Experts outline challenges of combination products in Europe

BRUSSELS – Combination products are increasingly important, increasingly complex and are increasing the pressure on the European regulatory network, according to Thomas Wejs Møller, senior director for regulatory affairs – devices at Novo Nordisk.

Article 117 of the EU Medical Device Regulation (MDR) and notified body opinions were key among the challenges discussed by Møller and colleagues during a panel discussion at the 2024 Combination Products in the EU Summit held jointly by DIA and the Regulatory Affairs Professionals Society (RAPS).

Article 117 requires a marketing authorization applicant or holder of an integral drug-device combination product (DDC) to get a notified body opinion (NBOp) that confirms the device portion is compliant with MDR’s general safety and performance requirements (GSPR). This is also the case when a company seeks to make a change to the device component of a product marketing under the old Medical Device Directive (MDD), Møller explained.

And while seeking an NBOp has become a fairly routine task for larger companies that focus on combination products – such as Novo Nordisk – it can be challenging for smaller and less specialized companies.

Tracey Burr, executive director – CMC regulatory affairs at Ionis Pharmaceuticals, noted that the need for an NBOp has accelerated their pre-launch timeline.

“The biggest challenge for us is that the notified body opinion is required prior to filing a [marketing authorization application (MAA)] and the timing of the serial submissions. If it takes longer to get the device approved, it might delay the MAA,” said Burr. “For us, some of the activities that historically would have been what we considered pre-launch activities, we’ve had to pull into early development. It’s not that we wouldn’t have done these activities; it’s that we are having to do them much, much earlier.”

Burr noted that previously she had worked at very small companies that couldn’t invest in device development early in the process. “Right now, you have to take a lot of those activities and pull them into early development, potentially even before you know if you have a viable product or not and I think that’s one of the bigger challenges that are facing small companies.”

Ionis is using a platform approach to try to reduce the time needed to get an NBOp, she said, when using the same device in a secondary MAA with a similar drug formulation but a different patient population. Working with their notified body to organize the technical documentation similarly to the first requested opinion allowed the notified body to focus on what was different about the second application, reducing the time needed to get an NBOp.

The next iteration of that thinking could be something like a device master file so that companies – small and large – don’t have to reinvent the wheel every time, she added.

Some of the combination product challenges faced by notified bodies are not so different from those faced by industry, according to Jonathan Sutch, Principal Medicinal Technical Specialist at BSI (UK).

Sutch recommended that manufacturers contact a notified body early in the process. “The manufacturers that come to us and have planned this out properly, asking about the review timeline and where the work fits in…. We don’t want to be blocking your path.”

He noted that under MDR, manufacturers need to provide solid evidence of GSPR compliance – and not just “a statement that says that you comply.” The evidence often can be quite substantial and much more challenging than under MDD, he added.

Provide as much detail as possible and do so using a structure that notified bodies are familiar with, he advised.

Finally, he underlined that changes to the device associated with a combination product can be a challenge but that few of the NBOps his company has issued were for device changes. “There have been some big companies that have come to us for an opinion on their legacy device, as a ‘preemptive strike’ to have the dossier ready in case they want to make a change and therefore expedite that second process, which is not a regulatory requirement, but a way they have tried to go about de-risking it.”

Knowing whether a change to a device requires a new NBOp also can be a challenge; however, TEAM-NB – an association of notified bodies – has put out guidance that can help, Sutch said.

Experts outline challenges of combination products in Europe

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