Gene therapy developers can expect less hand-holding from OTAT

A growing workload and insufficient staffing have prompted the US Food and Drug Administration’s (FDA) Office of Tissues and Advanced Therapies (OTAT) to institute new processes to expedite its reviews of new cell and gene therapies, said OTAT Director Wilson Bryan at a 6 December webinar sponsored by the Alliance for a Stronger FDA.
 
At the webinar, Bryan was asked to discuss the impact of the projected workload for OTAT, projections for approving new cell and gene therapies, changes in staffing to accommodate the growth, and lessons learned from the cell and gene therapy approvals.
 
Sort of swamped
 
Bryan told the meeting that the center is “sort of swamped now” with a growing number of cell and gene therapy applications. The center “long ago” surpassed its projections of receiving 200 cell and gene therapy applications a year.
 
He said in 2020, OTAT received 354 investigational new drug applications (INDs) and already received 275 so far in 2021. “I expect that it will hit over 300 again. The projection of 200 was a bit of an underestimate. I expect that the numbers we are seeing now are being held down by the pandemic, but as we come out of the pandemic, we will see an upsurge again.”
 
In the gene therapy area in particular, the pandemic “slowed us down a little bit” but has since turned around. “The gene therapy INDs increased from 67 in 2016 to 161 by 2019.”
 
There is also a backlog of more than 1,142 active cell therapy INDs and 1,201 active gene cell therapy INDs awaiting review, well above the projected estimate of 800. Bryan expects those number to rise as the pandemic abates.
 
Salary discrepancies make hiring an issue

Bryan noted that staffing has not kept pace with the increasing workload. While OTAT has a staff of 300 employees, “the number of employees and the growth in OTAT has not kept up with the growth of applications,” he said. “I mentioned earlier that gene therapy INDs increased and cell therapies increased by a similar amount. We have not doubled the size of OTAT in 3-4 years.”
 
Bryan said that recruiting staff has been a huge challenge. While OTAT has 40 staff openings, one difficulty in recruiting is the discrepant salaries between government and the private sector. “Our salaries are not commensurate with the booming cell and gene therapy industry,” said Bryan, adding, "I can't overstate how much of a challenge hiring has been for us."
 
Organizational changes underway
 
To address the growing workload against the backdrop of these staffing challenges, Bryan said that “we have to do things differently.” Sponsors can expect to receive less hand-holding: “I think in the years ahead there will be less individual attention for sponsors.” OTAT, he said, will have to “devise ways to communicate with our sponsors particularly with academic sponsors and small growth companies that don’t involve so much individual attention.”
 
By next year, OTAT is looking to update its website to institute “root communications” to deliver messages to wide audiences on its website. These communications will focus on preparing for meetings and how to ask the right questions at meetings.
 
For their part, sponsors can also do a better job of preparing complete INDs for cell and gene therapy products. “One challenge is that we are getting IND applications or a meeting request that really is so grossly deficient that we can’t communicate effectively with the stakeholders and that is taking up a lot of our time,” said Bryan “That is not productive and is not helping the sponsor much either.”
 
Some lessons learned
 
Bryan was asked to describe some of the lessons learned over the past few years in regulating cell and gene therapies. One learning is that clinical trials for gene therapy products do not have to enroll huge numbers of patients.
 
He said that many recently approved gene therapies “are life-savings products and they all got approved based on a single arm study because they had large effect sizes. That is one of the things that have been proven, if there is a large effect size, the clinical trials do not have to be big. We can do clinical trials in small populations.”
 
Bryan added that “We need to stop thinking about doing Phase 1 and Phase 2 and Phase 3 studies, in rare diseases, there simply is not enough patients for that paradigm,” added Bryan. ”Because of the huge unmet need -- people cannot wait; drug development takes too long. And because the science has advanced so much for gene therapy studies, we can see huge effect sizes so that we can have Phase 1 studies that provide evidence of effectiveness.” As examples, he pointed to recent approvals of Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl) and Novartis’ Zolgensma (onasemnogene abeparvovec-xioi), whose pivotal clinical trials each involved fewer than 50 people.
 
Bryan noted that two recently approved gene therapies, Luxturna (voretigene neparvovec-rzyl) and received approvals after two trials with 35 patients enrolled in each trial.
 
CMC holding up approvals
 
Another lesson learned is that chemistry manufacturing and controls (CMC), or manufacturing issues, are “holding up approvals.”
 
Bryan said that “we really need for sponsors to work on CMC issues early. Potency assays are a particular challenge. You have to understand your product and you have to figure out its mechanism of action and develop a good potency assay as early as possible in development.”
 
One positive development in the manufacturing realm is that after a setback from the pandemic, viral vector manufacturing is in the rise again.
 
“The pandemic has set back manufacturing, particularly for gene therapy. Supply chain issues have been a problem. People were not able to go to the lab to do the research. Vector manufacturing was being deferred during the pandemic as it should. We are now seeing vector manufacturing back for gene therapies, so it is picking up again.”
 
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