On January 30, 2018, FDA issued revised guidance documents: Refuse to Accept Policy for 510(k)s and PMAs (here and here). These revised guidances may have gone unnoticed by many as there was no federal register notice announcing or discussing the revisions from the policy in place since 2015. However, last week, FDA held a webinar discussing the updated Refuse to Accept (RTA) checklist.
FDA’s Refuse to Accept policy describes the preliminary requirements that a 510(k) or PMA submission must include to be accepted for review by the Division. These requirements are meant to improve the efficiency of a review by reducing the instances where reviewers must request additional information or clarification from the applicant.
The updated checklist now requires 510(k)s and PMAs to specifically identify whether or not it is a combination product. During the webinar last week, FDA indicated that it will assess whether an applicant has “correctly” identified the subject product as a combination product. This question seems fraught with potential complications.
There is often a debate as to whether some products are combination products or devices—for example, devices incorporating an antimicrobial where the antimicrobial acts solely as a preservative for the device. FDA’s 510(k) database often identifies these devices as combination products, but there is a legal and regulatory argument that these products are solely devices. Currently, if CDRH believes there is a jurisdictional question related to a product under review, shortly after acceptance of a submission, the Agency will direct the applicant to obtain a determination from the Office of Combination Products (OCP). This typically occurs when there is a question as to whether the 510(k) pathway is appropriate.
Under the revised RTA, if there is a debate as to whether a product is a combination product or strictly a device and a sponsor answers “incorrectly,” from FDA’s perspective, it is possible that the Agency could RTA the submission. Unlike our experience with the prior RTA checklist, the new question could prevent the submission from being filed, even if the response does not affect whether or not the product would proceed through the 510(k) pathway. During the webinar, FDA did not specifically mention the need for increased interaction with OCP prior to filing of 510(k)s or PMAs. This new question, however, certainly opens the door for CDRH to force more applicants to seek a definitive determination as to a product’s status from OCP prior to accepting a submission for review.
In addition, in December 2016, the 21st Century Cures Act (the Cures Act) amended the Federal Food, Drug, and Cosmetic Act provisions related to combination products. Among other revisions, the Cures Act required that sponsors of combination products incorporating an approved drug constituent part submit a certification with respect to any patent information identified in the Orange Book for the listed drug identified, and, in the case of a Paragraph IV certification, provide notice that the challenged patent(s) is invalid, unenforceable, or not infringed. If the NDA holder or patent owner timely brings suit, then clearance of the 510(k) or approval of the PMA for the proposed combination product can be delayed up to 30 months while patent infringement is litigated. After that, clearance or approval could be granted, but if patent infringement litigation is not finally resolved, then a combination product sponsor will need to decide whether or not to market its product “at risk.”
The changes to the 510(k) and PMA RTA checklists also implement this statutory change, and include a new section for combination products. The earlier iterations of the RTAs included a preliminary question regarding whether the product was a device or included a device constituent subject to clearance or approval. This was the extent of the combination product assessment. All applicants, of course, answered this question “yes” (otherwise they would not have been submitting an application for the product).
The revised RTA adds a new preliminary question asking whether a combination product contains as a constituent part an approved drug as defined in 21 U.S.C. § 503(g)(5)(B). Such combination products are those covered by the new provision in the Cures Act. A Sponsor would know if its combination product is of this type by searching for the drug constituent part in the Orange Book (available here). If the drug constituent part is listed in the Orange Book, an appropriate patent statement or certification and a statement that the applicant will give notice as applicable are required.
This new policy is worth noting and taking into consideration when preparing new 510(k) and PMA submissions. FDA highlighted during its webinar that the patent certification provisions relate not only to 510(k)s and PMAs, but to all other submission types even if they do not have an RTA. Therefore, sponsors will need to keep this provision in mind with other submission types as well, including for example de novos. Indeed, it likely adds an additional step for combination products that, if ignored, could result in getting an RTA.