Combination Products Under MDR: The Drug-Device Clinical Gap

Written by HATEM RABEH, MD, MSc Ing

Your Clinical Evaluation Expert And Partner

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Combination products expose a structural problem in how clinical evaluation teams are organized. The device specialists handle mechanical safety and performance. The pharmaceutical specialists handle the active substance. But MDR requires clinical evidence for the combination, not the components in isolation.

When you split the work by discipline, you lose sight of what the regulator actually needs to see.

What MDR Actually Defines as a Combination Product

MDR Article 1(10) defines a device incorporating a medicinal substance as an integral part. This is not a device and a drug. It is a single medical device where the substance and the device body form a unified product with a single intended use.

The clinical evaluation must therefore demonstrate that the combination achieves the intended clinical performance and safety profile. You cannot simply reference the drug’s marketing authorization and call it sufficient.

But here is what happens in practice.

The device manufacturer assumes the drug is already approved, so the clinical evidence for the substance is covered. The focus shifts entirely to the device component. The CER discusses biocompatibility, mechanical function, and usability. The drug part gets mentioned, but not evaluated in the context of the combination.

This creates a clinical gap that Notified Bodies will identify immediately.

Why the Drug Authorization Does Not Cover the Combination

The medicinal product authorization evaluates the substance in a specific formulation, delivery route, and dosing regimen. When that substance is incorporated into a device, the delivery dynamics change.

The device controls release kinetics. It determines the local concentration at the target site. It influences bioavailability and tissue interaction. The clinical performance of the combination depends on how the device delivers the drug, not just on the drug’s pharmacological properties.

If you reference a marketing authorization for an oral formulation, and your device delivers the same substance via a coated stent, the clinical evidence does not transfer directly. The delivery mechanism is different. The clinical claim must be supported by evidence specific to that delivery system.

This is not a theoretical concern.

I have reviewed CERs where the only clinical evidence for the drug component was the summary of product characteristics from an oral tablet. The device in question was an implantable reservoir. The release profile was completely different. The bioavailability was not comparable. The clinical performance claim had no supporting evidence.

The Notified Body rejected the submission.

What the Clinical Evaluation Must Actually Cover

MDR Annex XIV applies to combination products just as it applies to any medical device. The difference is in what you must evaluate.

The clinical evaluation must address:

• The clinical performance of the combination in achieving the intended use
• The safety profile of the substance as delivered by the device
• The interaction between the device component and the substance during use
• Any risks arising from the combination that would not exist for the components alone

This means your literature search must target studies that evaluate the combination or similar delivery systems. You cannot rely solely on pharmacology studies of the substance in isolation.

If no directly relevant clinical data exists for your specific combination, you must generate it. This typically requires clinical investigations under MDR Article 62 and the device-drug combination provisions.

This eliminates many equivalence pathways that device manufacturers assume are available.

The Consultation Requirement Under Article 117

MDR Article 117 requires the Notified Body to consult the relevant medicinal product authority before issuing a certificate for certain combination products. This applies when the device incorporates a substance that, if used separately, would be a medicinal product subject to authorization.

The consultation addresses whether the quality and safety of the substance meet the requirements of the pharmaceutical directive. But it also touches on whether the clinical evidence supports the intended use of the combination.

What this means for you:

Your CER must be structured to support both the device assessment and the pharmaceutical consultation. The evidence must demonstrate that the substance, as incorporated and delivered, meets quality standards and supports the clinical claim.

If your CER treats the drug part as secondary or assumes it is already covered by existing approvals, the consultation process will reveal the gap. The medicinal authority will ask for evidence specific to the delivery system. If you cannot provide it, the certification stalls.

I have seen timelines extend by months because this requirement was not anticipated. The device team thought the drug was handled. The pharmaceutical authority disagreed.

How to Structure the Clinical Evidence for Combination Products

The clinical evaluation should address the combination as a unified system. This requires integrating device and pharmaceutical perspectives from the start.

Your evidence base should include:

Pharmacokinetic and pharmacodynamic data for the substance as delivered by the device. This includes release profiles, local and systemic exposure, and tissue interaction data. If this data does not exist, you must generate it through preclinical studies or early clinical work.

Clinical performance data demonstrating that the combination achieves the intended effect. This cannot be inferred from separate studies of the device and drug. You need studies where the combination is actually used.

Safety data specific to the combination. This includes adverse events related to the interaction between device and substance, such as inflammatory responses to drug-eluting coatings or dosing variability due to device malfunction.

If you are using equivalence, the predicate must be a combination product with the same substance and delivery mechanism. You must then demonstrate that any differences in design do not impact the clinical performance or safety of the combination.

This is a higher bar than standard device equivalence.

What Happens When the Evidence Is Split

When the device evidence and the drug evidence are developed in silos, the CER reflects that separation. You end up with two disconnected sections. One describes the device. One describes the drug. Neither addresses the combination.

The Notified Body reads the CER and asks: Where is the evidence that this combination works as intended?

The manufacturer responds by pointing to the device studies and the drug approval. But that is not an answer. The question was about the combination.

This deficiency cannot be resolved by rewriting the report. You need actual clinical evidence that evaluates the combination. If that evidence does not exist, you must generate it.

This is why early planning is critical. If you wait until the CER stage to realize you lack combination-specific data, you are facing a major delay.

The Role of PMCF for Combination Products

Post-market clinical follow-up for combination products must monitor both the device performance and the drug delivery effectiveness. This includes tracking whether the substance is being delivered as intended across real-world use conditions.

Your PMCF plan should specify:

• How you will monitor drug release consistency in clinical use
• What clinical endpoints will confirm that the combination maintains its intended performance
• How you will detect adverse events related to the interaction between device and substance

If your PMCF plan only addresses device functionality, you are missing half the picture. The Notified Body will notice.

PMCF data should feed back into the clinical evaluation at each update. If post-market evidence suggests that drug delivery varies more than expected, or that safety signals emerge related to the combination, the clinical evaluation must reflect this and address the implications.

How to Coordinate Between Device and Pharmaceutical Expertise

The clinical evaluation of a combination product requires genuine collaboration between device and pharmaceutical specialists. This is not a matter of assigning sections. It is about ensuring the entire evaluation addresses the combination as a unified product.

In practice, this means:

The device specialist must understand how the substance is intended to function and what clinical evidence is needed to demonstrate that function.

The pharmaceutical specialist must understand how the device alters the delivery and what device-specific factors impact the substance’s clinical performance.

The clinical evaluator must integrate both perspectives into a coherent assessment of the combination.

If these roles are siloed, the CER will reflect the gap. The Notified Body will ask questions that neither specialist can answer fully because the answer requires understanding the combination, not just the components.

This is not a process problem. It is a knowledge integration problem. The solution is to structure the evaluation team so that combination-specific questions are addressed from the start, not retrofitted later.

What This Means for Your Next Submission

If you are preparing a CER for a combination product, start by asking: What evidence do I have that this combination, as configured, achieves the intended clinical performance?

If the answer relies on separate evidence for the device and the drug, you have a gap.

If your equivalence claim references a device without the drug or a drug without the device, you have a gap.

If your PMCF plan does not monitor combination-specific endpoints, you have a gap.

Close these gaps before submission. The Notified Body will not accept a CER that treats the combination as two separate products. MDR requires evaluation of the combination as a single medical device.

That is the standard. That is what your clinical evaluation must meet.