FDA's new draft guidance could hinder applications for digital combination products

Released yesterday, the document outlines FDA's preference toward single applications for combination products.
By Dave Muoio
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The FDA released new draft guidance yesterday regarding premarket review for combination products — those with a mix of components that span across the agency’s drug, biologic and device product categories.

, which may still be adjusted based on public feedback, broadly advises industry to submit a single regulatory application within the pathway that most closely aligns with that product’s “primary mode of action,” as opposed to submitting multiple types of applications. The draft also includes suggestions and examples of which kinds of products would be most appropriate for each regulatory center.

“Today, as part of several steps we're taking in this area, we're announcing a framework designed to enhance clarity, predictability, efficiency and consistency of premarket review for combination products,” FDA Commissioner Dr. Scott Gottlieb said in a statement announcing the draft guidance. “This framework will help ensure that the FDA coordinates effectively around the premarket review of these products. Among other steps, we're clarifying what pathways to approval are available depending on whether a combination product is drug-led, biologic-led or device-led. We're seeking feedback on this proposed approach and we'll also be publishing additional guidance on specific premarket considerations for combination products to ensure efficient product development.”

Despite the preference toward a single regulatory submission, a footnote in the guidance does indicate that multiple applications “would generally be permissible for the constituent parts of cross-labeled combination products” unless “the agency determines that a single application is necessary.”

Why it matters

In the accompanying statement, Gottlieb specifically highlighted a sensor-enabled pill, patch and drug product (like the kind developed by Proteus Digital Health and approved by the FDA) as an example of a combination product that would fall under the new guidance. The FDA’s draft guidance document itself, however, did not include any clear examples of or scenarios related to digital health products, noted Bradley Merrill Thompson, a partner at Epstein Becker Green who specializes in FDA law.

“It doesn't really contribute clarity with regard to digital health in particular,” Thompson wrote in an email to Babyforyou.net.ua. “It basically is suggesting … that the agency is predisposed to believe that one regulatory submission will be appropriate for digital health combination products.”

Thompson characterized FDA’s preference for a single submission as bad news for an industry that so far prefers to submit multiple applications for its devices, so as to better match the varying stringency of each regulatory center.

“The reasons industry wants the option of filing two different submissions include the fact that two submissions might better ensure an appropriate risk-based review for both the device constituent part as well as the drug constituent part,” he wrote. “Insisting on one application for a drug led combination product — which likely means an NDA — means that the device constituent part might end up overregulated.

“This is especially true in the context of software. Software that helps guide drug use, if regulated under an NDA, may be subject to steeper requirements than if the software is reviewed in a coordinated review but submitted through a separate device application.”

Also worth highlighting is the fact that some novel digital health products qualifying as a combination product come from a commercial arrangement between a drugmaker and a software or device maker, Thompson continued. In these cases, many partnerships might prefer to draft and submit individual applications based on the component of the combination product with which they are most familiar.

“But this guidance seems to discourage that commercial arrangement,” he wrote. “Software and drugs, if they form a combination product, is through cross labeling which to me presents unique and different regulatory issues from single entity combination products or even co-packaged combination product kits. All in all, I'll be reviewing it carefully, but I really don't see helpful improvements from the standpoint of software used in tandem with pharmaceutical products.”

What’s the trend

While the FDA has been consistently revamping its approach toward regulating digital health, medical devices and other medical products, the last few months in particular have seen a flurry of new draft guidances and rules. Mid-November saw a proposal that would classify the majority of apps and software released by pharmas that accompany a drug treatment as “promotional labeling,” and therefore require less stringent review. More recently, it locked in 510(k) guidance that shifts away from predicate devices in favor of a set of “objective, transparent and well validated safety and performance metrics.”

On the record

“Potential differences in the premarket review pathways across medical product centers can impact the regulatory processes and timelines for development,” Gottlieb said in a statement. “We're focused on implementing an efficient framework to ensure the timely and effective review of combination products to create the most robust pathway to advance these kinds of innovations. We're seeing innovations that hold out great promise, but they're increasingly blurring the lines across our medical product centers. We believe cross-center collaboration is key to successfully advancing safe and effective combination products.”