Companion Diagnostic for a KRAS Inhibitor: IVDR Classification and Article 48 Consultation
An IVD manufacturer has a real-time PCR kit that detects KRAS G12C mutations in formalin-fixed paraffin-embedded tumour tissue. The kit is intended to identify patients with non-small cell lung cancer who may be eligible for a specific targeted therapy. Under the IVDD the kit was self-certified and sold as a general mutation detection assay. The manufacturer now seeks IVDR certification and has submitted a performance evaluation report containing analytical sensitivity (limit of detection 1% variant allele frequency), precision, and a retrospective clinical study of 80 archived samples with known drug response. The drug's pivotal trial used a different, laboratory-developed test. The manufacturer proposes Class C, citing Rule 3, and a conformity assessment with a notified body. The notified body has 12 months to complete the assessment, but the manufacturer wants to launch in 6 months. Tasks: (a) Is Class C correct and what is the conformity assessment route? (b) What additional consultation under IVDR Article 48(3) applies, and how does it affect the timeline? (c) What clinical performance evidence is needed to support the companion diagnostic claim?
1. Is Class C correct, and what is the correct conformity assessment route?
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Class C is correct, but the cited rule is not. A device intended to identify patients who may benefit from a specific medicinal product is a companion diagnostic. Under IVDR Annex VIII, companion diagnostics fall under Rule 6 and are classified as Class C. Rule 3 concerns sexually transmitted agents and is not applicable. The conformity assessment route is Annex IX (QMS and technical documentation assessment) with a notified body, because Class C IVDs cannot be self-certified. The notified body must assess the QMS, technical documentation, and performance evaluation. The manufacturer's 6-month launch plan is unrealistic: the notified body has 12 months and must also complete the Article 48(3) consultation. The classification file should be corrected before submission; otherwise the notified body will raise a deficiency at the outset.
2. What additional consultation under IVDR Article 48(3) applies, and how does it affect the timeline?
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Because the device is a companion diagnostic, Article 48(3) IVDR requires the notified body to consult the competent authority responsible for the medicinal product, or the EMA where the medicinal product is centrally authorised. The consultation covers the suitability of the device in relation to the medicinal product, including the link between the biomarker and the drug's indication. This is a mandatory external step; the notified body cannot issue the certificate until the consultation is concluded and its views are taken into account. The consultation will add time beyond the notified body's own 12-month assessment and is outside the manufacturer's control. The manufacturer should prepare a concise medicinal product interface file, the drug's SmPC, the pivotal trial assay data, and a bridging plan. A 6-month launch is not feasible. The manufacturer should also clarify whether the drug is centrally authorised, because that determines whether EMA or a national competent authority is consulted.
3. What clinical performance evidence is needed to support the companion diagnostic claim?
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The performance evaluation must establish scientific validity, analytical performance, and clinical performance. Analytical performance is partly addressed by the LOD and precision data, but clinical performance must show that the kit identifies the drug-responsive population with sufficient accuracy. The 80-sample retrospective study is likely underpowered and may not reflect the drug's trial population. Because the pivotal trial used a different laboratory-developed test, a bridging study is needed to demonstrate concordance between the new kit and the trial assay, and to link the kit's results to the clinical outcome. The study should use pre-specified cut-offs, the intended sample type and collection conditions, and report clinical sensitivity, specificity, predictive values, and discordant analysis. If the drug's indication is restricted to G12C-positive patients, the kit's false-negative rate has direct clinical consequences. The notified body should require a prospective or well-designed retrospective validation with a sample size justified for the claimed performance. The performance evaluation report must also be updated for the IVDR, following MDCG 2020-1.