FDA releases PDUFA VI program report on combination products
A new independent report on the FDA’s review practices for combination products under the Prescription Drug User Fee Act (PDUFA VI) gives the agency generally positive marks but finds room for refinements in communication and technology to improve the pre-submission and review process.
The report, commissioned by FDA as part of its PDUFA VI commitments, was conducted by Eastern Research Group and looked at FDA staff and sponsor experiences with combination products reviews during the pre-request for designation (pre-RFD), RFD, inter-center consult request (ICCR) and application submission stages.
FDA first detailed its pre-RFD program in draft guidance in 2017 before finalizing the guidance the following year. The pre-RFD process is intended to allow combination product sponsors a flexible, informal way to get feedback about the identity or classification of a medicinal product before engaging in the formal RFD process.
According to the report, sponsors and FDA staff found the pre-RFD and RFD processes to be generally “effective and efficient despite some challenges.” Sponsors greatly preferred the pre-RFD route, with 46 pre-RFD and 3 RFD reviews completed during the review period.
Sponsors preferred the pre-RFD process “for two main reasons: the pre-RFT process provides more opportunities for interaction with FDA, and submission requirements are more flexible.” The report also found that FDA needed to email sponsors for more information for more than half (57%) of the pre-RFDs in order to have sufficient information to review.
Most of the requests for additional information were “for further explanation of how the product works and product components, ingredients, or specifications,” though the report notes that in some cases sponsors may have been reluctant to provide information that would work against their “desired recommendation for classification and center assignment.”
The report also found the time from receipt of a pre-RFD to acceptance for review ranged from 0-287 days with a mean and median time to acceptance of 27 and 9 days, respectively. FDA typically responded to pre-RFDs within its 60-day goal window.
While some sponsors said they appreciated the opportunity to have informal teleconference calls via the pre-RFD process, some did not realize they had to request the calls. FDA staff also pointed out that the informal teleconferences were, “Not worthwhile if used by the sponsor to present clinical data outside the scope of the primary mode of action determination or to argue legal topics.”
The report had less to say about the RFD process, noting that FDA filed all three RFDs in the sample within its goal of five business days after receipt and issued designation letters within 60 calendar days.
When it came to inter-center coordination, the report found the ICCR process “was effective in enabling the lead center to obtain information and expertise from the consulted center despite many instances of recommended ICCR process timelines not being met,” with delays mainly attributed to technological and communication challenges.
Just over half (56%) of ICCRs from the Center for Drug Evaluation and Research (CDER) to the Center for Devices and Radiological Health (CDRH) were sent within 7-14 days of application receipt, with CDER attributing the late submissions to delayed notification from a lead center submission contact to the lead center consult requestor and submissions being sent to the wrong group in CDRH.
“Subsequently, CDRH assigned 53% of ICCRs to reviewers within 2-3 days of ICCR form submission; because 44% of ICR forms were submitted later than recommended, this meant that CDRH assigned 38% of the ICCRs to reviewers within the recommended 9-17 days of application receipt,” the report finds.
“When CDRH took more than 2-3 days to assign reviewers to ICCRs, staff attributed delays to insufficient information in the ICCR form to decide who best to respond … and inconsistent access to lead center databases to review details needed to assign the ICCR.”
On the whole, the report finds that CDRH only completed one-third (34%) of ICCRs by the date requested by CDER, though CDER staff reported that ICCR practices were, “reasonably smooth, timely, and high quality once CDRH assigned a reviewer.” CDER staff also pointed to a switch from a SharePoint-based system to a Salesforce-based system as a major source of inefficiency in the process.
CDRH staff, on the other hand, characterized the ICCR process as “adequately efficient,” citing difficulties accessing data from CDER databases that slowed things down.
As for the submission and review of new drug applications (NDAs), biologics license applications (BLAs) and investigational new drug applications (INDs), the report finds most were “generally similar to those for noncombination product applications.”
RAPS: First published in Regulatory Focus™ by the Regulatory Affairs Professionals Society, the largest global organization of and for those involved with the regulation of healthcare products. Click here for more information.