| Respond to EMA/NCA questions | Regulatory Affairs (IVD) + Clinical Affairs | Regulatory Affairs Director | Drug Sponsor/MAH, R&D | Quality, Management |
Common Failure Modes and Remediation
Table 12: CDx Consultation Failure Modes
| Failure Mode | Description | How to Remediate |
|---|---|---|
| Late coordination with drug sponsor | Manufacturer starts CDx conformity assessment without aligning with drug MAA timeline | Begin coordination at least 12–18 months before planned CE marking; align with drug's centralized procedure timeline |
| Missing bridging study | Commercial CDx differs from CTA but no bridging data provided | Plan bridging study during drug pivotal trial; use retained clinical trial samples |
| Analytical performance incomplete | Cross-reactivity or interference data missing for specific biomarker variants | Complete full analytical panel per Table 4 before submission |
| Unfavourable EMA opinion | EMA concludes CDx is not suitable for the medicinal product | Address specific concerns raised; provide additional data; may require new clinical performance study |
| Drug label mismatch | CDx claims extend beyond what the SmPC supports | Restrict CDx intended use to match SmPC language exactly; coordinate with drug MAH for SmPC update if needed |
| Inadequate sample representativeness | Bridging study uses samples not reflective of intended population | Ensure bridging samples match disease prevalence, biomarker distribution, and specimen types in intended use |
| Underestimating NB capacity constraints | Only 8 NBs designated under IVDR as of 2023; limited capacity for CDx assessment | Engage NBs 12–18 months before planned CE marking; initiate NB application early per Regulation (EU) 2024/1860 deadlines (Class C NB agreement by September 26, 2026) |
Illustrative case timeline: One CDx manufacturer (KRAS mutation test for colorectal cancer, reported by Brilitas EU in 2025) achieved CE marking within 11 months from project initiation, with no EMA objections during scientific consultation, and launched in 6 EU countries within 3 months of certification. This timeline is achievable when the consultation file is complete and the drug sponsor coordination is well-managed.
Key Regulatory References
IVDR Article 2(7) — Companion diagnostic definition
IVDR Article 48(3) and (4) — Consultation of medicinal products authorities
IVDR Annex VIII Rule 3f — CDx classification as Class C
IVDR Annex IX Section 5.2 — Conformity assessment requirements for CDx
IVDR Annex IX Section 5.4 — Additional requirements for CDx technical documentation
MDCG 2020-16 — Guidance on classification of IVD devices (includes CDx flowchart in Annex II)
Team-NB Position Paper V2 (October 2025) — Changes to CDx devices under IVDR Annex IX Section 5.2
EMA Guideline on CDx consultation procedure — Procedural aspects for NB consultation
EMA Q&A on CDx consultation — Practical arrangements including letter of intent requirements
EMA CDx application forms — Initial consultation and follow-up consultation templates (available on EMA website)
IMDRF N91 (2026 draft) — Clinical evidence for IVD medical devices, including dedicated CDx section with detailed treatment of bridging studies, therapy stratification vs. therapy selection design, and clinical trial assay-to-commercial CDx comparability (open for public consultation through May 5, 2026)
Recital 12 IVDR — Clarification that monitoring devices are not CDx