FDA officials, experts discuss impact of COVID-19 on cell and gene therapies

Regulatory NewsRegulatory News | 15 October 2020 |  By 

While the US Food and Drug Administration (FDA) is still receiving investigational new drug applications (INDs) for cell and gene therapies, officials are concerned about the impact of the COVID-19 pandemic on clinical trials.
“It’s clear that COVID-19 has adversely affected all aspects of development of cell and gene therapies,” said Peter Marks, director of FDA’s Center for Biologics Evaluation and Research (CBER), said at the Alliance for Regenerative Medicine’s Meeting on the Mesa. “For some of the studies that are ongoing there are some real challenges to overcome in terms of endpoints that may have been missed.”
The pandemic also has disrupted global harmonization efforts around gene therapies, Marks said.
“We were on the cusp, in fact, working with global regulators trying to get towards more harmonization of gene therapy programs in different countries,” he said. “We’re trying to keep it moving but it’s a challenge to do.”
Marks noted that before COVID-19 he spent about 75% of his time on cell and gene therapies, but the pandemic has forced him to shift priorities. “Some things have less policy demands at this point in time. At this point in time it’s very much reversed and it’s probably 80% of my time on COVID-related activities.”
Marks also noted that CBER’s Office of Tissues and Advanced Therapies (OTAT) has been struggling to keep up with its workload even before the pandemic. With the influx of applications for cell and gene therapies over the last five years, Marks said the office, “Should have doubled in size and it’s only modestly larger, 15-20% larger in size.”
Marks said he is not satisfied with the level of dialogue the agency has been able to have with gene therapy developers. “Especially early on, we should be able to have this dialogue that really facilitates setting things up well so that our knowledge of the entire field—we help leverage that for every sponsor.”
“We’ve been so strapped in terms of personnel that it’s hard to do that,” Marks said, noting that COVID-19 has exacerbated things even further. “Because the number of gene therapy applications hasn’t fallen off dramatically, some of the trials may not be moving as quickly, but the applications keep coming in.” Marks said that OTAT has also had to shift priorities during the pandemic and that he hopes the next user fee cycle will bring in the resources necessary to staff up further.
Speaking on a separate panel with members of industry, OTAT Director Wilson Bryan echoed Marks’ sentiment.
“We were stretched thin before the pandemic, and with the flood of work that came in, it really had an impact,” he said. “Sometimes folks don’t like to admit this, but we all know we’ve had delayed meetings, we’ve had to delay review of some applications because of giving priority to the pandemic.”
However, Bryan said the office is getting its balance and is working to catch up on some of its delayed activities.
Bryan expressed some worry about the financial well-being of some of the smaller companies his office works with. “We’re hearing a lot about their struggles to stay afloat and continue and finish off their development programs and whether or not those development programs are going to be sufficient to meet regulatory standards,” he said.
One of the challenges, said Timothy Schroeder, CEO of CTI Clinical Trial & Consulting, will be dealing with gaps in data from clinical trials. “The question is going to be how do sponsors, how do regulatory authorities and how do companies such as ourselves fill those gaps?”
On the regulator side, Bryan said his office is working with companies on an individual basis to sort out those issues, which differ from one indication to the next.
Bryan added that one positive to come of the pandemic is greater interest in remote outcome assessments in clinical trials. “If we have an energy now to develop outcome measures and validate outcome measures that allow us to reliably capture information from patients in remote locations, that will ultimately facilitate development,” he said.
The pandemic also has significantly disrupted FDA’s ability to conduct surveillance and preapproval inspections. While the agency has resumed some domestic inspections and mission-critical foreign inspections, it also is leveraging other sources of information, including inspection reports from other regulators, and requesting documents from applicants and facilities in lieu of on-site inspections where possible. (RELATED: FDA issues pandemic inspections FAQ guidance, Regulatory Focus 19 August 2020).
“We’re considering virtual inspections, particularly for companies where the site has a track record, but if it’s a site that is brand new with no track record or if it’s a site with that has a bad track record, we’re hesitant to do that,” Bryan said.
Bryan also raised the prospect of FDA inspectors tagging along remotely for an inspection being conducted by other regulators. “Is it possible that we could have an inspection by European inspectors and have US regulators going along for a virtual inspection at the same time? We think about those things, I don’t know that we’ve done them yet,” Bryan said, adding that he is not sure whether FDA inspectors would be comfortable with the information they would get.
Curran Simpson, chief operations and technology officer at REGENXBIO, said he sees promise in virtual audits and believes the level of documentation a site provides can be indicative of its compliance.
“How often have I walked into a manufacturing facility that’s well-run but has terrible documentation? Almost never. I think virtual audits, if you do a risk-based approach and the audit partner has the ability to send documentation in an efficient way and you have experienced people doing this, I think you’re going to get the same flavor of an audit very quickly from the level of the documentation,” he said.
“Of course, you’ll want to accompany that to the extent possible with imaging of the facility,” Curran said, “To see if those practices are being followed, the overall cleanliness of the facility and the management of material movement … If you don’t get a good impression from the documentation that you’re working through, it’s probably a bigger issue that you want to escalate.”
Amy DuRoss, co-founder and CEO of Vineti, an enterprise software company specializing in advanced therapies, expressed some doubts about the current potential for fully remote audits.
“Certainly our piece of the chain because we’re enterprise software is readily auditable remotely, but I would say that the overall system and in manufacturing, I’m not sure we’ve evolved as a species yet to adapt our remote techniques to get a full picture … I don’t think we’re there yet,” she said.


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Tags: coronavirus, FDA, US

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