What to pay attention to when introducing combined products to the EU market

Auto-injector pens, smart inhalers, syringes filled with biologics; You don’t have to look far to see innovation happening in combination products.

As pharmaceutical companies develop and bring to market novel combinations of medicines and devices, they will face new requirements when introducing these products to the European Union (EU) market.

As with stand-alone medical devices, the process for introducing complex products into the EU has changed under Medical Devices Regulation (EU) 2017/745 (MDR). Requirements set out in Article 117 of the MDR are not only different from the previous Medical Device Directive (MDD), but are also more stringent than the requirements for stand-alone medicines, biological products and medical devices.

Here we will examine three main aspects of the EU regulation on combination products: the basic method of operation, 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 a product’s fundamental mode of action to determine which regulatory centers will take the lead. But they classify products differently.

CFR 3.2(e) assigns combination products to four categories: single, co-packaged, mixed-label and pre-approved and tested under different labels.

The MDR classifies products according to their mode of action: drug/device combinations, device/drug combinations and devices containing medicinal substances. Examples of the latter are devices containing an antibiotic or a paraffin dressing.

Obtaining the opinion of a notified body

Combination products are subject to new requirements under the MDR, especially if part of the device is not yet CE marked. The following steps apply to products containing regulated drugs, biologics, and devices.

Where the device constitutes the primary mode of operation, the national central authority shall carry out a conformity assessment as for a stand-alone device. The manufacturer would also submit documentation to the EMA to assess the safety and effectiveness of the medicine in accordance with Directive 2001/83/EC. The EMA would then issue an opinion confirming that the medicine is suitable for combination with a medical device.

If the medicine is its main mode of action, the manufacturer will submit documentation to the EMA to assess the safety and effectiveness of the medicine in accordance with Directive 2001/83/EC. They would also submit documentation to their NB who would issue an opinion (NBop) to confirm compliance with the general safety and performance requirements under the MDR. The opinion is attached to the application for admission to trading.

Authorities will want to see clinical evidence of the effectiveness of the device and drug combination. This means that if a drug developer has clinical trial data showing the safety and effectiveness of the drug itself, it will need to provide additional data showing that the drug is safe and effective when combined with the device.

“When you are developing an infusion pump for use with a specific drug, you need to determine that it is delivering the drug to the appropriate tissues and that the patient is receiving the appropriate amount,” said Dr. Peter Wirthschaft, senior manager, medical devices/IVD, consultant to the global health and safety organization public NSF. “These are issues that need to be explored in clinical settings.”

Full technical documentation is not required to obtain an NBO, but the file submitted is extensive. This position with Team-NB contains general documentation requirements, although specific requirements may vary by NB.

Expect long waits

Antal Solyom, director of the medical devices department at HungeroTrial, a CRO based in Central and Eastern Europe, he told the audience at Silicon Valley BIOMEDevice 2023 that the average time it takes NB to process certification is 18 to 24 months.

This time frame is still valid. However, companies with CE marking for combination products have a smaller pool to draw from because not all of them 49 N.B authorized to certify products under MDR have specialist product knowledge – and this knowledge matters.

“What is one of the main reasons why manufacturers do not undergo conformity assessment?” according to Wirthschaft. “They chose wrong (NB). And the fact that they are quite busy makes the shortages even more visible.”

AND EY position suggests that manufacturers use the following criteria when selecting NB:

To alleviate some of the delays, Wirthschaft suggests manufacturers identify and establish a relationship with NB during the conceptual stage of development. Starting a dialogue with NB at an early stage of development also allows manufacturers to clarify certain formalities and expectations before submitting technical documentation.

Quality management system requirements apply

Directive 2001/83/EC, which applies to medicinal products, does not contain requirements for a quality management system (QMS). However, manufacturers of combined products will need a documented quality management system that takes into account the regulatory compliance strategy and other aspects listed in the MDR. In addition, this quality management system will need to be audited by NB for compliance with ISO 13485.

Pharmaceutical companies can outsource production to a company with a compliant quality management system. Wirthschaft stated that if they choose this route, they will need to obtain a quality assurance agreement to verify that all aspects of the QMS are met. A contractual agreement and processes detailing the data sharing relationship will also become part of the NBO application.

For combination products where the primary mode of action is a drug, the vigilance requirements for MDR devices do not apply. However, manufacturers should incorporate technical knowledge and processes into their quality management system to handle, evaluate and investigate, as necessary, all product-related complaints.

“Both pharmaceutical companies and device manufacturers may be surprised to discover that clinical evidence requirements are higher and more complex and regulatory burdens are greater for combination products compared to stand-alone drugs and devices,” Wirthschaft said. “They need to be aware of what it takes to get these products to market.”

Notably, the Association for the Advancement of Medical Instrumentation (AAMI) offers: 6-part training series on combination products which examines the FDA and EU approach to regulating combination products and the impact of this approach on the product life cycle.