Analytical Evidence

Performance evaluation under IVDR requires a tripartite dossier:

• Scientific Validity: Clinical association between biomarker and disease
• Analytical Performance: Sensitivity, specificity, LOD, LOQ, precision
• Clinical Performance: Ability to predict clinical outcome or guide therapy

Sample values expected under IVDR:

• LOD: ≤0.1% mutant allele frequency for NGS panels
• Precision: CV ≤10% intra-assay and ≤15% inter-assay
• PPA/NPA: ≥95% compared to predicate assay

Explore detailed validation expectations at PharmaSOP.in.

Impact of IVDR on Companion Diagnostic Trials

For CDx used in clinical trials, the IVDR significantly affects both pre-market and in-trial activities. Key implications include:

• Mandatory notified body involvement for CDx clinical performance studies
• CE marking prerequisites before trial integration (unless exempted)
• Harmonization with therapeutic product development
• IVDR Annex XIII compliance for study design and documentation

Trials using investigational CDx must adhere to performance study regulations under IVDR Articles 57–77.

Interplay Between CDx and Medicinal Product Approval

Article 48(3) of the IVDR mandates that notified bodies consult with the European Medicines Agency (EMA) or national drug authorities when assessing CDx intended to guide therapy. This linkage ensures alignment between diagnostic and drug labeling.

Example: A CDx for EGFR mutations used to determine eligibility for osimertinib would require concurrent review by a notified body and EMA.

See guidance at EMA’s Medical Device Regulations portal.

Documentation and Technical File Requirements

IVDR technical documentation requirements are far more comprehensive than those under the IVDD. For CDx, manufacturers must include:

• General Safety and Performance Requirements (GSPR) checklist
• Device description and intended purpose
• Risk management file (ISO 14971 compliant)
• Design and manufacturing information
• Performance evaluation plan and report
• Post-market surveillance (PMS) and vigilance plans

Clinical laboratories acting as trial sites must ensure their laboratory-developed tests (LDTs) meet Article 5.5 exemptions or pursue IVDR compliance.

Notified Bodies and Capacity Constraints

One of the biggest bottlenecks for IVDR implementation is the limited number of designated Notified Bodies. As of 2025, only ~12 notified bodies are available for IVDs, leading to delays in CDx conformity assessments.

Strategies to mitigate this include:

• Early engagement with Notified Bodies for trial planning
• Bundled CDx-drug submission strategies
• Pre-submission consultations with EMA

Explore timelines and designation status at PharmaRegulatory.in.

Transitional Provisions and Deadlines for CDx

The EU has provided phased transition periods based on device risk class. For Class C CDx (most biomarker tests), the key deadlines are:

• Legacy CE-marked CDx: Valid until May 26, 2026 (if no significant changes)
• New CDx under IVDR: Must comply with full IVDR by the date of application
• Performance study start: Requires IVDR-compliant study design

Manufacturers should plan for full IVDR transition at least 12–18 months in advance of study initiation.

Case Study: NGS-Based CDx Under IVDR

A diagnostic company developing a 15-gene NGS panel for NSCLC patient stratification under IVDR followed this pathway:

• Device classified as Class C under Rule 3(k)
• Clinical performance study approved under IVDR Article 58
• Technical file submitted to Notified Body with EMA input
• CE marking granted 14 months after first engagement

Key Success Factors:

• Robust analytical validation: LOD ≤ 0.1%, reproducibility ≥ 97%
• Linkage to drug label supported by clinical bridging study
• Early notified body engagement reduced delays

Real-World Impact: CRO and Trial Sponsor Considerations

CROs managing diagnostic trials in the EU must be IVDR-aware. Responsibilities include:

• Verification of CDx CE-marking or Article 5.5 exemption
• Documentation of CDx performance in clinical protocols
• Trial site training on IVDR-compliant procedures
• Device accountability and traceability reporting

For sponsors, IVDR non-compliance may lead to data exclusion by regulators, delaying drug approval pathways.

Comparison with FDA CDx Pathway

Unlike the FDA’s centralized CDx PMA process, the EU’s IVDR uses a decentralized notified body approach. Key differences:

Parameter	FDA (USA)	EU IVDR
Approval Authority	FDA (CDRH)	Notified Body + EMA
Labeling Alignment	Mandatory cross-labeling	Mandatory under Article 48(3)
Validation Requirement	Clinical + analytical	Scientific, analytical, clinical
Process Time	6–12 months	12–18 months

Conclusion

The IVDR represents a transformative change in the regulation of companion diagnostics in the EU. It emphasizes scientific rigor, safety, and transparency. Diagnostic developers, CROs, and trial sponsors must adapt to this new landscape by implementing robust documentation systems, engaging early with regulatory bodies, and aligning CDx development with therapeutic timelines. Compliance with IVDR is not only essential for CE marking but is also critical for maintaining credibility and market access within the European Union’s clinical research ecosystem.