The U.S. FDA is well known for encouraging industry to meet with the agency “early and often” for complex premarket filings, but the Combination Products Coalition (CPC) says a recent draft guidance seems to offer the exception. The group said the December 2019 FDA guidance for feedback on combination product applications “seems to generally discourage” the use of the combination product agreement meeting (CPAM). It added that the complexity of some combination products suggests that such a meeting may well be crucial to an efficient application process.

The draft guidance is, in some respects, a response to Section 3038 of the 21st Century Cures Act and requires that applicants file a request for a CPAM meeting with both the Office of Combination Products and the product jurisdiction officer at the center that presumably would serve as lead. The associated Federal Register notice said that the FDA immediately would put the terms of the draft into operation as of that date, although the agency had received only one request for such a meeting since enactment of the Cures Act in 2016. The FDA also said it anticipates only one request for a CPAM meeting per center per year.

CPC: To CPAM or not?

The response by industry suggests a more intense interest in the CPAM meeting type than is perhaps anticipated by the FDA. Five trade associations and three manufacturers sounded off, including Washington-based CPC, which made the case that the draft falls short of the requirements spelled out in Cure’s Section 3038. Suzette Roan, who chairs the CPC’s product submissions working group, said the draft fails to make clear when a CPAM meeting would be used in lieu of other premarket meeting types.

Roan said the draft “seems to generally discourage the use of a CPAM meeting and frequently tells sponsors not to use a CPAM.” She explained that the draft cites application-based mechanisms as “the most efficient and effective” type of meeting, adding that the agency’s low expectations are disclosed in the prediction that each center will see on average only one such meeting a year.

CPC also urged the FDA to provide a more detailed set of guidelines for the timing of such meetings in the final version of the guidance. Roan also recommended that the agency delete the reference to the notion that non-CPAM meetings are generally the most efficient and effective approach. She emphasized that the agency should make a stronger commitment to making sure that the requested FDA staff are present at CPAM meetings, thus ensuring that the meetings are productive for both parties.

The Advanced Medical Technology Association (Advamed) had fewer observations about the CPAM process, but it recommended that the FDA tweak the draft for convenience-kit combination products. Advamed’s vice president for technology and regulatory affairs, Steve Silverman, said sponsors should be instructed to contact the lead center with product-specific questions, such as whether more review would be required when additional component processing is needed.

Silverman noted that this could be the case for sterilization that is invoked during assembly of convenience kits. He also urged the agency to provide information about how sponsors of the non-primary component can obtain feedback about their products.

The Pharmaceutical Research and Manufacturers of America (PhRMA) observed that many of the practices spelled out in the draft are not specific to combination products, and that the final guidance should reference these other practices in less detail so as to focus on the meeting types specific to combo products.

PhRMA’s director of science and regulatory advocacy, Matthew Raymond, said drug makers would find it unduly burdensome to provide complete information on the product when applying for a CPAM meeting. Raymond recommended that the FDA align this type of policy with those found in other pre-submission meetings, adding that the agency should offer feedback on the request five days prior to the meeting, which he said is “in accordance with current practices.”

Raymond said the FDA should establish a means by which the applicant can identify the primary point of contact within the lead center to ensure that the agency’s subject matter experts are all on hand for the CPAM meeting. The meeting would be rescheduled if a key FDA staffer is unavailable, he recommended.

PhRMA is concerned, Raymond said, that the draft’s provisions for communication regarding the non-primary component of a combination product stifles discussions with staff at a non-lead center. This could lead to “delays and extended timelines,” he said, suggesting that a more efficient process with a non-lead center could avert holdups at times when the lead center is dealing with “a particularly heavy meeting burden.” He stated that the process for a cross-labeled combo product in particular might suffer from the mandate that the sponsor get in touch with the point of contact at the lead center only.

Biocom: Feedback regarding device component could vanish

For its part, San Diego-based Biocom said the draft leaves unanswered the question of which center would take the lead on co-packaged convenience kits, adding that such products already are subject to regulatory confusion. Joe Panetta, Biocom’s president and CEO, explained that portions of the draft are focused on the holder of an NDA or BLA. The draft, Panetta said, “does not provide enough assurance that feedback given to the device constituent manufacturer will be honored” and relayed to the sponsor of the primary component product.

Panetta added that any feedback between the Center for Devices and Radiological Health and the device component manufacturer should be memorialized in master files or, when appropriate, 510(k) clearance orders. Any such decisions about the device component should be applicable to sponsors of future combo product applications that use that device as well, he said. Another consideration is that the draft should be more explicit as to whether a CPAM meeting or an alternative meeting type would be appropriate for human factors studies of the combo product.

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