Why combination products keep failing clinical evaluation
I see the same mistake in almost every clinical evaluation report for combination products. The manufacturer treats the device part and the drug part as separate entities, then tries to stitch them together at the end. By the time the Notified Body reviews it, the report fails because the therapeutic claim was never properly justified as a system.
In This Article
The problem is not obvious at first. The device component gets its own clinical data. The drug component gets referenced from established knowledge. The report looks complete. But the clinical evaluation never addressed the actual product: the combination itself.
This is not a minor oversight. It is a structural deficiency that collapses under regulatory scrutiny.
What MDR actually requires for combination products
Under MDR Annex I, the manufacturer must demonstrate the safety and performance of the medical device as placed on the market. For a device-drug combination, the product as placed on the market is not the device alone. It is the integrated system.
Article 1(11) of the MDR defines a device incorporating an ancillary medicinal substance. The device remains the principal mode of action, but the substance is integral to achieving the intended performance.
This means your clinical evaluation must establish that the combination achieves the intended therapeutic effect. You cannot assume the device works and the drug works, therefore the combination works. That assumption is not evidence. It is a regulatory gap.
The clinical evaluation must justify the combination rationale before addressing clinical data. Why does this device need this substance? What performance would be lost without it? This is not a formality. It is the foundation of your clinical claim.
Where the structural gap appears
In most reports I review, the device clinical data is handled in one section. The drug data is summarized in another. Then a final paragraph states that both components are safe and effective, so the combination is acceptable.
This structure reveals a fundamental misunderstanding. The clinical evaluation is not a checklist of component validations. It is a demonstration that the integrated product meets its intended purpose under its conditions of use.
Here is what gets missed:
The interaction profile. How does the device delivery mechanism affect the pharmacokinetics? Does the release rate match the therapeutic window? Is there a risk of dose dumping or incomplete delivery?
If your device delivers a drug over 24 hours but your literature only covers bolus administration, you have a data gap. That gap does not disappear because the drug is approved for other routes.
The use conditions. A drug-eluting stent is not just a stent plus a drug. It is a system where the drug must remain stable during storage, survive deployment, and release at the target site without migration. Each of these conditions affects the clinical outcome.
If your clinical data does not reflect these conditions, your equivalence claim will not hold. The Notified Body will ask how you know the performance translates.
The risk profile of the combination. Device risks and drug risks do not simply add. They interact. A device that causes minor irritation may become a major issue when combined with a substance that delays healing. A drug with low systemic exposure becomes a different risk when delivered directly to a vascular site.
Your clinical evaluation must address these interactions explicitly. A side-by-side safety summary is not sufficient.
Citing general pharmacology data without linking it to the device-specific delivery mechanism. Reviewers will note that the literature describes the drug, but not the drug as delivered by your device under your conditions of use. That distinction is non-negotiable.
How the Notified Body thinks about this
The Notified Body reviewer is looking for a coherent argument. Not two separate arguments placed next to each other.
They want to see:
1. A clear definition of what the combination product is and why it is designed this way
2. Clinical data that reflects the combination in use, not the components in isolation
3. A risk-benefit analysis that considers the interaction effects, not just additive risks
4. A rationale for why existing data is applicable, if you are claiming equivalence or literature reliance
If your report treats the device and drug as independent modules, the reviewer will ask: where is the evidence that this combination works?
And if your answer is that both components are proven separately, the response will be: that is not what we asked.
What happens when the data does not exist
This is where many manufacturers get stuck. They realize the existing literature does not cover their combination. The device data exists. The drug data exists. But the combination data does not.
At this point, there are two paths.
Path one: generate the data. This means clinical investigation. It means designing a study that evaluates the combination product under its intended use. It is resource-intensive and time-consuming, but it is sometimes the only path to compliance.
Path two: justify reliance on existing data through a robust bridging argument. This is acceptable under MDCG 2020-5 and MDCG 2020-6, but only if the argument is rigorous.
You must show that the existing data is relevant to your specific combination. This means addressing the delivery mechanism, the release kinetics, the local tissue response, and the systemic exposure. It means showing that the differences between the studied condition and your product do not materially affect the clinical outcome.
This is not a paragraph. It is a detailed technical justification supported by in vitro data, pharmacokinetic modeling, and risk analysis.
If your clinical evaluation contains a sentence like
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).
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Peace, Hatem
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