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Bloomberg Law – FDA Gene Therapy Head Raises Concern on Accelerated Approval Use (1)

Bloomberg Law – FDA Gene Therapy Head Raises Concern on Accelerated Approval Use (1)

More cell and gene therapies will likely come to market using FDA’s accelerated approval pathway, a shift that raises concerns for the agency’s outgoing gene therapy head since it could take a while to prove definitively that they work.

“If it takes years as suggested to tell if something works, then that means it takes years to tell if it doesn’t work,” Wilson Bryan said at the Biopharma Congress on Monday. The meeting was hosted by Prevision Policy and Friends of Cancer Research.

If five or 10 years after the accelerated approval, the confirmatory evidence either shows the drug doesn’t work or it’s unclear if it works, that means the gene therapy field “has just been sitting around waiting, because the patients are getting the gene therapy in a very rare disease.”

That means there’s an even smaller patient population to study the next product, raising concerns if another company will even develop another therapy, Bryan said.

“I really worry that will damage the field by approving something under accelerated approval, that at the end of the day doesn’t work,” he said. Bryan is the director of the Office of Tissues and Advanced Therapies in the Food and Drug Administration’s Center for Biologics Evaluation and Research, who’s announced he’s retiring from the agency. An FDA spokesperson said his retirement will likely be effective next month.

Cell and gene therapies represent an enormous field of growth for the biopharmaceutical industry, with more than 1,000 active clinical trials in cell and gene therapies registered with the FDA. The latest user fee agreement provided the agency with 125 new full-time employees and CBER is reorganizing its gene therapy office into a “super office” to prepare for this onset of new therapies.

This concern is particular to gene therapy, which modifies genes to treat diseases or stop a disease, Bryan said.

“And I don’t really have anything to do about that. We’re going to use accelerated approval and and I expect the accelerated approval will be used more and more frequently in gene therapy and cell therapy, but the confirmatory studies will take a while in some cases, and that’s going to be a problem,” he said.

Gene therapies aim to provide a one-time, or potentially curative, fix to a disease. But the nature of potentially curative therapies is that the long-term benefits often won’t be known for years.

“Some of these diseases are so slowly progressive, that it will maybe be difficult, and we have we will have to rely on biomarkers,” Bryan said. Biomarkers are a laboratory measure of a normal biological process, such as using blood glucose levels to measure how well a diabetes drug works.

“Dr. Bryan’s comments highlight the challenge that FDA faces in their role balancing timely access to new products, especially where there are no options available for patients, while also providing assurance to patients and clinicians that the product is safe and effective,” Reshma Ramachandran, a Yale School of Medicine family physician and chair of the Doctors for America’s FDA Task Force, said in an email.

In the case of gene therapies, which are often tested in very few patients, it’ll be critical to not only require post-approval studies under accelerated approval to confirm clinical benefit, but to also conduct real-world evidence studies to augment this to monitor long-term safety risks, Ramachandran added.

Finding the Right Balance

Accelerated approval has tremendously benefited rare disease patients, but it’s important to find the right balance in risks and benefits, Karin Hoelzer, director of policy and regulatory affairs for the National Organization for Rare Disorders, said.

“We do not want the standards to be so stringent that our patients cannot access gene therapies that have been shown to be effective based on the accelerated approval standard—surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit,” Hoelzer said

Accelerated approval allows drugs FDA to make treatments available earlier, if it treats a serious condition and fulfills an unmet medical need. Under accelerated approval, companies must demonstrate their drug will likely offer a clinical benefit based on based on a laboratory endpoint, known as a biomarker. In exchange, the drug company agrees to conduct postmarket studies that will demonstrate clinical benefit, or an outcome that can measure directly whether a patient lives longer, feels better, or functions better.

The approval has been used for years, particularly for cancer drugs, to expedite access to medicines. But the controversial decision to approve Biogen’s Alzheimer’s diseases drug Aduhelm under accelerated approval brought the FDA mechanism to the forefront of drug policy discussions. The 2023 omnibus spending law enacted last year included changes to accelerated approval, including provisions to make it easier for the agency to require postmarket studies and to withdraw drugs that don’t work.

“As accelerated approval provides a pathway for withdrawing the treatment should it fail confirmatory studies or be unnecessarily delayed in doing so, it’s critical that FDA has continued oversight as the study goes on—not just many years later when the submission deadline occurs,” Ramachandran said. “If there is a safety concern that emerges along the way, FDA should have the ability to stop market authorization of the drug and investigate in a timely manner to prevent further patient harm. Additionally, if there does not seem to be any signal of impending clinical benefit as the study continues, then the study should be stopped earlier and early withdrawal be considered.”

Hoelzer’s organization supported accelerated approval reforms in the 2022 year-end spending bill and is working to educate about the risks and benefits of risks of gene therapy products, to capture patient preferences, and to help generate the evidence for or against effectiveness as quickly as possible.

“In many cases, the decision whether to receive a gene therapy product is a life-or-death decision for our patients and we need to make sure our patients can make the best-informed decision,” Hoelzer said.

“Our patient populations are so small, we need to make sure that the clinical studies themselves are carefully designed and robust,” she said. “Nothing is more devastating for our rare disease community than to have a study fail just because it was poorly designed.”

To contact the reporter on this story: Jeannie Baumann in Washington at