On December 4, 2020, FDA finalized the guidance document, Requesting FDA Feedback on Combination Products (Guidance), which was issued to fulfill the requirement under Section 3038 of the Cures Act. As a reminder, Section 3038 contained several provisions to help facilitate FDA engagement and appropriate review of combination products by, among other things, reaffirming FDA’s task of choosing a lead Center to regulate combination products based upon their primary mode of action (PMOA), and nudging FDA to conduct premarket review of combination products under a single application, although it left open the continued possibility of FDA using separate applications “whenever appropriate” (see previous coverage here). With the intent of improving pre-submission interactions around combination product development, the Guidance updates the December 2019 draft of the same title and describes “ways in which combination product sponsors can obtain feedback from FDA on scientific and regulatory questions and to describe best practices for FDA and sponsors when interacting on these topics.” Guidance at 2. In comparing the final guidance to its draft, some re-organization and clarifications have been made, but the two documents are substantively very similar.
Combination products consist of any combination of a drug, device, and/or biologic and their regulation tends to be more complex than regulation of a single entity product. There are many times when a sponsor is uncertain whether the product should be regulated as a drug, biologic, or device, and in these situations, the Guidance recommends FDA’s Office of Combination Products (OCP) as the first line of communication, so that an Agency Center may be assigned based on the product’s PMOA. OCP can also be contacted for general questions related to combination products.
When a combination product’s lead Center is known, to communicate with FDA, combination product sponsors may use either (1) typical application-based mechanisms or (2) a Combination Product Agreement Meeting (CPAM). The application’s FDA Point of Contact (POC), when an application has already been submitted, or the Center’s Project Jurisdiction Officer (PJO) can be contacted with preliminary or general questions, or to discuss whether an application-based mechanism or CPAM is more appropriate.
Meetings with FDA: Traditional vs. CPAM
Traditional application-based mechanisms include the pre-submission process used in the Center for Devices and Radiological Health (CDRH) and the Center for Biologics Evaluation and Research (CBER) and formal milestone or guidance meetings used in the Center for Drug Evaluation and Research (CDER) and CBER. The Guidance suggests these mechanisms will be the most efficient and recommends their use to request feedback on “scientific issues, study design, testing approaches, or application preparation considerations for combination products or clarifying topics for which FDA has already published technical guidance.” Id. at 15. The application-based request should identify the product as a combination product and should include information on all constituents (i.e., drug, biologic, and/or device). For a drug or biological product-led combination product that includes a device constituent part, the request should include a description of the device (including images or drawings), identification of components, and identification of clearance or approval numbers, where applicable. For a device-led combination product, the request should include a description of the drug and/or biologic (including chemical name, established or proper name, and structure), route of administration, dosing information, and approval numbers, where applicable.
A CPAM is an alternative mechanism for communication available to combination product sponsors when previous feedback and agreement under an application-based mechanism has not provided enough certainty. In other words, while application-based mechanisms may be used to obtain FDA feedback on both general and more specific topics as a combination product moves through development, a CPAM should be used when a formal agreement with the Agency is warranted. It should not, however, be used to resolve disputes that are otherwise reviewed under existing dispute resolution and appeals processes. However, it should be noted that CPAM agreements can be invalidated if there are changes, including changes to a product’s intended use, design/contents, manufacturing processes, or the investigational plan. With this in mind, a CPAM should be used once development has reached a stage where changes that might invalidate an agreement are unlikely (e.g., the scientific basis of the sponsor’s proposal is mature), with application-based interactions being more appropriate when product design and/or scientific evidence is evolving. FDA plans to notify sponsors upon receipt of a CPAM request if they believe an application-based meeting may be more effective. Also, if FDA plans to notify sponsors if they determine, during a subsequent review of a marketing application, that CPAM agreements are no longer valid.
Operationally, a CPAM may only be used when the lead Center is assignment is clear. Also, FDA will meet with the sponsor within 75 calendar days of receiving the request.
Other Best Practices for FDA Communication
The Guidance provides a number of best practices for communication between FDA and sponsors of combination products. For sponsors, even if questions relate to a different constituent part, communication should always go through the lead Center, and the POC, when known. All submissions should identify the product as a combination product. Sponsors should be clear and specific in their requests for Agency feedback and questions should be appropriate for the stage of development. Comprehensive rationale and sufficient supporting information should be provided to allow FDA to consider the issue and provide feedback. For FDA, the Guidance recommends the Agency notify sponsors of the POC; engage relevant expertise from other medical product Centers and OCP to address sponsor questions; and provide consolidated, aligned, and reliable feedback.
Overall, the Guidance provides consolidated recommendations for combination product sponsors, including details about the content and format of submissions, and should be a useful reference for ensuring efficient and effective communication with FDA. Sponsors should also like FDA’s commitment to engage cross-Center experts and provide consolidated and aligned feedback as these have been areas of frustration to many during combination product development and review.