Earlier this year, the United States Food and Drug Administration (FDA) published a final guidance, “Principles of Premarket Pathways for Combination Products.” In the guidance, FDA outlines three pathways that are available for combination products, based on their primary mode of action. FDA also notes that a single application is usually appropriate for a combination product, but separate applications may be permissible for cross-labeled combination products.
This guidance includes general high-level information regarding what combination products are, coordination within FDA and interaction between FDA and sponsors regarding combination product regulation, and how combination products are reviewed by FDA before they are marketed. The guidance also includes recommendations on how to determine which type of premarket submissions may be appropriate for combination products.
The Three Pathways
Device-Led Combination Products
The first pathway is for device-led combination products. Under this pathway, applications are reviewed under either a premarket approval application, De Novo classification, or a 510(k) standard.
For the PMA, the application should contain sufficient data to demonstrate safety and effectiveness for both the combination product overall and its constituent parts. For De Novo classification, understanding of the biological product or drug constituent parts is important for determining the suitability of this pathway versus the PMA. For a 510(k) standard, FDA notes that generally, a device must be combined with a drug or biological product constituent part. It must also be substantially equivalent to a predicate product. Under the 510(k) review standard, the following products cannot be cleared: a product with a new intended use as compared to the predicate product or a product with different technological characteristics than the predicate product if such differences raise different questions of safety and effectiveness than the predicate product.
Drug-Led Combination Products
For drug-led combination products, they are reviewed under either a new drug application (NDA) or an abbreviated new drug application (ANDA).
An NDA is generally the appropriate pathway for drug-led combination products other than generic versions of already-approved drug-led combination products. An NDA for a drug-led combination product must contain (among other things) a demonstration of the safety and effectiveness of the product for the conditions prescribed, recommended, or suggested in the proposed labeling. An ANDA is generally the appropriate pathway for a drug-led combination product that has the same active ingredient(s), dosage form, strength, route of administration, conditions of use, and (with certain permissible differences) labeling as a product previously approved under section 505(c) of the FD&C Act. For an ANDA, a drug-led combination product should include sufficient information to demonstrate that the non-lead constituent part is compatible for use with the final formulation of the drug constituent part.
Biologic-Led Combination Products
Finally, biologic-led combination products are reviewed under a biologics license application (BLA) pathway outlined in Section 351 of the Public Health Service (PHS) Act: section 351(a) for a stand-alone BLA or section 351(k) for a biosimilar or interchangeable biological product.
A BLA submitted under section 351(a) of the PHS Act is a stand-alone application, all of the information and data necessary to demonstrate that these requirements are met are included in the application. This pathway is generally appropriate for biologic-led combination products other than products that are proposed to be biosimilar to, or interchangeable with, a previously licensed biological product.
On the other hand, Section 351(k) of the PHS Act sets forth the requirements for the licensure of biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product. To meet the interchangeability standard, an applicant must show that its product “is biosimilar to the reference product,” and must further show that the product “can be expected to produce the same clinical result as the reference product in any given patient.”
Examples
As we sometimes see in final guidance issued by the FDA, the agency did provide detailed explanations of examples for each pathway for clarity and better understanding by interested and involved parties.