Autoinjector pens, smart inhalers, syringes prefilled with biologics; one doesn’t have to look far to see the innovation happening in combination products.

As pharmaceutical companies develop and launch novel drug-device combinations, they will encounter new requirements when bringing those products into the European Union (EU) market.

As with standalone medical devices, the process for bringing combination products into the EU changed under (EU) 2017/745 Medical Device Regulation (MDR). The requirements under MDR Article 117 not only differ from the previous Medical Device Directive (MDD), they’re also more rigorous than requirements for standalone drugs, biologics, and medical devices.

Here, we’ll explore three primary aspects of EU combination product regulation: the primary mode of action, the notified body (NB) process, and the quality management system (QMS).

Is it a drug or a device?

Both the FDA and the European Commission use the product’s primary mode of action to determine which regulatory centers take the lead. But they classify products differently.

CFR 3.2 (e) assigns combination products into four categories: single-entity, co-packaged, cross-labeled, and previously approved, and cross-labeled investigational.

MDR classifies products by modes of action: drug/device combinations, device/drug combinations, and devices containing medicinal substances. Examples of the latter include a device that contains an antibiotic or a paraffin dressing.

Obtaining a notified body opinion

Combination products are subject to new requirements under MDR, particularly if the device portion is not yet CE marked. The steps to follow apply to products that combine regulated drugs, biologics, and devices.

If the device is the primary mode of action, the NB performs a conformity assessment much like it would with a standalone device. The manufacturer would also submit documentation to the EMA to assess safety and efficacy of the drug per Directive 2001/83/EC. The EMA would then issue an opinion to confirm that the drug is suitable for combination with a medical device.

If the drug is the primary mode of action, the manufacturer would submit documentation to the EMA to assess safety and efficacy of the drug per Directive 2001/83/EC. They would also submit documentation to their NB, which would issue an opinion (NBOp) to confirm conformity to general safety and performance requirements under MDR. The opinion is included with the Marketing Authorization Application submission.

The authorities will want to see clinical evidence of the device and drug working in combination. That means if a drug developer has clinical trial data to show safety and efficacy of the drug on its own, it would need to submit additional data showing evidence that the drug is safe and effective when used in combination with the device.

“When you develop an infusion pump for use with a certain drug, you have to determine that it delivers the drug to the right tissues and that the patient receives the correct amount,” said Peter Wirthschaft, PhD, senior manager, medical device/IVD consultant for global public health and safety organization NSF. “Those are issues that need to be studied in clinical environments.”

A full technical file is not required to obtain a NBOp, but the submission file is nonetheless extensive. This position paper from Team-NB lists general documentation requirements, though specific requirements may vary by NB.

Expect a long wait

Antal Solyom, director of the medical device unit at HungeroTrial, a CRO based in Central and Eastern Europe, told an audience at the 2023 BIOMEDevice Silicon Valley that the average time it takes for a NB to process a certification ranges from 18 to 24 months.

That time frame still holds true. However, companies CE marking a combination product have a smaller pool to draw from, as not all of the 49 NBs authorized to certify products under MDR have combination product expertise — and that expertise matters.

“What’s one of the main reasons manufacturers fail conformity assessments?” according to Wirthschaft. “They chose the wrong [NB]. And the fact that they are quite booked makes the shortage even more pronounced.”

A position paper from EY suggests manufacturers use the following criteria when selecting a NB:

To mitigate some of the delay, Wirthschaft suggests manufacturers identify and establish a relationship with a NB in the concept phase of development. Starting a dialogue with a NB early in development also allows manufacturers to clarify certain formalities and expectations in advance of submitting technical documentation.

Quality management system requirements apply

Directive 2001/83/EC, which applies to medicinal products, doesn’t include quality management system (QMS) requirements. However, manufacturers of combination product devices will need a documented QMS that addresses a regulatory compliance strategy and other aspects listed in MDR. And that QMS will need audited by a NB for ISO 13485 compliance.

Pharmaceutical companies can outsource manufacturing to a company with a compliant QMS. If they take that route, Wirthschaft said they’ll need to procure a quality assurance agreement to verify that all QMS aspects are in place. A contractual agreement and processes that outline the data-sharing relationship in detail will also become part of the NBOp submission.

For combination products where the drug is the primary mode of action, MDR device vigilance requirements don’t apply. However, manufacturers should build technical knowledge and processes into their QMS for handling, evaluating, and investigating, where necessary, all device-related complaints.

“Pharmaceutical companies and device manufacturers may both be surprised to find that the clinical evidence requirements are higher and more complex, and the regulatory burden is higher with combination products compared to standalone drugs and devices,” Wirthschaft said. “They need to be aware of what it takes to bring these products to market.”

Of note, the Association for the Advancement of Medical Instrumentation (AAMI) offers a 6-part combination product training series that examines the FDA’s and the EU’s approach to combination product regulation and how that approach affects product lifecycle.