FDA’s fast track process is under fire

The FDA’s accelerated approval pathway is in the spotlight for all the wrong reasons.

The biggest callout? The process “raised concerns” for three of 24 drugs in a January 14 report from the Department of Health and Human Service’s Office of the Inspector General (OIG), including an Alzheimer’s drug known as Aduhelm.

The OIG was motivated in part by a 2022 congressional report that also found faults in the FDA’s accelerated approval of Aduhelm. “These three cases underscore the need for additional guardrails in certain circumstances,” the authors wrote.

There are guidelines in place to help the approval process stay safe and effective, but things don’t always go off without a hitch.

The accelerated pathway began in response to the HIV/AIDS epidemic as a way to fast-track approval for drugs for serious or life-threatening conditions. Instead of proving that the meds have clinical benefit, which can be a lengthy and expensive process, sponsors can use a surrogate endpoint—an endpoint that reflects the drug’s effect on an aspect of disease that is “reasonably likely” to predict clinical benefit. From there, they’ll complete confirmatory studies after the drug goes to market (though the OIG report notes that neither the FDA nor federal law defines exactly what “reasonably likely” means).

“In many [cases], surrogate markers are not good predictors of clinical benefit,” Rita Redberg, a cardiologist and professor of medicine at the University of California, San Francisco, told Healthcare Brew.

The problem

The report specifically calls out Biogen’s Alzheimer treatment Aduhelm (aducanumab), Serepta Therapeutics’s Duchenne muscular dystrophy therapy Exondys 51 (Eteplirsen), and Covis Pharma’s preterm birth prevention treatment Makena (hydroxyprogesterone caproate).

The report found that FDA reviewers or advisory committee members had expressed concerns about the evidence behind all three drugs, yet the FDA approved them anyway.

For two of the three “concerning” approvals—Exondys 51 and Aduhelm—the FDA allowed sponsors to veer from their original analysis plan.

Biogen, for instance, didn’t originally apply for accelerated approval. It applied through the regular approval pathway, intending to collect evidence that Aduhelm reduced cognitive decline. But after the company’s clinical trials didn’t provide enough evidence of a benefit, the FDA decided to give it accelerated approval instead, using a surrogate endpoint, amyloid plaque, which some experts argued hadn’t been sufficiently linked to clinical benefit.

On top of this, the OIG’s report found some meeting minutes with sponsors were missing from administrative files for Aduhelm and meetings hadn’t been fully documented for other drugs. It’s not clear whether the missing meeting minutes were clerical errors or signs of something larger in scale, Redberg said. “​​It remains—I would say—unknown whether this behavior did depart from the norm in that the FDA staff was having secret meetings with the sponsor or whether this truly was an aberration,” Redberg said.

A 2022 House investigation found the FDA and Biogen “failed to follow the agency’s own documentation protocol,” and “inappropriately collaborated,” working “closely.”

Potential fixes

Today, Aduhelm and Makena are off the market. Biogen withdrew Aduhelm in January 2024. The FDA pulled Makena in April 2023 after a confirmatory trial failed to show effectiveness.

A trial to confirm Exondys 51’s clinical benefit has been delayed, the report said.

The OIG report recommended the FDA take steps to ensure proper meeting documentation in the future, which the FDA agreed to do.

It also urged the FDA to establish a protocol for involving its accelerated approval council during challenging reviews—like, for instance, whenever consensus is lacking. The FDA was mandated to create an intra-agency accelerated approval council in 2022, which was required to meet at least three times a year and publish an annual report of its findings. The council only met twice and published a one-page report for 2023, the OIG report said.

The FDA rejected the OIG’s suggestion as “inefficient,” according to the OIG. The FDA did not reply by deadline to additional questions from Healthcare Brew.

“It does seem to me that the FDA is not interested in having any public discussion of the current process of accelerated approval and whether it’s in the public interest,” Redberg said. “I suspect that there are a lot more failures of the accelerated approval system than were even noted in this report.”