The regulatory landscape for combination products has been somewhat of a “question-mark” for manufacturers for various reasons. This is because when drugs, devices, and/or biologics get combined to produce a combination product, there is uncertainty on which regulatory requirements will apply to the components of the product and the product as a whole. Furthermore, the required information is not always found in one place, and separate product-specific entities regulate combination products; indeed the approval pathway for these products is not as straight forward.
The US FDA is constantly making efforts in providing guidance documents to facilitate registration pathways for a range of products including combination products and enabling timely access to them. In January 2022, the US FDA released their final guidance ‘Principles of Premarket Pathways for Combination Products’ to provide information on requirements for the pre-market review pathway.
Who regulates combination products?
According to the guidance document, a combination product is one that is made up of 2 or more different medical products (i.e., drug, device, and/or biological product). These can include:
- a product made up of 2 or more regulated components;
- two or more separate products that are packages together as a unit;
- a drug, device, or biological product packaged separately but intended for use with an approved, individually specified drug, device, or biological product according to its label;
- an investigational drug, device, or biological product that is packaged separately but intended for use with another individually specified investigational drug, device, or biological product.
Different Centers under the FDA are responsible for regulating different products i.e., drugs, biologics, and devices. Thus, depending on the component of the combination product that provides the primary mode of action (PMOA)- whether it is a drug/biologic or device- the product is assigned to the Center which regulates that medical product; the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the Center for Devices and Radiological Health, who must all be aligned in order to obtain regulatory approval for the product. Sponsors are recommended to submit a request for designation (RFD) if they are unsure. It is important to note that combination products should follow the regulation for individual constituents as well as those for the combination product.
Available pathways and considerations for combination products
The document provides information and guidance on the pathways that are available for combination products (depending on the PMOA of the product component) and how to determine the appropriate pathway. These include pre-market approval applications (PMAs), De Novo Classification requests, and premarket notification (510(k)) submissions for device-led combination products; NDA and ANDA for drug-led combination products; and BLAs (for biological product or biosimilar) for biologic-led combination products.
What lies ahead for combination products?
As technology advances and diseases become more complex to treat, novel combination products are emerging that do not have a clearly defined PMOA. This highlights the need for more comprehensive categorization and robust regulatory approach. Indeed, the US FDA regulatory framework for combination products is primarily managed by a dedicated Center. However, in the European Union, different regulations apply to different components of the products. Can the two regulatory frameworks overlap for a more harmonized and systematic approach to combination product approval?
References and further Reading