Mode of Action Definition

Currently, § 3.7 requires a sponsor applying for designation to identify the APMA of the combination product and recommend an element of the agency responsible for regulating it. However, the APMP of a combination product is not defined in the statutes or regulations and can sometimes be difficult to identify. Requests to order combination products are usually made very early in a product`s development. This practice is encouraged because it allows proponents to work with a component of the agency as early as possible in the development process. However, for some products, neither the FDA nor the product sponsor will see the product`s AGPO at the time the application for assignment is submitted. Determining the APMI of a combination product is also complicated for products that have two completely different modes of action, neither of which is subordinate to the other. In limited cases, assignments may refer to subtle distinctions that relate to the determination of whether a mode of action is “primary” or not. The allocation process may seem unpredictable when two slightly different products are allocated to different components of the organization due to differences in their MPAs. Since it is not possible to determine which mode of action contributes most to the overall therapeutic effect of the combination product, it is necessary to apply the attribution algorithm. The APMI of the product is due to the action of the device component to mechanically maintain intervertebral spacing and stabilize the diseased region of the spine, while the effect of the therapeutic protein to promote bone formation in and around the cage plays a minor role. In this hypothetical example, the therapeutic protein does not have the mechanical properties necessary to maintain distance and stabilize the spine when used alone. In addition, clinically successful spinal fusion, that is, pain reduction and stability of the spine, can be achieved even without bone growth in the cage.

As a result, the FDA would assign the CDRH product to regulation because the component of the device provides the most significant therapeutic effect of the product. It is not necessary to proceed with the attribution algorithm, since it is possible to determine which mode of action provides the main therapeutic effect of this particular combination product. (Comment 3) One comment stated that the definition of mode of action in the proposed rule “almost presupposes that an ingredient itself may be a combination of objects” and that “an ingredient itself cannot be a combination product”. (ix) a description of all known modes of action, an indication by the sponsor of the only mode of action constituting the main therapeutic effect of the medicinal product and the basis for that determination. d. Contact lens combined with a drug for the treatment of glaucoma. This product is identical to the product described in Example c. in all essential respects. The RFD was submitted after naming the product in example c.

Since it is not possible to determine which mechanism of action contributes most to the overall therapeutic effect of the combination product, we would apply the attribution algorithm. This product would be attributed to CDER under the first criterion of the allocation algorithm because the product described in Example c. raises similar safety and efficacy issues for the combination product as a whole and is already associated with CDER. A mechanism of action is important for the classification of chemicals because it represents an intermediate level of complexity between molecular mechanisms and physiological outcomes, especially when the exact molecular target has not yet been elucidated or is controversial. One mechanism of action of a chemical could be “binding to DNA,” while its broader mode of action would be “transcriptional regulation.” [3] However, there is no clear consensus and the term mode of action is also widely used, especially in the study of pesticides, to describe molecular mechanisms such as action on certain nuclear receptors or enzymes. [4] [5] [6] [7] [8] [9] [10] Iorio F, Bosotti R, Scacheri E, et al. Discovery of the mechanism of action and repositioning of drugs from transcriptional reactions. Proc Natl Acad Sci USA. 2010;107(33):14621-14626. doi:10.1073/pnas.1000138107 The APMI of the product is due to the action of the biological component of the product to form new organic tissues that ultimately function as the native organ.

The action of the device component to provide a scaffold on which the new tissue forms is secondary. Although the scaffold is necessary to create the new tissue and give the necessary shape, the creation of a functional organ depends primarily on the role of the cells in the tissue organization and muscle layer needed to function as the native organ. As a result, the FDA would assign the product to CBER for regulation because the biological component of the product provides the product`s primary therapeutic effect. It is not necessary to proceed with the attribution algorithm, since it is possible to determine which mode of action provides the main therapeutic effect of this particular combination product.