FDA 'Leans In' to Accelerated Approval for Rare Disease Drugs

The FDA is "leaning in" to cell and gene therapies, expressing a willingness to use the accelerated approval pathway for these products, particularly as new leadership is set to take charge of a recently revamped office.

That was the tone of two talks given by Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research (CBER) at the FDA, during the American Society of Gene & Cell Therapy (ASGCT) meeting in Los Angeles this week. CBER oversees the regulation of cell and gene therapies via its newly created "super office," the Office of Therapeutic Products, which resulted from the reorganization of the former Office of Tissues and Advanced Therapies.

"When you're dealing with very small populations, we're probably willing to use some regulatory flexibility there ... with the note that we will have to have the confirmatory data at some point," Marks said during one of the talks.

"It's not about lowering the standard," he emphasized. "It's about fixing the environment so that we are able to provide the certainty such that people will bring things forward."

Marks' office has paid particular attention to rare disease therapies in recent months, noting that FDA plans to launch an Operation Warp Speed-style pilot program for bringing these treatments to market faster. In 2022, he said, the agency approved five cell and gene therapies, and hopes to increase that tally in the coming years.

Two cell and gene therapy products have been granted accelerated approval -- brexucabtagene autoleucel (Tecartus) for mantle cell lymphoma and elivaldogene autotemcel (Skysona) for cerebral adrenoleukodystrophy (CALD). In addition, the FDA is currently considering accelerated approval of delandistrogene moxeparvovec for Duchenne muscular dystrophy.

Part of the willingness to use the pathway appears to stem from the fact that last year Congress granted the agency new "teeth" to require confirmatory trials. "For all accelerated approvals, the new teeth we have is that we are going to want to see confirmatory trials well in progress, with some exceptions, as we grant accelerated approval so that we have a better sense that they are actually going to get done," Marks said.

But the CBER leader was adamant that his agency would work with industry and take a case-by-case approach to each individual product.

"With gene therapy under the Regenerative Medicine Advanced Therapy designation, a confirmatory trial could simply be following the cohort you have enrolled in your registration trial," he noted.

Marks emphasized that new leadership at the Office of Therapeutic Products -- the director job posting closes on May 31, he said -- "is going to have to be somebody who is willing to diffuse down through the organization a sense that we are leaning in here, and we are fundamentally doing things differently."

"That will take some leadership and it will take some work through the organization," he added. "I am the first to acknowledge that we are not there yet and it's probably going to take a little bit of time to get there. ... [But] I think you'll see an increasing receptivity to trying to work in that direction from our staff, and hopefully that will blossom further as we have new leadership that leans in here."

Accelerated approval will be particularly beneficial for conditions that take lives early or create such terrible morbidity that people can't function, as was the case with elivaldogene autotemcel for CALD, Marks said. In that case, drug developer bluebird bio was able to follow its treated subjects longer for its confirmatory trial.

"In those kinds of situations, our goal is to try to bring treatments forward as fast as we can," he said. "If occasionally we have something that gets accelerated approval but doesn't confirm out ... I'm not sure that's the worst thing at the end of the day, particularly in a case where these individuals are not likely to have some alternative that might have alleviated their morbidity or mortality."

Use of natural history studies may also be a helpful strategy for accelerated approval in rare disease therapeutics, he noted.

"With monogenic disorders and gene therapy, [which have] very small populations where it's very hard to have control groups, if we do our work right, we'll have a good model system or a good natural experiment that we can look to to see if what we are doing in terms of changing a level of some protein ... is potentially correlating with some clinical benefit," he said.

One of the most pressing questions from participants at the ASGCT meeting was what would happen if confirmatory trials are negative.

The overwhelming message from Marks was that FDA would work with sponsors on an individual product basis.

"The first thing that would happen is, we would look at the study that failed, and try to understand why it failed," Marks said. "The drug can have inherent activity and be an active drug ... but our study design may just not be appropriate. We might not have picked the right endpoints. We might not have understood the appropriate stratification of patients. So, first we would make sure there are no methodological flaws."

If there are no problems with the methodology, then the agency would "look at the threshold question, which is, does the drug actually have activity or not. ... If we're convinced it doesn't, we have some teeth now to help ... remove the drug from the market."

"If we do our job well," he added, "it won't happen often, but it is probably going to happen occasionally."

Another part of the reason why FDA is "really trying to lean in here is that we realize the moment is tender for gene therapy," Marks said, and there's an opportunity to "help salvage some of the gene therapies."

"I can think of 5 or 10 programs [with] promising clinical data where they're not that far off but they've been put on the back burner or transferred back to academics because of the commercial viability issues," he continued. "So we can try to get over some of those issues and get things back on track to some form of commercial viability, either by reducing manufacturing costs, increasing regulatory certainty, decreasing the costs of preparing regulatory submissions, or a combination of all of the above for these relatively small niches that are not commercially viable currently."

Coordinating submission requirements with regulators across the globe such as Europe and Japan could also help increase commercial viability, Marks noted.

With the specter of Alzheimer's drug aducanumab (Aduhelm) looming large over the accelerated approval pathway, Marks acknowledged that it's "Regulation-401."

"It's the graduate-level course," he said. "It's not a college-level course, because sometimes you have to deal with situations where there are multiple moving parts and multiple complexities, including the nature inherent to the disease you're dealing with, the nature of other potential alternative therapies versus the natural history of the disease, and the certainty or uncertainty you have around the drug you're dealing with."

"All of those things have to be put together," he added, "and it creates some very challenging situations."

Comment