8.6: Determining Regulatory Pathways

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Jack O'Grady
Austin Community College

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Primary Mode of Action (PMOA)

Regulations are based on the primary mode of action (PMOA) of that combination product (drug, device, or biologic), which in turn dictates which center primarily oversees this approval (CDER, CBER, or CDRH) in combination with all interested centers by committee. If there is not a clearly defined determination, the device manufacturer may file a Request for Designation (RFD) with the FDA. An RFD compels the FDA to classify the product and indicate the primary review group. The FDA has established an algorithm for assigning combination products when a PMOA is not set up with "reasonable certainty."

The FDA defines PMOA as "the single-mode (or greatest contribution) of action of a combination product that provides the most important therapeutic action of the combination product" (FDA.gov). For example, if a device is used to deliver a therapeutic drug, the PMOA would be the drug, and the Center assigned would be CDER. When a single, clear, mode of action is not established, the FDA utilizes an ‘assignment algorithm' to assign the Center to oversee the combination product. The FDA will consider the historical duties as well as the Center that may have the most expertise with similar products.

Request for Designation

It is highly recommended the manufacturer (sponsor) of the combination product seek assignment early in the process as this has a dramatic effect on regulatory strategy. When the PMOA is "clear," the sponsor may contact the OCP informally (phone or email) to seek advice – this process is not binding and is subject to change. The formal designation is made through a Request for Designation (RFD) – which is a written application for designation submitted to the OCP. In this formal written request, the sponsor must clearly state the product description, ingredients, and components. If any of these changes, the designation is no longer binding (and you may need to reapply for an RFD. In the RFD, you must also provide all known mode of action (MOA), the sponsor's identification of the PMOA, and a description of any related products with their regulatory status. The sponsor is also required to provide a recommendation of assignment with reasons why you recommend that assignment.

Premarket Review

Although the assigned Center is responsible for the review, other centers may also be involved in the review depending on the product. The FDA has created a streamlined Standard Operating Procedures (SOP) for the Intercenter Consultative and Collaborative Review Process to assist FDA staff in handling combination product submissions. The lead center typically applies its regulatory pathway – however, some situations require multiple applications – especially those combination products where the goods are separate products themselves.