By Mark McCarty, Regulatory Editor
The regulatory law firm of Epstein Becker Green (EBG) has petitioned the FDA to set a limit to the number of days the agency can take to review petitions regarding combo product designations, stating that as matters stand, the agency is “unaccountable for egregious delays in decision-making.”
The combination products dilemma has roiled relations between the FDA and regulated industries for some time, and the EBG petition, filed on behalf of the Combination Products Coalition, highlights yet another source of tension. Most of the controversy up to now has revolved around the process by which the Office of Combination Products determines a combo product’s primary mode of action, but the EBG petition alleges that “there is at least one appeal which has been ‘under consideration’ by FDA for 18 months and counting.”
EBG’s James Boiani, the author of the letter to the FDA, argued that in the absence of some mechanism of accountability, the FDA “cannot be counted on to act” to address the delays of these appeals regarding designation. Boiani remarked that the appeals process would likely require little or no more than the 15 maximum pages of documentation allowed for a request for designation, and suggested the agency invoke a deadline of 60 days to review an appeal for an unfavorable request of designation.
Boiani said inaction on the agency’s part may “thwart implementation of process changes” to the agency’s determination of primary mode of action (PMOA) as seen in the 21st Century Cures legislation. The petition further requested that the FDA handle any appeals filed before Oct. 1, 2016, by March 9.
Boiani told Medical Device Daily that this petition was driven in part by a matter he is handling for a client, but he added, “I don’t think it’s a volume issue.” He said the petition may land on the desk of an associate FDA commissioner for special medical products, but he said some of the delays on these appeals may be incurred by the agency’s Office of Chief Counsel.
In any event, Boiani said the delays in dealing with these product designation appeals is “in part managerial, because there’s no timeline” for responding to such appeals, in contrast to other types of appeals available at the agency. The Office of Combination Products might be bogged down due to a lack of responsiveness from the centers involved in these reviews, and Boiani noted that the lack of a deadline for these appeals stands in contrast to the deadlines for handling drug and device applications, and thus something from OCP is “pushed to the back of the pile over and over again.”
Drug and device makers might be predisposed to using the citizen petition process in order to push the agency to respond, but Boiani noted that the citizen petition process eliminates a large area of confidentiality. “As problems like this arise, industry starts looking for creative ways to get some response from FDA,” he shrugged. While Boiani’s letter had requested that the agency fix the problem via rulemaking, he remarked that the FDA could handle this with a guidance, or “they could do a direct final rule, which would publish the regulation right away without comment” because it affects FDA only. Regardless of which approach the agency took, “anything that gets some guidelines would help,” he said.
Boiani said he has discussed the predicament with some on Capitol Hill, and had several physicians write in to support the case he is handling for a client. “At some point, I may have to take them to court” for his client, he said, which would raise the profile of this question even further. The citizen’s petition would also serve to “make it more public so others can weigh in about their experiences” as well, he said.
COMBO PRODUCTS ABOUND
The combo product predicament has affected more than just the Office of Combination Products, and seems to have had a suppressive effect on guidance development and on a number of requests made to the agency by drug and device makers. The implications are that it will take more than the discussion of primary mode of action (PMOA) seen in the 21st Century Cures bill to cure the FDA’s difficulties with combination products.
One example of this is the January 2013 draft guidance for post-approval modifications made to a combo product, which drew five comments to the docket. The Combination Products Coalition said there seemed to be some differences between FDA staff and industry on the question of when a new submission is required for changes to a constituent part of that product.
Combo products were also cited in the March 2014 medical device classification rule, which would have made a device component a class III device in instances in which the associated new drug application or biologics license application was still pending. In addition, a search of Cortellis Regulatory Intelligence lists a draft guidance dated Jan. 17, 2017, dealing with human factors studies for drug-device combinations when submitted with a generic drug application. The Clarivate Analytics Cortellis database also pointed to the February 2016 draft guidance for human factors engineering studies for combo product design and development, which according to the listing at regulations.gov is not yet finalized.
Among the recent industry petitions regarding combination products was the Dec. 27, 2016, request by Mallinckrodt Pharmaceuticals of St. Louis, addressing the use of generic versions of Inomax (nitric oxide) and the Inomax DSir delivery system. Mallinckrodt said it had previously petitioned the agency on a similar matter in June 2016, but that the agency had issued a nonsubstantive denial due to the absence of a generic application for Inomax, and because of deadlines for response to such petitions said to be imposed by the statute under subsection 355 of Title 21 of the U.S. Code.