Combination products: Non-harmonized regulations are hurting manufacturers

Fort Worth, TX – Divergent global regulatory frameworks are making it tough for manufacturers to move ahead with innovative combination drug/device products, according to a panel of experts who spoke at the 2023 Combination Products Summit held by the AFDO/RAPS Healthcare Products Collaborative.

Despite some preliminary efforts at harmonization and good — but thus far unfulfilled —intentions to undertake more substantial changes, the regulatory landscape for these products remains a confusing maze of requirements that often frustrate companies. Although medical products are typically regulated by a country’s primary medical regulatory agency, decisions on combination products are often based on either the therapeutic agent or the device itself, depending on the intended therapeutic action. Additionally, different countries define combination products differently, making it tough to know exactly how to file an application for marketing authorization.

“These different definitions and requirements between the regions aren’t just a burden for commercial products, but for product users and buyers,” said panelist Mike Wallenstein, global head of regulatory medical devices, combination products and precision medicine at Novartis. “And we are not just talking about simple products like prefilled syringes. It affects many more highly sophisticated products that are supposed to come out very soon. Regulatory frameworks should support this, or at least establish clarity. If you’re trying to develop a global product and don’t even have access to all the global regulations, it’s very difficult.”

Regional political upheavals like Brexit move and Switzerland’s similar move to leave EU regulatory frameworks further complicate the regulatory landscape, Wallenstein said.

Regulations for combination products are currently in force in the US, EU, South Korea, Malaysia, Japan, Canada, Switzerland and China. In countries without specific combination product regulations, those products are regulated either as devices or drugs, depending on the primary intended action. Constituents of co-packed and cross-labeled products might be regulated as both a drug and a device.

In the 2010s, the Global Harmonization Task Force (GHTF) and Asia-Pacific Economic Cooperation (APEC) made some initial efforts to harmonize these standards (RELATED: IMDRF Offers Progress Updates at March Meeting, Regulatory Focus, 01 April 2016).

Unfortunately, that effort didn’t get very far, said panel co-moderator Susan Neadle, president of Combination Products Consulting Services. “It died on the vine,” she said bluntly. “It was just too complex and too overwhelming.”

More recently, ASTM International’s Combination Products Working Group drafted initial guidance on harmonizing terminology and current good manufacturing best practices. The group acknowledged the inherent challenges. “Although it may not be possible for international regulators to fully align with respect to definitions and authorization schemes for combination products, global harmonization of higher-level requirements tailored to the various types of combined use products might prove to be a realistic goal,” according to the guidance.

The document is still in limbo. “My understanding is that this is at the final stages of approval, but it’s been there for a long time,” Neadle said.

The International Organization for Standardization (ISO) published ISO 14971:2019, guidance on the application of risk management to medical devices, which was harmonized internationally in 2021. And the Association for the Advancement of Medical Instrumentation (AAMI) is also playing a part, adopting a harmonized combination product risk management standard in 2020.

The FDA has not been silent on the issue, Neadle added. Last year, the agency issued the proposed rule for the Quality Management System Regulation, which intends to harmonize some aspects of 21 CFR 820 to ISO 13485. It has yet to be finalized (RELATED: QMSR: FDA proposes QSR overhaul after years of delays, Regulatory Focus, 22 February 2022).

“We are expecting to get this finalized sometime this December,” Neadle said. “But we know that there’s a lot of complexity in it, because some of the regulations and definitions in the US differ from those under the ISO, so the FDA has to retain some of that. The harmonization effort is on its way but there’s still a rough, bumpy road ahead for us here.”

Although FDA’s international harmonization efforts in this arena are not complete, the agency’s established guidelines about combination device development and approval should stand as a global model, Wallenstein said.

“In the US, it’s so easy,” he said. “If you request a meeting, you will usually get one. You can consult the [Office of Combination Products], and at least you will get an answer, whether you like it or not; you still have something to deal with.”

In Europe, Wallenstein said, regulators sometimes cite the technological complexity of cutting-edge combination device products and the complexity of dealing with independent member states as the reason for vague or non-harmonized regulatory guidance.

“I really have some problems with this,” he said. “Complex environments are everywhere. Complex products are coming, and they are coming everywhere in the world. Why is this something that the FDA never uses as an excuse? We [in industry] really have the feeling that sometimes these regulations are being developed in isolation, not acknowledging what’s working in other regions.”

In the end, he said, the lack of guidance harmonization is hurting manufacturers. “These issues can easily lead to losing competitive advantage.”

2023 Combination Products Summit

Combination products: Non-harmonized regulations are hurting manufacturers

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