The RFD Process: Time for Reform?

The Federal Food, Drug, and Cosmetic Act (FD&C Act) has very different regulatory regimes for pharmaceutical products than devices. Knowing how a product will be regulated is essential to companies. The means to gaining that knowledge for combination products or single entity products where the regulatory classification is unclear is the Request for Designation (RFD). A sponsor may submit an RFD, not to exceed 15 pages, to the Office of Combination Products (OCP) to obtain the product classification (i.e., drug, device, biologic, or combination product) and/or review/lead Center (i.e., CDER, CDRH, CBER). In the 15 allotted pages, amongst other things, the submitter:

• Identifies “any component of the product that already has received premarket approval, is marketed as not being subject to premarket approval, or has received an investigational exemption,”
• Describes the “chemical, physical, or biological composition,” and
• Provides a “description of all known modes of action, the sponsor’s identification of the single mode of action that provides the most important therapeutic action of the product, and the basis for that determination.” (21 CFR 3.7 (c)(2)(iv), (v), (ix)).

The sponsor is also expected to provide their “recommendation as to which agency component should have primary jurisdiction based on the mode of action that provides the most important therapeutic action of the combination product.” (21 CFR 3.7 (c)(3)).

OCP then makes the binding determination within 60 calendar days of filing the RFD by determining the primary mode of action (PMOA). If OCP does not issue a decision within the statutory timeline, the sponsor’s recommendation for the classification or assignment of the product is the designation. (21 CFR 3.8 (b)).

FDA also offers sponsors the opportunity to submit a Pre-RFD (which we have blogged about here) and obtain FDA’s preliminary, nonbinding assessment of the product classification and/or review Center.  Unlike an RFD, the Pre-RFD does not have a page limit. Companies can use that feedback in deciding whether to submit an RFD, and if they decide to submit, how best to frame it. OCP’s goal is to provide feedback within 60 calendar days. While the content of Pre-RFD and RFD is different, in part because one allows for unlimited text and the other is confined to 15 pages, FDA would conduct the same PMOA analysis in both the Pre-RFD and RFD process.

In 2016, we said that “OCP has earned a reputation for designating products as drugs rather than devices.” (This was demonstrated in the decision to regulate PREVOR’s Diphoterine® Skin Wash product as a drug, which a District Court vacated after finding that FDA failed to provide a reasoned basis for its classification decision, which we summarized here. The District Court then vacated FDA’s classification decision to regulate the product as a drug a second time (see our previous post here).) Recently, we reviewed the most recently available data, which is the FY 2023 OCP Performance Report. This raises a separate question: where is the FY 2024 report, given that we are more than halfway through FY 2025? This is not the first time FDA has been delinquent in releasing information (see our De Novo post) that allows stakeholders to be more informed.  (In that vein, FDA just released the formal classification regulation for a device that had received De Novo authorization eight years ago.

The data from this report provide some interesting insights.  As shown below, when it comes to combination products CDER was identified as the presumptive review Center in 74% (23 of 31) of the assessments.  Those determinations were relatively swift, with 57% were issued within 60 days. In contrast, of the six presumptively assigned to CDRH, only two (33%) were decided within 60 days. For non-combination products, 75% of decisions (6 of 8), when assigned to CDRH, were made within 60 days; in contrast, only 15% (2 of 13) had a decision in 60 days when OCP determined the product to be non-combination with CDER as the review Center.  In all comparisons except for the non-combination products assigned to CDRH, OCP performed worse in 2023 than in 2022.   The tailing off for non-combination products assigned to CDER was particularly pronounced, with only 15% being issued in 60 days.  Given that the FY 2024 OCP report has not been released, we don’t know if these patterns have persisted, worsened, or improved.

Perhaps more important, our 2016 comment about drug determinations being more common is still valid. The table above clearly shows that 74% (25 of 31) of combination products were found to have a chemical PMOA. The proclivity for finding chemical PMOA in FY 2023 was not an anomaly. In FY 2022 a chemical PMOA was also more common, albeit by a less lopsided margin (63% (19 of 30))     Since most companies that submit Pre-RFDs want to be designated as devices and believe that device classification is appropriate, presumably  the majority of submitters are disappointed by the outcome.

The FY 2023 report also acknowledged 66 RFD submissions. Of those 66, only seven RFDs (11%) had a decision issued, 54 (82%) had insufficient information for filing, three (4%) were withdrawn, and two (3%) were still under review at the close of FY 2023 (these were later determined to lack sufficient information for filing). Similarly, the FY 2022 report stated that OCP received 41 RFD submissions. Of those, four (10%) had a decision issued, 35 (85%) had insufficient information for filing, one (2%) was withdrawn, and one (2%) was within the 60-day review period at the close of FY 2022. A process which results in so few decisions obviously needs revamping.

This raises the question of why so many of these RFDs were deemed insufficient. We had proposed changes in 2018 to remove the 15-page limit such that there be a “free exchange of relevant information about a proposed product.” This limitation is burdensome in light of the heavy expectations for submitters. In our experience, if anything, OCP is demanding even more details now than it did before. And while one can argue that removing the page limit does not necessarily ensure sufficient information is included, it can’t hurt. As the administration looks at ways to reduce the regulatory burden, eliminating the 15-page limit would be a good candidate. While ordinarily one would expect shorter submissions to be less burdensome, that is not the case here; squeezing complex technical arguments into 15 pages is highly challenging.

Of the eight RFD determinations (one was received in FY 2022 and completed in 2023) made in FY 2023 (all of which were issued by the statutorily mandated 60-day deadline), half were classified as combination products; the other half were classified as non-combination products. More specifically:

Notably all eight RFD assessments which reached a decision were completed on time. As noted above, that was not the case for Pre-RFDs. These data show that by imposing mandatory deadlines coupled with consequences, Congress can ensure prompt action by FDA.  If FDA will not itself make improvements to the RFD program, perhaps Congress will.