On January 31, 2022, the U.S. Food & Drug Administration (FDA) published a notice in the Federal Register announcing the availability of a final guidance for industry and FDA staff entitled “Principles of Premarket Pathways for Combination Products”. The final guidance is available on the FDA’s website. It provides FDA’s current thinking on principles for premarket review of combination products. It finalizes previously available draft guidance, dated February 6, 2019, which altogether are part of FDA’s efforts to implement section 3038 of the 21st Century Cures Act expressly addressing combination products. The final guidance is nonbinding.
Context on Combination Products
Under section 503(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and its implementing regulations, a combination product is a product comprised of two or more different types of medical products. Its components, called constituent parts, may include drugs, devices, and biological products. Combination products can be single entity (e.g., a prefilled syringe), co-packaged (e.g., a first-aid kit containing bandages and an antiseptic drug), and cross-labeled (e.g., a light-emitting device together with a light-activated drug for treating a dermatologic condition).
FDA reviews marketing authorization submissions for combination products by first assigning a center, the so-called lead center, with primary jurisdiction for conducting the review. Under the FD&C Act, FDA bases this determination on which constituent part provides the primary mode of action (PMOA) of the combination product. Based on FD&C Act requirements, FDA states that a single application would generally be appropriate for a combination product to encourage overall efficiency, but separate applications may be permissible for certain cross-labeled combination products.
Key Points from the Final Guidance
In the final guidance, FDA outlines three pathways available for combination products based on their PMOA.
- Device-led combination products are reviewed under the premarket approval application (PMA), De Novo classification, and 510(k) pathways. For the PMA (required for class III devices), FDA states that 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, FDA states that 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), FDA states that a device that is not combined with a drug or biological product constituent part, or a product with a different active ingredient from a predicate, generally could not be successfully used as a predicate for a device-led combination product.
- Drug-led combination products are reviewed under a new drug application (NDA) or abbreviated new drug application (ANDA). For an NDA, FDA states that a drug-led combination product could rely on specific pathways under section 505(b) of the FD&C Act, based on whether it contains a new molecular entity or the applicant seeks to rely on a “scientific bridge” with a related product to establish safety and effectiveness. For an ANDA, FDA states that 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 are reviewed under one of the two biologics license application (BLA) pathways under section 351 of the Public Health Service Act—either a section 351(a) BLA (a “stand-alone” BLA) or a section 351(k) BLA (for a biosimilar or interchangeable biological product). For a section 351(k) BLA, FDA identifies existing guidance on biosimilarity and interchangeability, which likewise apply to biologic-led combination products. In the alternative, a section 351(a) BLA would be appropriate where a sponsor is not seeking to rely on FDA’s licensure of another product to demonstrate biosimilarity or interchangeability.
To illustrate the applicability of these three pathways, the final guidance also includes a detailed Annex with examples for each pathway.
Combination products continue to be a priority area for innovation in the biopharmaceutical, medical device, and digital health sectors. The final guidance is an important step towards greater clarity around how FDA conducts premarket review of combination products. As with all FDA guidance, FDA accepts comments at any time which, for this final guidance, enables stakeholders to provide feedback to FDA as it continues to shape its policies on combination products.
The final guidance also relates in part to the U.S. Court of Appeals for the District of Columbia Circuit’s April 2021 decision in Genus Medical Technologies, LLC v. FDA, which held that any product meeting the definition of both a drug and device must be regulated as a device. FDA intends to publish a notice in the Federal Register with a list of approved drugs that will transition to device status, although some have argued that Genus does not give FDA the authority to reclassify existing products. FDA intends to solicit comments before the list is finalized.