Revised pre-RFD guidance reflects FDA’s efforts to clarify pre-RFD process

Since its creation in 2002, FDA’s Office of Combination Products (OCP) has sought to clarify for sponsors the regulatory classification of human medical products—that is, whether a product will be regulated as a drug, device, biologic, or combination product, and which FDA Center will regulate it and take the lead in premarket review as needed.

Sponsors have two routes for obtaining this clarity:

• An RFD, or request for designation, under 21 CFR Part 3, which results in a formal, binding determination of a product’s classification and FDA Center jurisdiction; or
• A Pre-RFD, which provides non-binding feedback from OCP and the relevant FDA Centers to guide early-stage regulatory planning.

OCP implemented the Pre-RFD program in February 2018 in response to growing demand for an approachable, less formal pathway to obtain classification insight early in development. Under the program, OCP coordinates review with the relevant FDA Centers (CDER, CBER, and CDRH), consolidates feedback, and provides a written response explaining its reasoning. While not a formal decision, this early assessment can clarify regulatory strategy and guide subsequent communications with the appropriate FDA Center.

A more structured process

The Pre-RFD program remains a non-binding one, but the revised guidance takes a more structured approach in several material respects, summarized below:

• Structured—but limited—meeting framework.The 2025 revision creates a formal two-tier meeting framework and establishes timelines and content expectations. But unlike in the pre-submission context in CDRH where meetings with FDA are commonplace, OCP makes clear that it generally considers meetings to be unnecessary for Pre-RFDs and, that if it does grant a meeting, it prefers a virtual one to an in-person one.
  • In general, in the Pre-RFD context, OCP may accommodate “informational meetings”—conducted before a Pre-RFD submission, to help understand the product and context—and “explanatory meetings”—conducted after a Pre-RFD assessment, to discuss the agency’s written feedback and next steps (such as potentially a new Pre-RFD).
  • OCP aims to hold informational meetings within six weeks after receiving “a complete meeting package,” which should include “a complete explanation of the topics [a sponsor] would like to address and any supportive information.” OCP aims to hold explanatory meetings within two weeks after receiving a meeting request, which should include simply the questions on which the sponsor is seeking clarity regarding OCP’s decision. In both cases, a sponsor should keep its meeting request “targeted” and avoid submitting extraneous or unnecessary information.
• Existing resources and developed concepts first, then Pre-RFD. While the 2018 guidance effectively encouraged Pre-RFD submissions, the 2025 revision moderates that approach. OCP now underscores that sponsors should first “exhaust any applicable FDA resources regarding product classification and center assignment” and that sponsors should find these points “clearly established” for “most products” without a Pre-RFD. A Pre-RFD “is not appropriate for a developing technology/concept that has no defined composition, proposed use, and/or indication,” OCP says, given the lack of such basic information.
• Expanded content recommendations for Pre-RFDs.Relatedly, the 2025 revision is more prescriptive about the content expected in a Pre-RFD submission, now recommending in some cases information that is more detailed or that had been optional under the 2018 guidance (or both)—especially around a product’s components. These details include:
  • Sponsors still must list a product’s components, such as ingredients, but now must also list each component’s sources and regulatory and marketing history. Similar to the 2018 guidance but now spelled out in more detail, the list must clearly describe each component, including whether it’s active or inactive; its “material composition”; a “detailed explanation of the reason/purpose for inclusion of the component”; and the “specific amount/concentration for each ingredient,” i.e., not a range. These components continue to include any “biologically-derived materials,” the sources of which sponsors must likewise now describe along with analysis showing what the final product actually is and how the sponsor has verified it analytically.
  • Sponsors still must explain how the product works, including the mechanisms of action and supporting study data if available, but that now also includes how each component works. The studies required to provide this explanation will typically differ from those required to obtain a product’s marketing authorization. “For studies that cannot be cited to a publicly available source”—such as unpublished data—a sponsor “should provide a description of how the study was conducted, the conditions of testing, the identity of all test articles and controls, a summary of the results, and [the sponsor’s] conclusions as they pertain to [its] product’s classification and center assignment.” OCP now expressly recommends that sponsors consider this issue through the lens of its existing classification guidance.
  • For combination products, OCP continues to recommend that sponsors provide “any available information to support the relative contribution of different components to the overall intended therapeutic/diagnostic effects of the combination product (e.g., primary mode of action).” A sponsor should also still include a proposed use, intended use, or indication for use statement, as applicable; the instructions for use or conditions for use, as applicable; any additional claims that the sponsor has made or plans to make; and an explanation of how the sponsor will market the product.
  • Consistent with the 2018 guidance, a Pre-RFD should not include “information that relates to the overall safety and effectiveness of a product” or “disease/condition prevalence and impact,” as such information does not “help OCD understand how the product works.” In addition, “a Pre-RFD should focus on a single intended use.”
  • In line with the additional rigor OCP now expects of Pre-RFD submissions, FDA expressly instructs that “information should be succinct and sufficient”: statements should be “clearly written and not contradictory within the submission,” assertions should be supported, and assumptions should be explained. Although there previously had been no page limit for Pre-RFDs—unlike RFDs, which are limited to 15 pages—FDA now encourages sponsors to “limit [a] Pre-RFD to a succinct summary” of relevant information, which FDA says can “typically be effectively conveyed in 15-20 pages, not including any courtesy copies of published literature.”
• New protocols for information requests. The 2025 revision adds a standard process for responding to OCP questions and information requests. A sponsor should not only respond directly to OCP’s questions and requests but should also incorporate its responses into a revised version of the Pre-RFD submission reflected in both a tracked-changes version and a clean version, instead of a supplement providing additional information. This is consistent with recent OCP requests on Pre-RFDs.
• Clarified timelines. The 2025 revision clarifies that OCP’s 60-calendar day review “goal” begins after it has acknowledged acceptance of a sponsor’s Pre-RFD submission. OCP will also aim to deliver that acknowledgement or request more information within 10 business days after receiving the submission. Again, OCP cautions that needlessly long or poorly organized submissions may take longer to consider.
• New advice on use of the Pre-RFD assessment. OCP’s response to a Pre-RFD will include its “preliminary classification and/or center assignment assessment.” It is therefore not surprising that OCP advises sponsors to “use that information regarding which FDA center to interact with going forward” and to provide the Center with FDA’s response.

Some practical takeaways for sponsors

The 2025 revision clarifies aspects of the Pre-RFD process and formalizes some of OCP’s existing, unwritten practices, though it remains to be seen whether the revision will make the process more efficient and predictable. Going forward, sponsors might consider the following: :

• Sponsors should view the Pre-RFD process as a structured pathway to be approached carefully. OCP’s feedback can influence which FDA Center a sponsor engages and can, in turn, affect evidence expectations and review timelines. Sponsors should argue for a clear classification and jurisdictional assessment aligned with their strategic objectives.
• If a Pre-RFD is indeed required, prepare a thorough but concise submission. While OCP expects enough information to be able to make a decision—for example, relevant granular details of unpublished data—it also expects focused content, not a data dump. OCP repeatedly emphasizes in the 2025 revision that organization and precision determine, in part, its review timing, and it is likely to review more efficiently submissions that are well-structured and logically cross-referenced.
• The 2025 revision raises expectations for scientific details. Sponsors should describe how each component contributes to the product’s overall effect, especially for combination products. Quantify ingredients and other components precisely—no ranges—and explain why each is included. For biologically derived materials, summarize processing, source, and analytical characterization to show what the final material is and how it’s verified. Include a clear mechanistic rationale supported by data, where possible.
• Although the Pre-RFD process is still non-binding, OCP expects sponsors to reference its assessment in subsequent communications with the relevant Center. Include and consider OCP’s assessment as part of subsequent agency interactions, including potentially a formal RFD. Doing so demonstrates alignment with OCP’s prior feedback and may help streamline Center review.

The revised Pre-RFD process is a structured mechanism for early regulatory alignment. While sponsors may receive faster OCP feedback, we do not expect a major shift in process as the revisions are largely consistent with OCP’s expectations for Pre-RFDs in recent years.

Authored by Lina Kontos and Kristin Zielinski Duggan.