Despite industry confusion and concerns, the FDA has unveiled a long-anticipated final rule designed to create consistent, complete postmarket safety reporting requirements for combination products.

More than seven years in the making, the rule – which largely follows the proposed version with some clarifications and additions – applies to combination products or their constituent parts that have received FDA marketing authorization. It goes into effect Jan. 19, 2017.

The agency acknowledged that it had not issued regulations previously on postmarket safety reporting specific to combination products. "Instead, [it] has applied provisions to combination products from the postmarketing safety reporting regulations applicable to the constituent parts [i.e., reporting requirements specific to drugs, devices and biological products]," the agency said.

While similarities exist in terms of how those products are regulated, there are differing reporting requirements, standards and timeframes. As a result, the FDA had seen inconsistencies in postmarket safety reporting with those products and their constituent parts.

Though the proposed rule sought to provide a remedy to the combination product community, the 15 groups and one individual submitting comments appeared confused and provided the agency with a number of suggestions. In fact, several expressed concerns about how it could be implemented, saying it could needlessly muddy the waters.

MORE GUIDANCE NEEDED

"After a review of the agency's proposed rule by a number of pharmacovigilance experts, we find that the process outlined in the proposed rule is confusing, and would be complicated to implement," the Pharmaceutical Research and Manufacturers of America (PhRMA) stated. PhRMA added that those perplexed by the proposals contained in the rule might submit information the FDA does not intend to collect, complicating, rather than simplifying, the process, PhRMA maintained.

The group suggested that the agency create guidance to minimize the potential for over-reporting.

PhRMA was not alone in suggesting the need for accompanying guidance on issues relevant to the rule. The Advanced Medical Technology Association (AdvaMed) asked the FDA to issue guidance on cross-labeled combination products before issuing the final rule. It also called on the agency to clarify in the rule what distinguishes a cross-labeled product vs. one for concomitant use.

The agency disagreed that it had to issue the requested guidance ahead of the final rule; it did acknowledge AdvaMed's concerns. "This issue may be relevant not only for purposes of postmarketing safety reporting, but to all aspects of the regulation of such combination products," the agency said. It added that it intends to publish a guidance with recommendations on how to comply with the requirements under this rule, including cross-labeled combination products.

Others requested clarification of safety reporting requirements for investigational combination products, either through guidance or expansion of the scope of the rule.

The agency declined to expand the scope of the rule, adding that safety reporting requirements for investigational new drugs and devices are in 21 CFR 312.32 and 21 CFR 812.150, respectively. That said, the FDA plans to develop guidance related to the topic and urged those with questions about reporting requirements for investigational combination products to conduct the review team within CDER, CBER or CDRH, or the Office of Combination Products.

In a win, Genentech Inc., part of the Roche Group, called for the final rule to reference biological product deviation reports (BPDR), something omitted in the original proposal. The FDA agreed to explicitly include BPDRs as a type of report that an applicant must submit if its combination product includes a biologic.

Also, the FDA agreed with the Combination Product Council that the rule should address how device corrections and removals fit into the proposed system. Specifically, the FDA should confirm that a correction or removal report is not required if the agency already has received that information under the new rules.

The final rule also adds a section clarifying that all applicants must comply with the applicable postmarket safety reporting requirements with respect to their product.

"A constituent part applicant must comply with applicable requirements for the constituent part it is marketing, and a combination product applicant must comply with applicable requirements for the combination product it is marketing," the FDA wrote in a Federal Register notice.

In addition, the agency added definitions for BPDR and correction or removal report to reflect their incorporation in the final guidance. It also added a definition for "product development protocol" and de novo classification request. Further, it added definitions for "applicant," "combination product applicant," "constituent part applicant" and "device application" to clarify which entities are subject to certain duties under the rule.

Another change was the elimination of the obligation to comply with blood fatality reporting requirements for combination products that received marketing authorization under an application other than a BLA. The agency made that change after concluding that facilities at which such events could occur already are required to make blood fatality reports, regardless of the type of application. "Because these facilities must make such reports, we concluded that it would be unnecessary for a combination product applicant [who is not also the operator of the facility] to report the same information as well," the agency said.

In addition, the FDA revised the requirement for all combination product applicants to submit 15-day reports. Now, affected parties may submit those reports within 30 days for combination products that received marketing authorization under a device application.

The change came after the FDA determined it could still respond in a timely manner if those reports were submitted within 30 days. Further, it would be in line with the submission of medical device reports.

The FDA is continuing its work on combination products, at least according to a blog post from earlier this month. Commissioner Robert Califf and Nina Hunter, the agency's associate director for science policy in the Office of Medical Products and Tobacco, highlighted some of the progress made as well as work that still needs to be done.

Among the work that remains outstanding is the finalization of guidance on human factors and cGMP, as well as the issuance of guidance on the pre-RFD process for requesting feedback on combination products.