The final guidance is being published as FDA looks to implement the 21^st Century Cure Act (Cures Act) as the agency wants to keep with their commitment of transparency, efficiency, and regulatory consistency to facilitate development of safe and effective combination products. The guidance outlines CDER, CBER, and CDRH premarket submissions and their respective submission processes for combination products associated with each specific review center and the pathway.

As in the draft version, the final 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 from the draft version reappear in the final guidance:

• “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 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.”

However, in the final guidance, FDA added the following additional items:

• FDA specifically calls out that while sponsors may propose the classification and/or assignment they believe should apply for a pre-RFD, and must do so for an RFD, OCP makes the final determination form relevant agency components.
• “Cross-labeled combination products for which separate marketing authorization are being sought for constituent parts (e.g., a new drug application (NDA) for the drug and a premarket notification (510(k)) for the device) can raise distinct considerations. Prior to the filing of separate marketing authorization submissions, all interactions with FDA should be through the lead center for these combination products, regardless of the feedback being requested.”
• The guidance ensures that in conjunction with OCP when needed, meetings between the FDA and sponsors are attended by review staff from each center as appropriate in light of the topics and purpose of the meeting, and that consulting centers complete their reviews in a timely manner.
• The guidance emphasizes that it is important that combination products be identified on the appropriate form or document: Form FDA 1571, INVESTIGATIONAL NEW DRUG APPLICATION; Form FDA 356h, APPLICATION TO MARKET A NEW OR ABBREVIATED NEW DRUG OR BIOLOGIC FOR HUMAN USE; or in the cover letter of a pre-investigational new drug application (IND) submission, investigational device exemption (IDE) application, Q-submission, 510(k) submission, premarket approval application (PMA), and/or request for classification submitted under section 513(f)(2) of the FD&C Act (De Novo request).
• FDA’s current thinking is that a single application would generally be appropriate for a combination product, to streamline regulatory interactions with the agency and to avoid unnecessary duplication that may occur with multiple applications.
• For combination products that include device constituents that may be subject to De Novo classification, where the device may be the primary mode of action, understanding of the biological product or drug constituent parts, including limitations of such understanding, need to be considered when determining the suitability of the De Novo pathway for such device-led combination products.

Generally, the final guidance is consistent with the existing practice regarding Center jurisdiction and pathway processes for combination products. In the examples annex, for instance, FDA reiterates the existing approach to when a 510(k) is not an available pathway to market, but the agency does not suggest a mechanism for determining the appropriate pathway in those circumstances, leaving significant leeway for FDA discretion.

If you have questions about this guidance or may be interested in submitting a comment, please contact any of the authors of this blog or the Hogan Lovells lawyer with whom you regularly work.

Authored by Jemin Jay Dedania