Inspections emerge as flashpoint in BsUFA II assessment meeting

Biosimilar industry groups expressed frustration at the lack of transparency and communication from the US Food and Drug Administration (FDA) on inspections during the COVID-19 pandemic during a meeting to review the final assessment report on the agency’s enhanced review transparency initiative under the Biosimilar User Fee Amendments (BsUFA II) program.

“The BsUFA program final assessment performed by [Eastern Research Group] ERG appears to be consistent with the findings of the PDUFA program final assessment. As with the PDUFA program assessment, there are more first cycle approvals and fewer complete responses in the program cohort compared to the applications which were in the cohort prior to the implementation of the program,” said Sarah Yim, director of the Office of Therapeutic Biologics and Biosimilars.

Yim noted that one sore spot in the report had to do with the impact of COVID-19 on FDA’s inspectional program. “During the pandemic the program has continued to operate effectively, with the possible exception of some inspections which were impacted by travel restrictions. As ERG noted, to some extent, FDA was able to mitigate this challenge by instituting an alternate records review process in cases where that was appropriate. Nevertheless, some inspections and therefore, FDA actions, were deferred.”

Yim said that whether alternate methods are appropriate is “product and application specific” and cited the agency’s requirement for a preapproval inspection for facilities that have not previously been inspected “really did impact our flexibility in those areas.”

She added that the agency will be “soliciting for specific communication best practice” to incorporate into updated guidance as part of the BsUFA III effort.

“The overarching program findings do not indicate a need for major operational process changes for applications within the program, with the possible exception of inspections, which is a topic area on its own and not specific to the program, perse, and is an area identified for additional evaluation in BsUFA III,” Yim concluded.

The two groups representing biosimilar manufacturers at the meeting noted many of the BsUFA II program’s successes but stressed that inspections have been a major shortfall during the pandemic.

David Gaugh, senior vice president for sciences and regulatory affairs at the Association for Accessible Medicines (AAM) spoke on behalf of the group’s Biosimilar Council. He highlighted the role that “additional communication touchpoints introduced during [biologics license application] BLA reviews played” in boosting the number of first-cycle approvals under BsUFA II.

He also said that, “New program enhancements that are going to be introduced in BsUFA III will address many of the communication deficiencies ERG identified in the current BsUFA development and review process.”

Some of those enhancements include allowing the discussion of demonstration of biosimilarity at earlier stages of development, the new biological product development (BPD) Type 2a meeting and the ability for sponsors to submit clarifying questions to the agency for all meeting types.

But Gaugh said that inspections have been a “significant challenge” for biosmilar applicants who have “found themselves in the position of receiving a facilities-only [complete response letter] CRL instead of an approval, because FDA was unable to conduct preapproval inspections.”

“FDA needs to find a way to communicate more transparency around preapproval inspections, especially when the lack of inspections is the sole barrier to approval of an otherwise approvable application,” he said.

Gaugh also urged FDA to report out data on its use of alternate inspection tools for biosimilar 351(k) BLAs separately from 351(a) BLAs.

“While ERG and FDA found that no action was needed for inspections, we believe that there are actions that could be taken, even during the COVID-19 pandemic,” Gaugh said. “We would encourage the agency to parse out its reporting to make it clear around what is truly happening in the biosimilar program versus all BLAs.”

Camelia Thompson, senior director, science and regulatory at the Biotechnology Innovation Organization (BIO), painted a rosier picture of the inspection situation. While noting that inspections were an exception to an otherwise positive assessment of the program, she praised FDA’s effort to find alternatives.

“The main exception was the predictability of inspections, some of which have been disrupted by operational changes and travel restrictions; however, FDA acted to mitigate this challenge to the extent possible, by initiating an alternative records review process where appropriate,” Thompson said.

Rachel Turow, associate general counsel at Teva Pharmaceutical, who spoke on behalf of the Biosimilars Forum, gave a starker assessment of FDA’s inspection issues.

Turow disagreed with the ERG report’s conclusion that FDA’s communications around inspections have generally been clear and that no action is needed to improve performance. “The Forum respectfully disagrees with this conclusion. As of 31 December 2021, four biosimilar applications are still awaiting FDA action due to COVID-19 pandemic-related inspectional delays. Communication surrounding how and when the agency plans to address these delays, as well as the remaining backlog of inspections for biosimilar applications has been poor,” she said.

She added that, “Often, responses about inspection delays are cursory and perfunctory, lacking specific timeframes to help an applicant understand where they stand in the queue.”

“As we pass the 2-year mark of the pandemic, it is frustrating that the agency has yet to meaningfully address how it intends to tackle the inspections backlog. None of the enhanced communications, recommendations or timelines in the ERG report that are promised matter if biosimilar approvals are held up indefinitely due to inspectional delays,” Turow said.

Turow urged FDA to “use the tools at its disposal” to improve communication and address its backlog of inspections. She suggested the agency consider requests from establishments to conduct remote interactive evaluations for surveillance or preapproval inspections and to further utilize mutual recognition agreements on inspections with other regulators. Further, Turow said that FDA could provide a “detailed plan” of how it intends to address the backlog.

Turow also called on FDA to prioritize the development of a new postapproval manufacturing changes guidance to replace or revise the agency’s 1997 document and encouraged FDA to allow greater flexibility on meeting scheduling and format.

Yim acknowledged industry’s frustrations surrounding inspections toward the end of the meeting. “As the Biosimilar Forum noted, we did try to use the remote and alternative sort of inspection tool approach during the pandemic for biosimilar applications. I think that folks raise a valid point about trying to expand the use of these things, and I think there are efforts within the agency now to try and work on this further,” Yim said.

“My hope is that we’ll have a consistent approach to alternatives to an onsite facilities inspection, especially in the event of these kinds of public health emergencies and other kinds of emergencies,” she added, noting the agency’s need to fulfill good manufacturing practice regulations despite the pandemic.

Inspections emerge as flashpoint in BsUFA II assessment meeting

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