03/22/2022
The US Food and Drug Administration (FDA) released a final guidance, “Principles of Premarket Pathways for Combination Products” in January 2022. Section 3038 of the 21st Century Cures Act amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) regarding combination products. This included requirements for consistent premarket regulatory expectations and aligned premarket review for combination products. The guidance describes principles for premarket review of combination products in line with the amendments implemented by the Cures Act.
Background
A combination product is made of two or more different types of medical products: drug, device, and/or biologic. They can be combined into a single product (e.g., a prefilled syringe), two or more products packaged together (e.g., a first aid kit with bandages and antiseptic), or two or more products packaged separately but intended to be used together to achieve the desired outcome, also called a cross-labeled combination product (e.g., a photosensitizing drug and activating light source). Since different Agencies within the FDA are responsible for drug/biologic versus device, the Agency that is responsible for regulating the combination product is based on the component that has the primary mode of action (PMOA). In the example of the prefilled syringe, the PMOA is the drug within the syringe, so the Center for Drug Evaluation and Research (CDER) would regulate that product. If unsure which Agency would regulate a combination drug, the sponsor can submit a request for designation for classification and assignment or informally request feedback from the FDA to assist in determination.
Combination products must follow both the regulations for the individual components and regulations for the combination product. For example, a prefilled syringe follows both drug and device regulations. There are also specialized regulatory requirements for combination products that focus on where the regulations for the individual components overlap and where there are differences.
Information needed in an application to consider the safety and effectiveness of combination products is different than that needed for a single product application. The application should adequately describe each component to allow the same level of evaluation that separate applications would provide and include how the components may interact and interrelate. For example, a device may incorporate a small, localized drug that would work very differently from the drug used systemically as a stand alone drug.
Summary of Guidance
The type of application submitted should align with the PMOA. In the prefilled syringe example, a New Drug Application (NDA) would be indicated. Pathways and considerations for different types of combination products are dependent on the PMOA as follows.
Combination products that have a primary mode of action from the device follow one of these regulatory pathways:
Premarket Approval Applications (PMA)
De Novo Classification Requests
Premarket Notification (510(k)) Submissions
Drug led PMOA products follow one of these regulatory pathways:
New Drug Application (NDA)
Abbreviated New Drug Application (ANDA), which is used for approval of products that are equivalent to an approved product (generic application).
Biologic led PMOA products are licensed through either:
Biologics License Applications (BLAs) Submitted Under Section 351(a), or
BLAs for Biosimilar and Interchangeable Biological Products Submitted Under Section 351(k)
The annex provides examples of pathways to address the most commonly asked questions about device led combination products and includes an example table of identified risks and potential mitigations.
Generally, it is preferred for a single application to be submitted for a combination product, but it is acceptable to submit separate applications for the components if the sponsor decides it is necessary and the FDA concurs. An example of when this may occur is for cross-labeled combination products. A single application reduces potential duplication and burden.
Questions about regulatory pathways or drug/biologic or device regulation? Clinical Pathways can help! Contact us at info@clinicalpathwaysresearch.com to learn about our training and consulting services.
- The Clinical Pathways Team
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