On Tuesday, FDA announced the availability of a draft guidance, “Principles of Premarket Pathways for Combination Products,” with high-level information on ways to bring combination products to market.  Although the draft guidance doesn’t break new ground, it provides some useful clarity; for example, it includes detailed illustrations of five circumstances when those pathways apply.

Citing existing FDA manuals and guidance documents, the 22-page draft guidance addresses the:

• definition of combination products under 21 CFR 3.2(e)
• jurisdictional assignment of combination products to agency Centers
• approval pathways available for device-led, drug-led, and biologic-led combination products, as well as considerations for making such pathway determinations
• safety and effectiveness data and information sponsors must offer, depending upon the pathway

Other key issues:

• The draft guidance says “a single application is generally appropriate for a combination product,” but “may not be appropriate in limited cases.” With that in mind, FDA is seeking comments about when two applications – one to the lead jurisdictional agency Center and one to the non-lead Center – should be submitted.
• FDA’s Office of Combination Products (OCP) directs the Centers to coordinate on combination product approval requests, “including by ensuring that Agency components and staff coordinate appropriately on premarket review of these products, and that Agency thinking is aligned in conducting these reviews.” This may suggest an internal FDA view that the Centers have not been fully aligned in reviewing submissions, and perhaps it signals greater OCP involvement, both to encourage robust involvement across the agency and to mediate any resulting conflicts.
• FDA expressly addresses an issue that may have been imperfectly understood and inconsistently applied, stating that “the data and information needed to address safety and effectiveness questions related to the non-lead constituent part of a combination product may differ from the data and information needed to obtain marketing authorization for that article as a stand-alone product that is not part of a combination product.”

Generally, the draft guidance is consistent with the existing practice regarding Center jurisdiction and pathway processes for combination products, and doesn’t add much in the way of substance.  In the examples annex, for example, FDA reiterates the existing approach to when a 510(k) is not an available pathway to market, but the agency doesn’t suggest a mechanism for determining the appropriate pathway in those circumstances.  This leaves significant leeway for FDA, and fails to provide needed clarity of direction for industry.

In a press release announcing the guidance, Commissioner Gottlieb touted the potential benefits of combination products, saying the draft guidance aims to “enhance clarity, predictability, efficiency and consistency of premarket review for combination products.”  The draft guidance is intended to comply with the 21st Century Cures Act’s mandate of greater transparency in combination product designations.  Earlier efforts toward this end include the September 2017 final guidance on the agency’s classification process for distinguishing between a drug, device, biologic, and combination product, which we analyzed here.  FDA also issued a proposed rule in May 2018 related to streamlining combination product regulations, but it was generally limited in scope.

FDA will accept comments on the new draft guidance until May 29. 

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