On Tuesday, February 5th, FDA published a draft guidance explaining the principles for premarket review of combination products, including how to determine which type of premarket submission is appropriate. These submissions include new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for drug-led combination products; stand-alone or biosimilar biologics license applications (BLAs) for biologic-led combination products, and 510(k), De Novo, or premarket approval (PMA) applications for device-led combination products. Read about this below, or contact us for expert guidance.
The draft guidance, entitled “Principles of Premarket Pathways for Combination Products,” is part of the FDA’s effort to implement Section 3038 of the 21st Century Cures Act (“Cures Act”). This section, enacted in December 2016, substantially amended section 503(g) of the Federal Food, Drug, and Cosmetic (FD&C) Act and is the principal section specifically addressing combination products. “General themes of these amendments include enhancing clarity, predictability, efficiency, and consistency of premarket regulatory expectations for combination products, including by ensuring that Agency components and staff coordinate appropriately on premarket review of these products, and that Agency thinking is aligned in conducting these reviews.”
In a recent statement, Scott Gottlieb, M.D., Commissioner of the FDA, stated that “because combination products often combine a drug or biologic with a device, these products can sometimes be more complex to develop—and it can be less clear to innovators on how to best engage the regulatory process to advance these innovations.”
Combination products are any “product composed of two or more different types of medical products (i.e., a combination of a drug, device, and/or biological product with one another).” Included in the combination products are drugs, devices, and biological products which are referred to as “constituent parts.”
Under 21 CFR 3.2(e), combination products include:
Combination products will be assigned to an Agency Center that will have primary jurisdiction (i.e “the lead”) for premarket review and regulation of that combination product.
The assignment to the lead Center is based on a determination of which constituent part of the combination product provides the primary mode of action (PMOA). For example, if the PMOA of a device-biological product combination product is attributable to the biological product, primary jurisdiction for the regulation of the combination product will be the Center responsible for premarket review of a biological product. Therefore, the Agency Center with primary jurisdiction will work with other Agency Centers to ensure adequate premarket review.
The lead Center is a Sponsor’s primary point of contact and the focal point for the FDA to present their views to the Sponsor. The Cures Act ensures that meetings between the FDA and Sponsors are attended by review staff from each Center, as appropriate. Premarket approval and procedures for the lead Center are available, and the FDA suggests that Sponsors utilize the procedures, such as pre-submissions meetings and other mechanisms for obtaining Agency feedback.
“Sponsors may request in writing the participation of representatives of the Office of Combination Products (OCP) in meetings regarding their products, or to have OCP otherwise engage on regulatory matters concerning the product.” OCP can assist sponsors in identifying appropriate points of contact, resolving substantive issues, or otherwise facilitating interactions with the FDA and collaboration among Agency components.
In its draft guidance, FDA emphasizes that drugs, devices, and biological products retain their discrete regulatory identities when they are constituent parts of a combination product. Therefore, premarket requirements for demonstrating the safety and effectiveness of a combination product is applicable to the statutory and regulatory requirements of its constituent parts.
FDA states that a single application for a combination product is generally appropriate with regards to premarket authorization pathways. Furthermore, the Agency believes that this single application will eliminate unnecessary duplication of multiple applications and will streamline submissions and communication with FDA. To assess the safety and effectiveness of a combination product in a single application, a similar evaluation that would be submitted if each constituent part were reviewed under separate submissions should be included.
The marketing application should coincide with the PMOA of the combination product, however “if application coinciding with the PMOA of the combination product (PMOA-based application type) does not enable such an evaluation, the combination product should typically be reviewed in a different PMOA-based application type.”
The draft guidance states that premarket review of a combination product can be “significantly streamlined” where Sponsors are legally authorized to rely on FDA’s prior findings of safety or effectiveness or substantial equivalence with respect to an approved or cleared constituent part, or where the sponsor has a right of reference for another sponsor’s data.
FDA discusses various pathways that are available for combination products based on their PMOA, and considerations for determining the correct pathway, including:
At the end of the draft guidance, FDA provides an annex which includes five illustrative examples of device-led combination products. These examples include: antimicrobial coating added for the first time to a previously classified device type, new drug indication added, different method of drug coating, some drug constituent part with a lower concentration, and replacing a drug constituent part with a different antimicrobial.
The FDA is seeking feedback on its draft guidance is accepting written and electronic comments until May 7, 2019.
Are you in the process of developing a combination product? We can help you navigate the sometimes difficult and confusing process of obtaining FDA approval. To learn more about our services and how we can help you achieve successful interactions with the FDA, contact us today.
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