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Companion diagnostics

Regulatory basis

IVDR Art. 2(7) (definition); IVDR Art. 48(3) (mandatory EMA/NCA consultation); IVDR Annex VIII Rule 2 (Class C minimum for companion diagnostics). Companion diagnostics require mandatory coordination between the IVDR pathway and the pharmaceutical regulatory pathway.

Disclaimer

This site provides general information only and does not constitute legal or regulatory advice. The companion diagnostic pathway involves complex interactions between IVDR and pharmaceutical regulation — always seek specialist advice.

Definition​

A companion diagnostic (CDx) is an IVD device that is essential for the safe and effective use of a corresponding medicinal product by:

  • Identifying patients who are most likely to benefit from a particular medicinal product, or
  • Identifying patients likely to be at increased risk of serious adverse reactions from a particular medicinal product, or
  • Monitoring response to treatment with a medicinal product for the purpose of adjusting treatment to achieve improved safety or effectiveness

The key word is essential — not merely "useful" or "associated." If the treatment can be safely and effectively administered without the diagnostic, it is not a companion diagnostic.

Classification — always Class C minimum​

All companion diagnostics are classified as at minimum Class C under IVDR Annex VIII Rule 2. This means:

  • Notified body involvement is mandatory
  • Enhanced technical documentation review
  • Mandatory EMA or NCA consultation (see below)

If the companion diagnostic falls under a higher-risk Rule (e.g. Rule 1 — blood group typing for a cell therapy product), it takes the higher class.

The mandatory consultation — IVDR Art. 48(3)​

Before the notified body can issue a certificate for a companion diagnostic, it must consult EMA (for medicinal products subject to centralised authorisation) or a national medicines authority (for nationally authorised products):

  1. The notified body submits a request for scientific opinion on the IVD's suitability as a companion diagnostic for the medicinal product
  2. EMA/NCA has 60 days to issue an opinion (extendable)
  3. The notified body takes the opinion into account when making its certification decision
  4. Any departure from EMA/NCA's opinion must be documented and justified

This creates a mandatory interdependence between the IVDR CE marking process and the pharmaceutical authorisation process.

Parallel development — the co-development challenge​

Because the CDx must be validated against the medicinal product and vice versa, co-development is strongly encouraged:

Development stageCoordination required
Early developmentAlign intended use statement of CDx with therapeutic indication of drug
Clinical trialsCDx must be validated using samples from the drug clinical trials (ideally pivotal trials)
Regulatory submissionCoordinate IVDR application timeline with EMA/NCA drug review
Post-approvalCDx label and drug label must remain consistent; updates to either may require the other to be updated

Performance evaluation for companion diagnostics​

CDx performance evaluation must demonstrate:

  • Analytical performance: sensitivity, specificity, accuracy for the biomarker
  • Clinical performance: demonstrated link between CDx result and clinical outcome (drug response / adverse event risk)
  • Concordance: if the CDx is not the assay used in the pivotal clinical trials, concordance with the trial assay must be demonstrated
  • Cut-off validation: the threshold between "positive" and "negative" results must be clinically validated

MDCG 2020-16 provides guidance on CDx performance evaluation requirements.

Post-market obligations​

  • PSUR required at minimum annually (Class C)
  • PMPF to monitor real-world performance
  • If the medicinal product's indication changes: re-evaluate CDx intended use and performance
  • If the CDx's intended use changes: notified body and EMA/NCA must be notified

Official references​

ReferenceDescription
IVDR Art. 2(7)Companion diagnostic definition
IVDR Art. 48(3)EMA/NCA consultation for CDx
IVDR Annex VIII Rule 2Class C classification for CDx
MDCG 2020-16Companion diagnostic guidance
EMA guidance on CDxQualification/classification for regulatory purposes