Your diagnostic works. But does the drug? That’s your problem now.
A companion diagnostic can have perfect analytical performance—95% sensitivity, 99% specificity, tight reproducibility. But if the drug it’s paired with doesn’t deliver the claimed clinical benefit, your device file collapses. Because under IVDR Article 56, your clinical evaluation must now prove not just that the device works, but that the link between your result and therapeutic efficacy actually holds.
In This Article
This is not theoretical.
I’ve reviewed files where the IVD performed flawlessly in biomarker detection, but the clinical evaluation stopped there. The manufacturer assumed that demonstrating analytical validity was enough. It wasn’t. The Notified Body asked: where is the evidence that patients who test positive and receive the drug actually benefit? Where is the evidence that patients who test negative are spared unnecessary treatment?
The file had no answer.
Why companion diagnostics are regulated differently
A companion diagnostic is not just another IVD. It is a device whose result directly determines whether a patient receives a specific therapeutic product. The diagnosis is inseparable from the treatment decision.
IVDR Article 56 recognizes this. It requires that the clinical evidence for a companion diagnostic must include data demonstrating the link between the device’s result and the clinical outcomes associated with the therapy.
This means your clinical evaluation cannot focus only on the device’s technical performance. It must address the clinical utility of the entire diagnostic-therapeutic pathway.
Most manufacturers underestimate what this means in practice.
Analytical validity answers: does the device detect the biomarker correctly? Clinical validity answers: does the biomarker predict the outcome? Clinical utility answers: does acting on the result improve patient outcomes? You need all three.
The clinical evidence structure for companion diagnostics
The clinical evaluation for a companion diagnostic has a more complex structure than for a standard IVD. You are not just proving that your device works. You are proving that the entire system—device plus drug—produces the intended therapeutic benefit.
This requires three interconnected evidence layers.
Layer 1: Analytical performance
This is what most manufacturers do well. You demonstrate that your device accurately measures the biomarker. Sensitivity, specificity, precision, reproducibility, stability.
This is necessary. But it is not sufficient.
Because even if your device correctly identifies the biomarker, that tells you nothing about whether the biomarker predicts drug response.
Layer 2: Clinical validity of the biomarker
This is where the gaps begin to appear.
Clinical validity means: does the presence or level of the biomarker actually correlate with the clinical outcome you claim? Does high expression of the target predict response to the drug? Does low expression predict non-response?
This evidence usually comes from the drug’s pivotal clinical trials. But here is the problem: those trials were often conducted with a different diagnostic device. Maybe a laboratory-developed test. Maybe a research-grade assay. Maybe a predecessor version of your device.
If the drug trial did not use your exact device, you must bridge the gap. You must show that your device produces equivalent results to the one used in the trial.
This is not optional. This is not a detail. This is the foundation of your claim.
The clinical evaluation references the drug’s pivotal trial but provides no bridging study showing that the subject device produces concordant results with the assay used in that trial. The link between device result and drug efficacy is assumed, not demonstrated.
Layer 3: Clinical utility—does the test change outcomes?
This is the layer most often missing.
Clinical utility asks: do patients benefit from being tested? Does using your device to select patients for therapy lead to better outcomes than not using it?
For a companion diagnostic, this means showing that patients who test positive and receive the drug do better than if they had been treated without testing. And that patients who test negative are correctly excluded from a therapy that would not benefit them—or worse, harm them.
This evidence is difficult to generate prospectively. But it is exactly what IVDR Article 56 and MDCG 2020-16 require you to address.
You cannot claim clinical benefit for the diagnostic-therapeutic pair without evidence that the testing strategy improves outcomes.
The bridging study problem
Most companion diagnostics rely on drug trial data that was not generated with the subject device. This creates a critical evidence gap.
You must bridge that gap with a study demonstrating concordance between your device and the assay used in the drug trial. This is not a small validation study. This is a formal bridging study with sufficient sample size, appropriate clinical specimens, and statistical analysis showing that your device classifies patients the same way the trial assay did.
If the concordance is not near-perfect, your claim collapses. Because if your device classifies 15% of patients differently than the trial assay, you cannot reliably predict which patients will respond to the drug.
I have seen files where the bridging study showed 85% overall agreement. The manufacturer considered this acceptable. The Notified Body did not. Because 15% discordance means that a significant proportion of patients will be misclassified—either denied effective therapy or exposed to ineffective therapy.
The threshold for acceptable concordance is not defined in regulation. But in practice, anything below 95% positive and negative agreement raises serious concerns.
If your device was not used in the drug’s pivotal trial, the bridging study is not a supporting document. It is the central pillar of your clinical evaluation. Without it, you have no valid link to therapeutic efficacy.
What about post-market evidence?
PMCF for a companion diagnostic is not the same as for other IVDs. You are not just monitoring device performance. You are monitoring the entire diagnostic-therapeutic pathway.
This means your PMCF plan must capture:
- Whether patients classified as positive by your device actually receive the drug
- Whether those patients respond as predicted by the drug trial data
- Whether patients classified as negative are appropriately excluded
- Whether any adverse outcomes occur due to misclassification
Real-world evidence is critical here because the controlled conditions of the drug trial do not reflect routine clinical use. Specimen handling may differ. Patient populations may differ. Interpretation criteria may be applied inconsistently.
Your PMCF must detect these discrepancies. And if real-world performance diverges from trial-based predictions, you must investigate and act.
This is not passive surveillance. This is active monitoring of clinical utility.
The reviewer’s perspective
When I review a companion diagnostic CER, I am looking for one thing above all: does this file prove that the device result reliably predicts therapeutic benefit?
If the evidence chain is broken at any point—if the analytical performance is not validated, if the bridging study is missing or weak, if the drug trial data does not support the claimed clinical utility—the file fails.
Because a companion diagnostic is not just a measurement device. It is a clinical decision tool. And if that decision is wrong, patients are harmed.
Notified Bodies understand this. That is why the questions are sharp and the evidence bar is high.
The CER treats the companion diagnostic like a standalone IVD, focusing on analytical performance and device-specific clinical studies. The link to drug efficacy is stated in the intended use but not substantiated with appropriate clinical evidence.
What this means for your file
If you are preparing a clinical evaluation for a companion diagnostic, start by mapping the complete evidence chain:
From biomarker detection → to biomarker-outcome correlation → to patient benefit from testing.
Identify where each piece of evidence comes from. Identify the gaps. Then determine how you will fill them—through bridging studies, through post-market data collection, or through additional literature analysis.
Do not assume that strong analytical performance is enough. Do not assume that referencing the drug trial is enough. Do not assume that the Notified Body will accept weak concordance data.
The regulatory expectation is clear: you must demonstrate that your device, when used as intended, enables appropriate therapeutic decisions that improve patient outcomes.
If you cannot demonstrate that, your device should not be on the market.
Because in this case, the stakes are not just diagnostic accuracy. They are therapeutic success or failure.
Peace,
Hatem
Clinical Evaluation Expert for Medical Devices
Follow me for more insights and practical advice.
Frequently Asked Questions
What is a Clinical Evaluation Report (CER)?
A CER is a mandatory document under MDR 2017/745 that demonstrates the safety and performance of a medical device through systematic analysis of clinical data. It must be updated throughout the device lifecycle based on PMCF findings.
How often should the CER be updated?
The CER should be updated whenever significant new clinical data becomes available, after PMCF activities, when there are changes to the device or intended purpose, and at minimum during annual reviews as part of post-market surveillance.
What causes CER rejection by Notified Bodies?
Common reasons include inadequate equivalence demonstration, insufficient clinical data for claims, poorly structured SOTA analysis, missing gap analysis, and lack of clear benefit-risk determination. Structure and logical flow are as important as the data itself.
Which MDCG guidance documents are most relevant for clinical evaluation?
Key documents include MDCG 2020-5 (Equivalence), MDCG 2020-6 (Sufficient Clinical Evidence), MDCG 2020-13 (CEAR Template), MDCG 2020-7 (PMCF Plan), and MDCG 2020-8 (PMCF Evaluation Report). IVDR Article 56, MDCG 2020-16
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Peace, Hatem
Your Clinical Evaluation Partner
Follow me for more insights and practical advice.
– Regulation (EU) 2017/746 (IVDR), Article 56: Conjunction of a device with a medicinal product
– MDCG 2020-16: Guidance on Clinical Evidence for In Vitro Diagnostic Medical Devices
Deepen Your Knowledge
Read Complete Guide to Clinical Evaluation under EU MDR for a comprehensive overview of clinical evaluation under EU MDR 2017/745.
