On January 31, 2022, the United States Food & Drug Administration (FDA) published a notice in the Federal Register announcing the availability of final guidance for industry and FDA personnel titled “Principles of Premarket Pathways for Combination Products”. The final guidelines are available on the FDA website. It provides current FDA thinking on premarket review principles for combination products. It finalizes previously available draft guidance, dated February 6, 2019, which is part of the FDA’s effort to implement Section 3038 of the 21st Century Cures Act relating specifically to combination products. The final guidelines are not binding.
Background on combination products
Under Section 503(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and its regulations, a combination product is a product that consists of two or more different types of products. medical. Its components, called building blocks, can include drugs, devices, and biologics. Combination products can be single entity (eg, pre-filled syringe), co-packaged (eg, first aid kit containing dressings and antiseptic), and cross-labeled (eg, gas-emitting device). light with an activated drug for the treatment of a dermatological condition).
The FDA reviews marketing authorization applications for combination products by first assigning one center, the so-called primary center, primary jurisdiction to conduct the review. Under FD&C, the FDA bases this determination on the constituent part that provides the primary mode of action (PMOA) of the combination product. Based on FD&C requirements, the FDA states that a single application would generally be appropriate for a combination product to encourage overall efficacy, but separate applications may be permitted for certain cross-labeled combination products.
Key points of the final orientations
In the final guidelines, the FDA outlines three available pathways for combination products based on their PMOA.
- Device-driven combo products are reviewed for Premarket Approval (PMA), De Novo Classification, and 510(k) pathways. For the PMA (required for Class III devices), the FDA states that the application must contain sufficient data to demonstrate the safety and efficacy of the combination product as a whole and its components. For De Novo classification, the FDA states that understanding the components of the biologic or drug is important in determining the suitability of this pathway for PMA. For a 510(k), the FDA states that a device that is not combined with a constituent part of a drug or biologic, or a product with an active ingredient other than a predicate, cannot generally not be successfully used as a predicate for a combined product-device led.
- Drug combination products are reviewed as part of a New Drug Application (NDA) or an Abbreviated New Drug Application (ANDA). For an NDA, the FDA states that a combination drug product could rely on specific pathways under FD&C Section 505(b), depending on whether it contains a new molecular entity or the plaintiff seeks to rely on a “scientific bridge” with a related product to establish its safety and efficacy. For an ANDA, the FDA states that a combination drug product must include sufficient information to demonstrate that the non-primary constituent part is compatible for use with the final formulation of the drug constituent part.
- Biologically based combination products are reviewed under one of two biologics license (BLA) application pathways under Section 351 of the Public Health Services Act – either a Section 351(a) BLA (a “stand-alone” BLA ) or a Section 351(k) BLA (for a biosimilar or interchangeable biologic product). For a Section 351(k) BLA, the FDA identifies existing guidelines on biosimilarity and interchangeability, which also apply to biobased combination products. Alternatively, a 351(a) BLA would be appropriate where a sponsor is not seeking to rely on FDA approval 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.
Take away food
Combination products continue to be a priority area of innovation in the biopharma, medical device and digital health sectors. The final guidelines are an important step toward greater clarity about how the FDA conducts premarket review of combination products. As with all FDA guidance, the FDA welcomes comments at any time, which for these final guidelines allows stakeholders to provide feedback to the FDA as it continues to shape its policies on combination products. .
The final guidelines also relate in part to the April 2021 decision of the United States Court of Appeals for the District of Columbia Circuit in Genus Medical Technologies, LLC c. FDA, that any product that meets both the definition of a drug and a device must be regulated as a device. The FDA intends to post a notice in the Federal Register with a list of approved drugs that will upgrade to device status, although some have argued that Kind does not give the FDA authority to reclassify existing products. The FDA intends to solicit comments before the list is finalized.