Thousands of gene and cell therapies are inundating FDA reviewers as the agency tries to keep up

The FDA’s staff is flooded with thousands of cell and gene therapy trials making their way through a short-handed regulatory workforce.

While the FDA has plans to add to its ranks of reviewers, it could take years before its capabilities catch up to the biotech industry’s pipeline. There are more than 2,500 cell and gene therapy trials underway, with the bulk of those added from 2016 to 2020, according to FDA officials. The huge number of programs, combined with an understaffed agency, are likely to result in delays in the review of trials and applications, more caution and clinical holds from the agency, and in some cases more time needed for successful treatments to reach patients.

Wilson Bryan

So far, the agency has been mostly meeting its deadlines for approving the handful of drugs that have reached the market. But those products are just a small, first wave. Peter Marks, head of the FDA’s Center for Biologics Evaluation and Research, said that there have been cases where the FDA has “been unable to provide as timely feedback for” cell and gene therapy sponsors “as we would have liked during the past few years.”

The FDA has plans to train 125 new reviewers, but until it can catch up, it is likely to struggle to stay on top of the rapid progress of new treatments for blood disorders like sickle cell and hemophilia A, as well as other gene editing-based treatments that are incoming.

“It’s coming and we’re excited, but it’s important that we follow the science and not get ahead of it,” outgoing Office of Tissues and Advanced Therapies director Wilson Bryan said at an industry event on Monday.

Fight for talent

Steven Bauer

The agency’s staffing challenges don’t just extend to its reviewer workforce. At least four of its most senior cell and gene therapy experts, some with 20 to 30 years of experience, have either recently departed or are on their way out: Bryan, the tissues and advanced therapies director, will retire in March; deputy director Rachael Anatol moved to the industry lobbying group BIO in December; and Steven Bauer, chief of the Cellular and Tissue Therapy Branch at CBER, and Mercedes Serabian, head of OTAT’s pharma/tox branch, both of whom are leaving for undisclosed next roles.

Given the wide gap between what industry can pay for cell/gene therapy experts compared to the government, FDA workers flipping to industry is little surprise, and it’s made it all the more difficult to bring on experienced staff.

“There’s just a tremendous war for talent,” Fabian Gerlinghaus, CEO at cell therapy manufacturer Cellares, told Endpoints News in a phone interview. “The process failure rates for industry are sky-high at more than 20%, so operators need very specific training. And a lot of education.”

The agency has gained some resources. It now has more money than ever before thanks to the recently signed PDUFA VII agreement through 2027. And the 21st Century Cures Act gave the FDA the authority to pay top leaders annual salaries of up to $400,000, more than double the salary cap for other government workers. But the starting salary for the new OTP super-office head is $250,000, while the industry can offer salaries closer to $300,000 for director-level positions, according to the jobs site Glassdoor.

More delays, more caution

Marks recently acknowledged that a rise in clinical holds is the product of the increase in the number of trials, and also of some INDs missing key pieces of information, like a chemistry, manufacturing and controls section. “There are some cases where we have bona fide sponsors who have issues that probably could be resolved with interactive review where we just don’t have the bandwidth,” Marks said. Instead, the agency has had to rely more on giving companies written responses instead of more time-consuming meetings to iron out issues.

Ken Mills

Ken Mills, the CEO of Regenxbio, said that drug developers sometimes get back relatively pro-forma responses from what appear to be less experienced staff.

“When you get a document back from FDA that’s a written response, it appears that it’s written by an inexperienced reviewer who is just quoting the regs back to you, which is not helpful,” Mills said in an interview in New York.

Regenxbio has several gene therapies in development, and Mills said that the changes happening at the agency are necessary, but are taking time. “The efficiency with which you can make changes in government often lags industry, and the science itself,” he said.

Cellares’ Gerlinghaus echoed those comments.

Fabian Gerlinghaus

“The innovators in our industry are certainly hungry for early collaboration and continued engagement throughout the development cycle, especially informal conversations, rather than just communication over email,” he said. “Something like a designated contact at OTP would be tremendously helpful.”

There have already been delays. Cell and gene therapies from BioMarin, Astellas, Sarepta and bluebird bio have all faced lengthened timelines in recent years due to FDA requests related to manufacturing, safety, efficacy and dosing.

Astellas last month had a hold lifted on its gene therapy trial for Pompe disease that had been in place since last June. The safety signal and pause were similar to other pauses for gene therapies that are delivered via viral vectors called AAVs.

Astellas’ gene therapy unit is built around a 2019 buyout of Audentes Therapeutics, and the lead program is a gene therapy for X-linked myotubular myopathy, or XLMTM, a rare muscle weakness disease. In 2020, the trial was halted after three patients died. The trial resumed at a lower dose, with the FDA’s blessing, only to have a fourth patient die — an episode that illustrates just how much there is still to learn about safely conducting tests of these new therapies.

In some cases, like BioMarin’s hemophilia A gene therapy Roctavian, the US delays have meant the European Medicines Agency has beat the FDA to an approval, which is rarely seen for novel products.

Amicus Therapeutics in October said that a Covid-related delay from FDA in inspecting a China-based WuXi facility that makes part of its potential Pompe therapy would push the application’s approval back. Two months later, in December, the EMA signed off on the same enzyme replacement therapy, and is expected to see the European Commission do the same this quarter.

Marks and Bryan said that it may take years, particularly as FDA transitions new reviewers and new leadership, and as staff adjust to the new structure of the OTP super-office, which is meant to more evenly distribute the managers.

“FDA is struggling on many levels,” Bruce Levine, CAR-T pioneer and professor in cancer gene therapy at the University of Pennsylvania Perelman School of Medicine, told Endpoints via email.

And some of its challenges aren’t unique to the agency, but are a wider symptom of a field that’s growing rapidly and is long on innovation but short on workers. Levine said while there are more professionals now entering the cell and gene therapy space, “we need many more in all sectors at all levels.”

More accelerated approvals 

Adding to the pressure, more of these new therapies will go through the accelerated approval pathway — a fast-track regulatory process meant to get treatments to patients based on surrogate endpoints, with a promise that companies will conduct further studies to make sure the efficacy is there. And as part of new changes to the program and signed into law, FDA “may require, as appropriate, a [confirmatory] study or studies to be underway prior to approval, or within a specified time period after the date of approval.”

But Bryan raised questions about whether FDA will push back hard enough on mediocre data.

“Does the agency have the willpower to say OK, the data is ambiguous, [the gene therapy] probably doesn’t work, let’s take it off the market? I’m not sure the agency has the will to do that,” Bryan said at the Biopharma Congress in Washington, DC on Monday.

“We’re going to get into trouble with accelerated approval for gene therapies if it takes years to tell us something works,” Bryan added.

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