Author offers advice for navigating combination products approval pathways

With few comprehensive resources available covering combination products, RAPS’ recently released book, International Combination Products, by Jocelyn Jennings, MS, RAC (US, Drugs, Devices), fills a significant need for practical guidance on navigating the regulatory pathways for products combining multiple technologies. Prior to writing the book, “there was no place that I found that I could look to find all of the information I was interested in on different topics to do with combination products in one place,” said Jennings during a live, ‘meet the author’ session online.

What is a combination product?

A combination product is any therapeutic or diagnostic that includes some combination of two or more product types—drugs, medical devices, and/or biologic products. Examples of combination products include prefilled syringes, metered dose inhalers, transdermal patches, and drug-eluting stents. They can be single products, two separate products packaged together to be used in combination, or two separately packaged products that are designed to be used together. Even something as simple as a toothbrush packaged with fluoride toothpaste is classified as a combination product.

The book’s first chapter, “What are Combination Products?” provides an important introduction, particularly for those new to the category. “You really need to have a foundation,” said Jennings. “I think that’s a good place to start because people sometimes confuse certain products as combination products, and they are not.” It’s critical to understand the definition.

FDA must determine primary jurisdiction

On their own, drugs, devices, or biologics are each regulated by separate, product-specific Centers within the US Food and Drug Administration (FDA). The approval pathway for combination products is not as straightforward. FDA must first determine and assign primary jurisdiction for review of a combination product to one of the agency’s Centers.

Primary jurisdiction is determined by a product’s “primary mode of action,” defined in section 503(g) of the Medical Device User Fee and Modernization Act of 2002 (MDUFMA) as “the single mode of action of a combination product that provides the most important therapeutic action of the combination product.”

One of the first and most important questions to ask, said Jennings, is “Have you really determined the primary mode of action of your combination product? Because your primary mode of action determines which FDA Center will have jurisdiction over your combination product, so if you make the wrong decision, and you submit the wrong application, that is a huge issue.”

“There are processes you can go through with the Office of Combination Products to figure out who has jurisdiction over your product,” said Jennings. “You really need to make sure you know what type of combination product you have—if it’s device-led, biologic-led, or drug-led­­—because that determines your application type, and it determines which Center you have to submit the application to.”

Approval pathways in Europe, Canada

In addition to the ins and outs of FDA’s approval pathways, International Combination Products also covers the processes for combination products in Europe and Canada. “The EU and Canada have [types of combination products and examples] really specifically written in their guidelines,” said Jennings. “They tell you exactly what process it goes through, so there’s not really this jurisdictional question for those like there is with the US.” Europe also makes some things easier with pre-populated forms and specific gateways for different submissions, she said.

Need for expertise in multiple areas

Jennings noted one of the greatest challenges for device-centric companies is understanding all the different types of testing needed, particularly for device-biologic combination products. “There are these different aspects of biologics that a device company just may not be familiar with,” she said. “The difficulty is learning all you need to learn about either the drug or biologic aspects of regulatory that you may not know if you’re strictly a device company.”

While one FDA Center takes the lead, at least one other Center may also be involved. The primary center “will look to see who the second Center should be…and they will ensure that they have reviewers and staff available from that Center that can help the lead Center with any questions,” said Jennings. “They are very integral in the review process.”

With multiple FDA Centers taking part in the review, the process can present a significant challenge to companies and regulatory professionals who may have more experience working with one product type, but less so with the other(s).

There can also be an additional challenge if a product is determined to be under the jurisdiction of an FDA Center outside your company’s core product area. “If it turns out that your product is not device-led, it’s either drug- or biologic-led, then the company may not have the expertise or understanding of what goes in an IND vs. an IDE,” said Jennings.

The book is intended to be flexible and can be relied upon as a handy desk reference, or be read cover-to-cover, depending on the individual need, said Jennings, and will be useful to regulatory professionals at all job levels.

International Combination Products is available in print and e-book versions for $125.00 for RAPS members, and $175.00 for nonmembers.