The Food and Drug Administration (FDA) has published guidance dedicated to requesting FDA feedback on combination products. The document is intended to improve the clarity and transparency of the existing regulatory framework for combination products. Due to its legal nature, the document does not introduce any legally binding obligations the parties involved shall follow but provides additional recommendations and clarifications instead. The Agency additionally emphasizes that an alternative approach could be applied, providing that such an approach has been agreed with and approved by the regulating authority in advance.
Regulatory Background
The document is intended to address the aspects related to requesting feedback from the regulating authority regarding the scientific and regulatory questions related to combination products. In particular, the guidance describes the best practices to be applied in this sphere, including the ones related to the interactions and communications between the interested party (a sponsor) and the FDA. According to the document, there are three main approaches:
- Application-based pathways (pre-submission process),
- Formal meetings, or
- Combination Product Agreement Meetings (CPAMs).
For the purpose of this guidance, “a sponsor” refers to a party interested in submitting an application for premarket review – for instance, an entity developing a combination product. In particular, the applications available in the case of combination products include:
- Investigational new drug application (IND),
- New drug application (NDA),
- Abbreviated new drug application (ANDA),
- Investigational device exemption (IDE) application,
- Premarket approval application (PMA),
- Humanitarian device exemption (HDE) application,
- Premarket notification (510(k)),
- Product development plan (PDP),
- Request for classification submitted under section 513(f)(2) of the Federal Food, Drug, and Cosmetic (FD&C) Act (De Novo request – a special pathway used for novel medical devices), and
- Biologics license application (BLA).
At the same time, the regulating authority additionally emphasizes that in certain cases, the humanitarian device exemption (HDE) application may not be used for placing combination products on the US market. In this regard, the Agency recommends discussing such cases with the Office of Combination Products.
Combination Products: General Approach
The most important part of the guidance describes the concept of a combination product, and also the key aspects related to the operations with them, including the way they should be assigned to a “lead center” – a state body responsible for the regulatory procedures with regard to the particular combination product in question, coordination between centers in the course of premarket review, and also the way the questions regarding the combination products should be submitted to the regulating authority.
According to 21 CFR 3.2(e), a combination product is a product comprised of any combination of a drug, device, and/or biological product, while in accordance with 21 CFR 3.2(k), the drugs, devices, and biological products included in combination products are referred to as “constituent parts” of the combination product.
As it is prescribed by the general rule, a combination product subject to review should be assigned to the appropriate center (“lead center”), that would carry out the premarket review and regulation. In accordance with the applicable regulation, the determination of the particular lead center should be based on the part of the combination product in question that provides the primary mode of action (PMOA). The Agency also mentions that the center performing the premarket review would be also responsible for postmarket activities. At the same time, irrespectively of the primary mode of action, all divisions of the FDA would cooperate.
In case if the manufacturer of the combination product subject to review has reasonable doubts regarding the particular center that should be responsible for the review of the combination product, the manufacturer shall request additional clarifications from the Office of Combination Products (OCP). In particular, the interested party may submit a request for designation (RFD). As a response, the Agency would inform such party about the classification of the combination product in question.
In case if the manufacturer already knows the particular lead center the application should be submitted to, it shall contact the FDA Point of Contact (POC) or the lead center Product Jurisdiction Officer (PJO). However, the Agency also mentions that certain combination products do not require premarket authorization. For all other questions arising with regard to the combination products any issues related thereto, the interested party shall contact the Office of Combination Products.
Best Practices of Sponsor-FDA Interactions
As it was already mentioned before, the FDA guidance of requesting feedback on combination products also describes the best practices regarding interactions between the Agency and interested parties applying for the authorization of combination products. In accordance with the general principles, all interactions should be aimed at ensuring the safety and effectiveness of any and all combination products allowed to be marketed in the US. In particular, the FDA places additional emphasis on the effectiveness of the information exchange between the regulating authority and a sponsor as a core precondition of efficient communication.
The document also provides the list of considerations the communications should be based on, namely:
- Appropriate Submissions and Processing (each submission should be filed to the appropriate lead center),
- Timely Use of Appropriate Communication Procedures (all interactions between the regulating authority and sponsor should be performed in a timely manner, and using the means of communications explicitly prescribed by the Agency in the applicable guidelines),
- Clear, Robust Information Sharing (all information exchange should be as efficient, as possible).
The Agency outlines certain recommendations to be considered by sponsors applying for the authorization. These recommendations include, inter alia, the following ones:
- Any and all submissions and requests should be filed to the appropriate lead center. As it was already mentioned before, in case a sponsor has any doubts, it shall contact the FDA in advance and request the determination accordingly,
- The questions submitted by a sponsor should be clear and appropriate. Moreover, they should correspond to the current stage of combination product development.
- The request submitted to the FDA should be supplemented with all the information reasonably necessary to the regulating authority to assess the case and make a conclusion on the matter.
- All communications should be performed through the designated POC. This approach should be applied even if the request actually falls outside the scope of the lead center.
The guidance also describes the best practices employed by the regulating authority in order to facilitate all processes related to combination products, namely:
- Informing the sponsors through the POC. In particular, the Agency emphasizes the importance of a role the POC shall play in building efficient communications between the regulating authority and sponsor.
- The lead center responsible for the review of the application shall request additional expertise from other centers when it is reasonably necessary to assess the application.
- The feedback to be provided by the Agency should be complete and reliable to the maximum extent possible due to the completeness of the information initially provided by the sponsor.
Summarizing the information provided here above, the FDA guidance on requesting feedback on combination products is dedicated to the most important aspects related to communications between the regulating authority and sponsors. The document also outlines certain recommendations to be considered by both the Agency and sponsors in order to improve the overall effectiveness of interactions related to combination products and applications associated thereto.
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