Expert: Combination product firms need EU guidance amid regulatory ambiguity

COLUMBUS, OH – The EU Medical Device Regulation (MDR) created confusion for medical device manufacturers in Europe, including drug-device combination (DDC) producers. As stakeholders seek more guidance from regulators, one expert said that clarity needs to come from the European Commission (EC) and the planned revision to the EU pharmaceutical legislation.

Timothy Chesworth, a senior director of regulatory affairs at AstraZeneca, spoke about MDR and how it has created confusion for combination product developers at the Combination Products Summit 2022 hosted by the Regulatory Affairs Professionals Society (RAPS) and the Association of Food and Drug Officials (AFDO). He honed in on Article 117 of MDR, which amends the medicinal product directive, and a Q&A guidance issued by the European Medicines Agency (EMA) on combination products.

The guidance notes that while Article 117 does not apply retrospectively to DDCs that are already authorized in the EU or to products with Marketing Authorization Applications (MAA) submitted before 26 May 2021, there are conditions when a change to the product may require a new notified body opinion (NBO) or a conformity assessment. Those conditions include changes to the design or intended purpose of the device, changes to the primary function, changes to the operating principles and changes to the route of administration.

“It is relatively high level, it doesn’t give a huge amount of precision, and is therefore creating quite a lot of challenges for us as industry to figure out what is that threshold,” said Chesworth, who chairs the European Federation of Pharmaceutical Industries and Association (EFPIA) Medical Devices Regulatory Working Group and leads their regulatory advocacy efforts in relation to combination products. “That’s the key question for many of us in the room today, what is that trigger or threshold for a notified body opinion.”

Chesworth noted that when combination product manufacturers reach out to EMA and notified bodies with that question, they often get conflicting answers. In the short-term, he said there needs to be EMA guidance on the topic that creates a framework for when the requirement for an NBO would be triggered for on-market single integral combination products, clarifies the threshold that affects either the established conditions or critical quality attributes of the medicinal product, and defines a pathway for the Marketing Authorization Holder (MAH) to get advice from EMA and other competent authorities that addresses changes outside the framework.

“It’s critical for us to be able to make those appropriate and consistent decisions about how we manage our products when they’re already on the market,” he said.

While industry has been lobbying for more guidance, Chesworth said that EFPIA has proposed revisions to the general pharmaceuticals legislation. The revisions would be a long-term solution and develop a new framework for combination products.

Chesworth said that EFPIA's proposal would streamline the assessment framework for combination products by making it clear that EMA has overall accountability for the assessment of such products that are regulated as medicinal products. It would also create a new legal definition for combination products in the EU, he said.

“A real realization I've had over probably the last 6 to 9 months is that (the EC) is the key to unlocking this because they are the people that control the legislation,” Chesworth told Focus. “If you don't change the legislation, you can't make fundamental change.”

Chesworth said that EFPIA has been laying the groundwork and building relationships with the EC to encourage legislative change, but he noted that the Commission has been sidetracked with other major issues, including the COVID-19 pandemic. So far, EFPIA has been making the argument to the Commission that the current regulation risks delaying patient access to treatments and is also making the region less appealing to combination product manufacturers.

“Europe, I believe wants to have a vibrant, innovative pharmaceutical medical device combination product industry but if you haven't got an effective regulatory framework, you're going to stifle that, not encourage it,” warned Chesworth.

Not only is the current regulation confusing to manufacturers, Chesworth said, but it also creates unnecessary burdens for notified bodies which are already short on resources.

"One of the biggest challenges of MDR implementation is a lack of capacity and capability in the notified bodies for stand-alone medical devices,” he said. “Ignoring combination products and medicinal products for a moment, this change has placed an additional burden on the notified bodies to provide that (service).”

Chesworth also said that EMA wants to have more oversight of the medical device component of a combination product, especially as the combination products market has grown in recent years, but they don’t want to take on the additional workload. For manufacturers, that means that they end up being bounced between EMA and notified bodies when there are questions about changes to a combination product.

Expert: Combination product firms need EU guidance amid regulatory ambiguity

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