Drug-device combinations: When MDR doesn’t actually apply

Written by HATEM RABEH, MD, MSc Ing

Your Clinical Evaluation Expert And Partner

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The question seems simple: when a product contains both a drug substance and a device component, which regulation applies?

But in practice, I see manufacturers struggle with this determination. They apply the wrong regulatory framework, prepare the wrong clinical evidence package, and face rejection or significant delays.

The stakes are high. Choose wrong, and your entire submission strategy collapses.

The Core Principle

MDR Article 1(8) defines the boundary clearly. If a product incorporates a substance which, if used separately, would be considered a medicinal product, and the device-drug combination has action ancillary to that of the device, then MDR applies.

The word “ancillary” is the turning point.

But ancillary to what? How do you determine the principal mode of action when both components are therapeutically active?

This is where most confusion begins.

Principal Mode of Action

The classification depends on identifying the principal intended action. Not the most visible action. Not the action you prefer to emphasize for marketing. The principal intended action as defined by the therapeutic objective.

MDCG 2022-5 clarifies this: the principal mode of action is the single action that contributes most to achieving the principal intended therapeutic effect.

If the medicinal substance is the primary driver of the therapeutic effect, the product falls under pharmaceutical legislation. Even if there’s a sophisticated device delivering it.

If the device is the primary driver, and the substance plays a supporting role, then MDR applies.

I’ve seen manufacturers argue that their delivery technology is innovative, therefore the product should be regulated as a device. That’s not how the classification works.

Where Teams Go Wrong

The most common error I encounter is wishful classification.

A company has device expertise, device quality systems, and relationships with notified bodies. They want their combination product to be a device. So they frame the principal mode of action to fit that conclusion.

This doesn’t survive regulatory scrutiny.

Another frequent mistake: assuming that because the substance is already approved as a drug, the combination must be a device. That’s backwards logic.

If the drug substance provides the principal therapeutic action, and the device merely delivers it, you’re developing a medicinal product with an integral device. That means pharmaceutical regulation applies, with the device component assessed as part of the medicinal product dossier.

The Ancillary Action Test

When MDR does apply, it’s because the substance plays an ancillary role. Ancillary means secondary, supportive, subordinate to the device’s action.

Consider a wound dressing that incorporates an antimicrobial substance. If the dressing’s physical barrier function and moisture management provide the principal therapeutic action, and the antimicrobial prevents secondary infection, the substance is ancillary. MDR applies.

But if the antimicrobial is the primary treatment and the dressing simply holds it in place, you’re looking at a medicinal product.

The distinction seems subtle, but it determines your entire regulatory pathway.

Here’s what changes in practice:

Under pharmaceutical regulation, you need clinical trials demonstrating efficacy and safety according to ICH guidelines. You need pharmaceutical quality control. You need a marketing authorization from a medicines agency.

Under MDR, you need clinical evidence of safety and performance, typically based on clinical data, literature, and potentially clinical investigations. You need conformity assessment by a notified body. You need CE marking.

Different timelines. Different costs. Different expertise required.

The Consultation Requirement

MDR Article 117 creates another layer of complexity.

Even when MDR applies because the substance is ancillary, if that substance is a derivative of human blood or plasma, the notified body must consult the relevant medicines authority before issuing a certificate.

This consultation is mandatory. It’s not optional. It’s not a formality.

The medicines authority assesses the quality and safety of the substance component. They may request additional data. They may raise objections that delay or block certification.

I’ve seen notified bodies wait months for this consultation to complete. The clock doesn’t stop. Your submission timeline extends.

Manufacturers sometimes discover this requirement late in the process, after they’ve already prepared their technical documentation assuming a pure device assessment. Then they scramble to generate pharmaceutical-quality data for the substance component.

Practical Impact on Clinical Evaluation

The regulatory classification directly shapes your clinical evaluation strategy.

If you’re developing a device under MDR with an ancillary substance, your clinical evaluation report must still address both components. You can’t ignore the substance just because it’s ancillary.

You need literature on the substance’s safety profile. You need justification for the dose, the release profile, the duration of exposure. You need data showing the substance doesn’t pose unacceptable risks in the specific combination.

But you’re not required to prove the substance’s efficacy independently. That’s the difference. The substance supports the device’s intended purpose. It doesn’t carry the therapeutic claim alone.

Your state of the art review covers both device technologies and the relevant substance class. Your equivalence analysis, if you use one, must consider whether equivalent devices use similar ancillary substances.

If you claim equivalence to a device without a substance component, you’ve introduced a difference that may break equivalence. You’ll need clinical data on your specific combination.

The Borderline Decision Process

When classification isn’t obvious, what do you do?

You don’t guess.

You don’t proceed with one pathway and hope for the best.

You prepare a formal borderline case and submit it to the relevant authorities. In Europe, this often involves both the medical device authority and the medicines agency in your chosen member state.

Prepare a clear technical rationale. Describe the product. Explain the intended use. Detail how each component contributes to the therapeutic effect. Provide evidence of the mechanisms of action.

Then let the authorities decide.

This takes time, often several months. But it’s faster than building an entire submission under the wrong regulation and facing rejection.

I’ve worked with teams who resisted this step. They were confident in their classification. They wanted to move fast.

Then the notified body disagreed. The entire project stopped while they pursued reclassification. Months of work was unusable.

Interface With National Regulations

Here’s another complication: even if MDR applies at the European level, individual member states may have additional requirements for products containing medicinal substances.

Some countries require notification to their medicines agency even for devices with ancillary substances. Some require specific labeling. Some restrict which healthcare settings can use such devices.

These national rules layer on top of MDR. They don’t replace it, but they add compliance obligations.

Your regulatory strategy must account for this. You can’t plan only for CE marking. You need to map the national requirements in your target markets.

I’ve seen manufacturers obtain CE marking, then discover they can’t legally sell in certain member states without additional national approvals for the substance component.

What This Means for Your Next Project

If you’re developing a combination product, classification is your first critical decision. Not your first technical decision. Your first decision, period.

Before you draft protocols. Before you design studies. Before you engage a notified body.

Get the classification right.

Involve both device and pharmaceutical expertise in that determination. Don’t let one discipline dominate the analysis.

Document your reasoning. Keep records of how you reached the classification decision. If authorities challenge it later, you need to show you applied a structured, evidence-based process.

And if there’s genuine uncertainty, seek formal guidance. The time invested upfront protects your entire project timeline.

In the next part of this series, I’ll walk through how to structure clinical evidence when MDR does apply to your combination product, and your device incorporates a substance with its own safety profile.

Because even when the classification is clear, integrating two evidence streams into one coherent clinical evaluation is where the real work begins.