Separating Gene Therapy ‘Wheat’ From ‘Chaff’: CBER Facilitators Could Help Inexperienced Sponsors

Surge of interest prompts US FDA to consider how to adjust feedback, including potentially creating a separate team to answer more basic questions.

The surge of interest in gene therapies among inexperienced developers is prompting the Center for Biologics Evaluation & Research to consider whether a separate team should be formed to answer the more basic questions on the mechanics of regulatory development in order to free up more resources for the review of applications and programs that have a higher likelihood of success.

While CBER welcomes the broad interest in gene therapy development, especially in rare diseases, the resulting avalanche of requests and applications has the potential to overwhelm the gene therapy regulatory team – a situation that has gotten worse with CBER’s role in the response to the SARS-CoV-2 pandemic. (Also see "US FDA’s Gene Therapy Work Feeling The Effects Of Pandemic Response" - Pink Sheet, 10 Jun, 2020.)

That has led to a frank realization by CBER leadership that not all gene therapy sponsors or applications should be expected to be equal – or at least not equal in the type of feedback and advice needed from the agency.

The best way to address that delineation may be by assigning a coaching staff of sorts to walk less-experienced sponsors through gene therapy basics. That would allow other reviewers to focus on applications more ready for prime time.

CBER Director Peter Marks outlined the challenges of meeting the needs of novice gene therapy sponsors during a virtual panel session of the World Orphan Drug Congress on 25 August. “We are overwhelmed with applications, many of which need so much help that it takes our folks a tremendous amount of time in meetings, and it detracts from being able to have meetings with sponsors who are very responsible and very capable,” he said.

“On the other hand, we want to be able to help these other people to get there, but it is almost a different type of help. One of the things that we’re thinking about is once we come post-COVID, when we can get some more manpower, is you almost need a group that really specializes in mechanics and very specific scientific aspects, and the other that can deal with the normal advanced development issues.”

National Institutes of Health’s National Center for Advancing Translational Sciences Director Chris Austin, who served as moderator of the discussion, shared Marks’ sentiment a bit more bluntly: “There are all kinds of new people who are coming to the field who have never before thought about this. The problem is … a very large number of people, to be frank, have no business bothering the FDA. I’ll just put it frankly. Because they are just not there yet.”

Austin used a sports analogy to underscore his point. “It would be like if I and a whole bunch of people like me who love to play basketball all flooded the Olympic tryouts. They would never be able to get to the people who actually are good basketball players. So you have to have a way to get people like me to get my basketball training a little bit better.”

Who Should Help Novice Sponsors?

The extra work inherent in novice sponsors also has been a factor in the Center for Drugs Evaluation & Research. A decade ago (leading up to the PDUFA V reauthorization talks) then-Office of New Drugs Director John Jenkins spoke publicly on the extra time needed to walk first-time “emerging sponsors” through an otherwise unfamiliar drug development and review process, and began tracking and reporting metrics associated with those sponsors.  (Also see "An Emerging Approval Trend At FDA: More First-Time Sponsors" - Pink Sheet, 19 Jan, 2012.)

PDUFA V was designed in part to address the needs of those first-time sponsors, with funding dedicated to new communication mechanisms. (Also see "Emerging Sponsors And FDA: Will Better Communication Under PDUFA V Ease Inherent Tensions?" - Pink Sheet, 2 Jan, 2012.)

That is one solution for CBER’s current funding crunch: now heading into PDUFA VII talks, many stakeholders are calling for additional user fees to support the gene therapy program. (Also see "US FDA's Biologics Center May Get Its Day In PDUFA VII" - Pink Sheet, 23 Jul, 2020.)

But perhaps some hand-holding is better coming from outside FDA. Whether this is the role of FDA or the role of NIH is “a really critical question,” NCATS’ Austin said. “In my view, it’s both. We couldn’t do this at NIH without being joined at the hip with our FDA colleagues, but the fundamental function … has to happen before we get to FDA. And that’s a function which needs to be dramatically extended to solve this problem,” he said.

The question of whether an FDA sister agency could guide early-stage drug development has echoes elsewhere within HHS: at points in the development of the advocacy role for the Biomedical Advanced Research and Development Authority, it was suggested that the agency could act as a facilitator for helping inexperienced sponsors get medical countermeasure products through the FDA regulatory process and inclusion into the Strategic National Stockpile.

During COVID-19, BARDA’s role has transitioned more to a major funding entity in what appears as a small version of NIH dealing with commercial issues like late-stage clinical development and manufacturing.

Gene Therapies On Back Burner – For Now

Marks sees the need to shift resources within CBER as a “lesson learned” from the coronavirus response. “COVID-19 has produced incredible challenges for us at the Center,” he said, and in triaging that work, “it brings up something that we may wish to do in the future as we move out of COVID, which is to try to sort out the wheat from the chaff in some way that we actually help the chaff.”

“Part of it for us is we need to staff up very significantly, because gene therapy has grown much faster than we have,” he acknowledged.

“I’m not going to defend our record on meeting times, because I’m not happy with it, and I commit to trying to do whatever we can to improve it. We’re doing so by trying to staff up. We’re also trying to do so by educating people to only ask for things that we really think are important, not just things that are nice to have.”

CBER was prepared for an anticipated influx of applications in the second half of this year, but the COVID duties and multiple major vaccine efforts are clearly changing the atmosphere for the center.

Marks has previously talked about an internal hierarchy to prioritize the non-COVID-19 workload at CBER. Addressing user fee deadlines, for example, has had to take priority over meeting requests for programs like cell and gene therapies.  (Also see "Gene Therapy May Pack US FDA’s Calendar This Fall; CBER Staffs Up" - Pink Sheet, 23 Apr, 2020.)

Marks reiterated his disappointment in how COVID-19 has changed the discussion of rare diseases and gene therapy issues.

“Going into last winter, there was a lot of momentum towards trying to further what we do for very rare diseases, and that was getting global traction,” he said. “COVID really knocked that aside. I’m hoping that as we recover, we get back to that, because it would be a shame to have potential cures for certain diseases put off by extra years because it takes us a while to get back on our feet.”