FDA finalizes guidance on premarket review of combination products

Regulatory NewsRegulatory News | 31 January 2022 |  By 

The US Food and Drug Administration (FDA) has finalized guidance for industry and agency staff on the use of premarket pathways for combination products, including providing details on how the lead FDA center is determined and current thinking about cross-labeled products.
The final guidance, announced in the Federal Register on 31 January 2022, defines combination products, the coordination between the agency and sponsors, and recommendations on how to determine the types of premarket submissions for a particular product. The 25-page guidance implements Section 3038 of the 21st Century Cures Act, related to premarket regulatory expectations for combination products. It also includes an Annex with specific examples of how the guidance may be applied.
The agency published its draft guidance on this topic in 2019 (RELATED: Combo Product Reviews: FDA Drafts Guidance, Regulatory Focus 05 February 2019).
Determining center jurisdiction
The final guidance defines combination products as being composed of two or more different types of drug, device, or biological products. These components may be contained in a single entity, such as a drug-eluting stent, co-packaged as a first-aid kit with an antiseptic drug, or they could be individual products that are intended for use together and are cross-labeled, such as a light-emitting device with a light-activated drug.
Under the guidance, the agency intends to assign each combination product to an FDA center that will have primary jurisdiction. The lead center will be based on which component provides the mode of action “expected to make the greatest contribution to the overall intended therapeutic effects” of the combination product, known as the primary mode of action (PMOA). For instance, if the PMOA of a device-biological combination product is determined to be the biological product, then the Center for Biologics Evaluation and Research (CBER) would take the lead on premarket review and regulation.
If a sponsor disagrees with the product’s lead designation, the company may submit a request for designation (RFD) to obtain a binding classification and/or assignment determination from FDA, or a Pre-RFD to obtain informal feedback on the assignment. The Office of Combination Products (OCP) makes the final determination, with input from the FDA centers.
Agency interactions
The designated lead center is the sponsor’s primary point of contact during the premarket process and for pre-submission meetings. But there are special considerations for cross-labeled combination products, in which sponsors may seek separate marketing authorizations for the constituent parts.
Interactions on cross-labeled combination products should be conducted through lead center prior to the filing of marketing authorization submissions, regardless of the types of feedback being requested, according to the final guidance. Sponsors can contact OCP about ensuring coordinated engagement among the centers, including having representative from other centers present at meetings with the sponsor.
Types of marketing applications
Consistent with the draft guidance, the FDA’s final guidance document sticks with the approach that premarket review of a combination product generally occurs under a single application. As with determining the lead center, the PMOA would determine the type of marketing application. For instance, a device-led combination product might use a Premarket Approval application (PMA), De Novo classification, or 510(k) submission, while a drug-led combination product would use a New Drug Application (NDA) or Abbreviated NDA (ANDA), and a biologic-lead combination would use a Biologics License Application (BLA).
For cross-labeled products, separate applications would generally be allowed but applicants are encouraged to coordinate with the centers involved to ensure timely consideration of issues relevant to each part and their combined use.
Although single applications are appropriate in most cases, the FDA guidance emphasizes that sponsors should provide data on all components of a combination product. “To appropriately ensure the safety and effectiveness of a combination product in a single application, such application should enable a substantially similar evaluation to that which would be applied to each constituent part if they were reviewed under separate applications (e.g., an ANDA or NDA for a drug and a PMA, De Novo, or 510(k) for a device), including consideration of data and information that would be reviewed under the separate applications,” the FDA wrote.
For instance, a combination product that is not device-led but includes a device constituent part, should include engineering, biocompatibility, performance data, and other design validation data as part of the marketing application.
Final guidance: Principles of Premarket Pathways for Combination Products


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