In January 2022, the U.S. Food and Drug Administration (FDA) released finalized guidance on premarket pathways for combination products.
While the guidance is not binding, it provides industry participants with valuable insight into how the FDA will regulate combination drug-device products moving forward and provides some clarity on information device makers will need to submit in premarket review applications. The guidance reflects changes to the Food, Drug, and Cosmetic Act implemented in the 2016 21stCentury Cures Act.
This follows a December 2021 announcement from the FDA noting that some previously approved products were likely to transition from drug to device status, based on a ruling by the U.S. Court of Appeals for the D.C. Circuit in Genus Medical Technologies v. FDA that any product meeting the definition of both a drug and device must be regulated as a device. The FDA noted that combination products previously classified as drugs would be newly classified as devices, unless Congress indicated intent to regulate a combination product as a drug. This announcement was consistent with the FDA’s August 2021 notice in 86 FR 4553.
The term “combination product” encompasses many types of products, including:
- “Single entity” combination products, such as prefilled drug delivery systems.
- “Co-packaged” combination products, such as surgical trays that include both surgical instruments and antimicrobial swabs.
- “Cross-labeled” combination products, which are separately packaged products intended for use only in combination with other specified products, such as photosensitizing drugs and activating light sources.
The finalized guidance clarifies the FDA’s current interpretation of the laws regulating premarket review of combination products. Importantly, the FDA noted that it will assign combination products to “lead centers” based on which component provides the “primary mode of action” (PMOA) of the product. The lead centers will serve as the main coordinating body for premarket reviews.
Manufacturers may submit requests for designation (RFDs) to obtain binding classification determinations from the FDA. Manufacturers may also submit pre-RFDs “to obtain informal feedback related to the classification … of their products.” The Office of Combination Products makes the final classification determination for combination products.
Per the finalized guidance, “FDA’s current thinking is that a single application [for premarket review] 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.” However, separate applications for the constituent parts of some cross-labeled products may be permissible, provided that applicants coordinate with both relevant lead centers. The marketing application type submitted will generally coincide with the PMOA of the combination product.
The FDA noted that, as it evaluates combination products for safety and effectiveness, it will consider the products as a whole and will evaluate each constituent part, including how constituent parts interact and interrelate.
The guidance also sets out separate pathways for the following types of combination products:
- Device-led combination products.
- Drug-led combination products.
- Biologic-led combination products.
The FDA noted in December 2021 that it intends to publish a Federal Register notice with a preliminary list of combination devices currently classified as drugs that are likely to be reclassified as devices, but such a list has not yet been published. Stakeholders will be able to submit comments in response to this list, once it is published.
New market participants may welcome classification changes, as it is generally less expensive to develop and market a device than a drug. However, for market participants that have already secured approval for combination drug-device products under the drug classification, this process may introduce new burdens for regulatory approval, in addition to new considerations for quality and manufacturing compliance. Given the potential costs of compliance with such a classification transition, combination product manufacturers should watch closely for further developments in this area.