Authored by Innovative Science Solutions, now part of Lumanity

On January 26, 2022, the US Food and Drug Administration (FDA) published final guidance on Premarket Pathways for Combination products. The edits in the final guidance mainly seeks to clarify matters previously addressed in the draft guidance from February 6, 2019.

A combination product is defined by the FDA as a product comprised of two or more regulated components. The combination can be “single entity” (e.g. prefilled syringe or drug-eluting stent), “co-packaged” (e.g. surgical kit containing bandages and a antiseptic drug), or “cross-labeled” (products that are packaged and sold separated by intended for use with only an approved product; e.g. light-emitting device and a light-activated drug).

Lead Center

A combination product is assigned to an Agency center (i.e. CDER, CBER, or CDRH) that will have primary jurisdiction over the combination product – in other words, serve as “the lead.” The sponsor may file a request for designation (RFD) if the sponsor is uncertain or in disagreement with lead center assignment or with product classification. The final guidance highlights that “[w]hile sponsors may propose the classification and/or assignment they believe should apply for a pre-RFD, […] the Office of Combination Products (OCP) makes the final determination with input from the relevant Agency components.” The final guidance also adds that if the OCP does not respond to an RFD within 60 days, the classification or assignment proposed by the sponsor will become the final classification.

The lead center is the sponsor’s primary point of contact with the Agency, and also the Agency’s primary point of contact with the sponsor. In the final guidance, the FDA adds that while this general approach should be used for all combination products, including cross-labeled products; until separate marketing authorization submissions are submitted, all interactions with the FDA should be through the lead center regardless of the subject matter of the interaction. Sponsors should seek to actively engage with the Agency (and in particular the OCP when needed) regarding the coordination of different centers, especially regarding harmonization of review timeline and target review date in light of different target review dates set forth by FDA User Fee Programs.

Separate Applications

The Federal Foods, Drugs, and Cosmetic Act (FD&C) posits that the FDA will perform the premarket review of a combination product “under a single application, whenever appropriate.” The sponsor is free to submit separate applications for constituent parts unless the Agency requires a single application. Separate applications for a cross-labeled product are generally permissible; however, sponsors should discuss with the Agency to harmonize review timelines to enable review of issues that may be relevant to either or both of the constituent parts. The FDA may require separate applications for each constituent parts in “limited situations.”

Illustrative Examples

The guidance includes an annex of illustrative examples, mostly focused on device-led combination products. This section addresses common questions associated with the analyses of pathway availability for device-led combination products and illustrates expectations on the requirements that single applications be substantially comparable to constituent parts under separate applications. The Agency recommends Sponsors with specific questions beyond the hypothetical examples presented, to contact the lead center or OCP for assistance.

We have two decades of experience in developing regulatory strategies including support for premarket applications for combination products. For more information on how we can help you prepare for your next application, contact us.