From another HC post but really relevant to where Imugene are at with the FDA and helps to explain the recent licence aquisition data data data is what FDA want to fast track!
FDA biologics center director Peter Marks said the agency plans to encourage sponsors to use the accelerated approval pathway, particularly for rare disease treatments, as the agency also moves ahead with an Operation Warp Speed-like pilot for rare diseases later this year.
In an expansive interview with Endpoints News, Marks said he expects to see more accelerated approval applications in the rare disease gene therapy space as well as potentially in cell therapies. Marks said the rare disease Operation Warp Speed effort, which he announced in February, will “start small” to make sure the agency can work closely with the first round of participants.
Marks spoke with Endpoints on Aug. 15. This interview has been substantially edited for length and clarity.
Lia DeGroot: I wanted to start with a question about the Office of Therapeutic Products. You’ve brought on Nicole Verdun to lead that office and are staffing up. How are things going?
Peter Marks: It’s great to have her on board because that stability will help us get to our hiring goals. People like to know who their bosses are going to be.
We’re making reasonable progress toward getting our reviewer positions filled, including physicians and CMC reviewers. It’s a little early to tell how far we’re going to get by the end of the year. I’d always love if we had more people wanting to come work at the agency.
DeGroot: A few months ago, there was a bit of a backlog with cell and gene therapy applications. Is there still?
Marks: There’s probably a slight backlog still. We’re still trying to do better with the timeliness of the feedback that we’re giving. We’re trying to make sure we get through the backlog and then cut down the time it’s taking to give people things like interact meetings and some of the more helpful meetings that we don’t have quite the same statutory timelines on as type A, B, C meetings. That’s what staffing up helps with.
There is something that is still a valid concern, which is that we’re doing more written responses than industry would like. We’re doing that simply because of bandwidth.
DeGroot: I wanted to switch gears a little bit to accelerated approvals. FDA is now working with some more authorities around requiring confirmatory trials to have started before decisions. Any progress on implementing that?
Marks: Yeah, although it’s a work in progress, we are very actively working on making sure sponsors understand that we are serious about wanting good evidence, as required by the FDORA, that we be able to have compelling evidence that these clinical trials are either underway, enrolling or completed before we actually take our regulatory action, or at least enrollment is completed.
Some of this that we’re doing right now is trying to understand what we need, when. When someone submits something for accelerated approval, what will we be requiring?
If you’re going to be submitting for accelerated approval, we’ll need to have reasonable evidence that you’re serious about conducting your clinical trial for confirmation. The exact form of that seriousness is something that we’re still working on.
DeGroot: I’m also wondering how difficult it might be for some applicants to be able to carry out those studies. What are you hearing from industry?
Marks: I haven’t heard a lot of pushback on this. I think people are feeling like they should be able to negotiate with the agency reasonable confirmatory trials. I think it’s accepted that if you’re going to get an accelerated approval, you’re going to have to do something to convert to a traditional approval.
That actually brings up a really important point, which is that we only do accelerated approvals when we need to. For instance, CAR-T cell therapies, we didn’t need to do accelerated approvals. Why? Because the data were compelling enough that it wasn’t necessary. Why make more work if we don’t have to?
Experience over time has helped us understand what’s possible for a confirmatory trial and what’s not. If one has a disease where the treatment-eligible population is, say, 100 people in the United States and the confirmatory trial you need to do is 200 patients, there’s a problem. We can’t ask for that.
DeGroot: Do you anticipate that you’ll continue to see an increase in the number of accelerated approvals or even applications for cell and gene therapies?
Marks: We’re going to be encouraging people in the direction of accelerated approval when they can, especially for rare diseases. Because for rare diseases, and especially things that are like neurodegenerative diseases, it could take a long time to get to clinical endpoints. I suspect we’ll continue to see more accelerated approvals in this rare disease, gene therapy space potentially also in the cell therapy space.
We see accelerated approval in the rare disease gene therapy space as not just trying to get there fast. It’s a way of getting there that will benefit individuals in medical need, at the earliest possible timepoint, while ultimately giving us the opportunity to get the data we need for turning those to traditional approvals.
We hope that 95% of the time, we’re going to be right. If a couple percent of the time it turns out that we can’t get the confirmation, I think that’s something we’re going to have to accept.
We may not be able to get the confirmation because the product doesn’t work. Alternatively, it may just be because the endpoints for some of these rare diseases might be hard to get right.
DeGroot: In the vein of rare disease, you’ve previously mentioned this Operation Warp Speed-like effort. Is there any progress on that?
Marks: I hope people will be able to look to the Federal Register this fall and see something published as a request for applications for the program. That’s when we’re targeting.
The pilot will start small because we want to make sure that if we do it, we really do it right. We don’t want to have to say, we can’t give you the full Operation Warp Speed because we’re too busy with someone else.
We want to actually do it like we did it during Operation Warp Speed with vaccine development, which was really that the sponsors, we were very encouraging of them to contact us at any time as issues came up.
DeGroot: I wanted to dig in a little bit on the Sarepta gene therapy approval for DMD. You went against the reviewers on that call. What was it you saw in that application or in the landscape for that treatment that led you to go against the reviewers’ opinion?
Marks: In general, different people looking at the same data can come to different conclusions. I took into account the potential benefits and risks and the uncertainties and came to a different place than the reviewers.
I do that with great trepidation. In this particular case, between the data that was there — granted it was not pre-planned subset analyses — but the data was compelling in a population that’s got a rare disease that’s pretty serious.
One of the really helpful things in this particular case has to do with the confirmatory trial, which was already fully enrolled. By the time we come into September, that trial will be fully dosed and crossed over, so we’ll actually have additional data coming into fall to know whether we’ve gotten it right or wrong.
This was a case where you could have said, ‘Well, why don’t we just wait?’ For a parent of a child who’s deteriorating, waiting any longer than you have to is not a very pleasant answer from FDA.
This made the product available to those who at least there was the most compelling data for, while we get the clinical trial data that will hopefully either confirm or refute that it has benefit in both 4- and 5-year-olds as well as in the older age group, the 6- and 7-year-olds.
DeGroot: It’s incredibly rare for people in your position to go against reviewers. I’m wondering if you envision more instances where you’d overrule reviews. Was this an effort to move the agency in a different direction, or just one particular case?
Marks: I don’t anticipate doing this very often, if at all, in the future. I hope not to have to do it again. Is it possible it could come up again? It is.
That’s just the nature of what we do at FDA. But I’m hoping that by having a policy, that we as a center are going to lean into what we can do to help move forward rare disease gene therapies, that we are able to better work with companies as they come through the process upfront, to develop a comfort level that as they come in for an accelerated approval, that we are comfortable with what we are seeing.
DeGroot: There have been a few gene editing companies that have gotten FDA holds in recent history while gene editing technologies are being tested abroad in places like the UK first. What’s leading to those holds, and what kind of data is the agency looking for that those companies aren’t initially producing?
Marks: I’m going to have to be very general in my response to you. We take very seriously when we put something on a clinical hold. We do so when we have scientific questions that remain about whether it will be safe to go ahead and treat individuals with the therapies in question.
Now, there have been enough adverse issues with gene therapies, that has led us to be somewhat cautious. Our goal is that when we put something on clinical hold, we do so in a very thoughtful manner because we are concerned about the safety of people, and we want to get people off hold as quickly as possible.
We have put things in place in the center to try to reduce the number of clinical holds to the minimum, but we do sometimes need to use them to feel comfortable that we’re protecting people.
It’s always hard to get compared to foreign regulators because we can always find places where they were probably ahead of us and right. But we can also find places like thalidomide where they were ahead of us and wrong.
DeGroot: When you look ahead to the next five years, what are three major issues in vaccines, and cell and gene therapies that you think are the most important for FDA to improve?
Marks: Top of mind for all of these, but especially for gene therapy, is getting on top of manufacturing and moving it from what is currently almost a benchtop process, to a more automated process and taking advantage of all of what artificial intelligence can bring to automated processes.
The second is really having us at FDA start to leverage our authorities that Congress has given us, including the platform technologies provisions, and making full use of accelerated approval to help move gene therapies through more swiftly than we have in the past — making sure that what gets out there is a quality product that’s both safe and effective.
Then finally, and this goes to something that’s mainly in the area of vaccines, is to make sure that people understand that what we do at FDA is done with great care, and when we give an approval or an authorization of, for instance, the vaccines, that we do so having looked at the scientific data to make sure that they are products that are safe, quality, and effective.
As we come into the next season, it will be really important for people to understand that we very carefully looked at the Covid-19 vaccines. They’ve been very thoughtfully developed for this coming season. And hopefully people will benefit by going out and getting vaccinated.
AUTHOR
Lia DeGroot
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(20min delay)