Convergence: Experts look for greater international alignment on combination products

PITTSBURGH — Experts acknowledged significant differences in the US and EU approaches to regulating combination products and called for greater collaboration and use of harmonized standards by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).

The experts, who spoke at RAPS Convergence 2025, said there are initiatives in motion—including the launch of a new combination product operational group in Europe next month—but acknowledged the difficulties of aligning combination product regulatory requirements in these two regions.

Kimberly Trautman, a medical device, in vitro diagnostics, and combination product expert and former FDA official, said combination products have historically been “something very, very difficult from an FDA perspective” and was “practically hands off” in the more than 20 years she served at the agency.

“[F]ailing to address combination products really isn't the answer, but because it was really one of the harder ones, it's been pushed off,” Trautman said.

The differences of opinion are not just been FDA and other regulatory agencies, but between centers at FDA, she noted. “The fear on FDA’s part historically has been, we need to better align even within the FDA before we align with some of our international partners,” she said.

FDA’s use of a master file for combination products “really made some of the consultations across the centers more efficient, more effective,” Trautman said. However, that concept may not be applicable abroad depending on the structure of the regulatory agency, she said.

Manufacturers may need to look to international standards for guidance on combination products. In international guidances, “there’s still some great ways that manufacturers can navigate combination products globally, even if everything's not perfectly aligned from the regulator's perspective,” she said.

Efforts to harmonize

In Europe, the COMBINE program is one example of trying to align the evaluation of clinical trials of medicinal products, clinical evaluations of medical devices, and evaluations of in vitro diagnostic products, Donal O’Connor, clinical manager for medical devices at the Health Products Regulatory Authority in Ireland, told attendees.

“What I hope will happen—it’s part of the process—and it is anticipated that pre-submission meetings will be available in that new system, which hopefully will again improve the predictability and not quite replicate, but get a little bit closer to the pre-submission facility that that the FDA have implemented quite successfully over years,” he said.

However, that does not change the fact that Europe is bound by different definitions for both medical devices and pharmaceuticals, Sabina Hoekstra-van den Bosch, global director of regulatory strategy at TÜV SÜD, told attendees.

While it is “absolutely right that there is room for improvement there,” Hoekstra-van den Bosch said, “the principle that that the product is governed by that legislation—that will not change.”

That is not to say it is impossible for the regulatory agencies to work together. Alberto Gañan Jimenez, head of committees and quality assurance department at EMA, said the “channel of engagement is already established” between FDA and EMA on combination products.

“[F]or the moment, we have only had discussion about general topics we want to work together with,” he said. “[O]ur ambition is, in the future, to [collaborate] as much as possible, always within the remit of the competences of the agency.”

The EMA is also creating a multidisciplinary operational group for combination products that will launch in November, he noted. The operational group will include representatives from authorities of medical devices, notified bodies, the EMA, and the European Commission.

“The idea will be to have everybody on the table in order to try to find all these areas where there is overlap, there [are] going to be gaps,” Gañan said.

Combination products as integrated system

Commenting on the discussion, Fubin Wu, co-founder and president of GessNet, said that the current regulation and guide views combination products as a siloed approach, rather than a single system that a patient would see it as. Taking a “first principles approach” to combination product safety may be one approach to regulating these products, he said.

“From that perspective, I believe you will find it totally can be streamlined,” Wu said. “It's not that hard, but it takes a different level of thinking rather than looking at it from a societal perspective.”

Trautman also said manufacturers should be developing combination products as one coordinated integrated system product.

“How you then split that design file, technical documentation to get to the right regulators, you have people that can sort that and sort the submissions,” she said.

Expectations may not be aligned even within manufacturers, Trautman noted. “I still culturally don't think even the manufacturers are there,” she said. “They speak some of the same words, but the same expectations [are] not there.”

“[I]f the manufacturers of combination products start really coalescing around the good scientific principles instead of some of these cultural divides, it's absolutely possible to do what you want as a scientist or an engineer, develop it as a single integrated product, and so forth,” she added. “It may be a little painful or a little less efficient as to who and how you submit the information to, but that shouldn't change your development process.”

Convergence: Experts look for greater international alignment on combination products

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