BALTIMORE – A top official at the US Food and Drug Administration on Wednesday reiterated the regulator's commitment to expediting treatments for rare, genetic diseases to market utilizing the accelerated approval pathway.
Under this pathway, the FDA has the flexibility to approve drugs faster based on how they affect biomarkers likely to predict clinical benefits, rather than waiting to see whether the drugs improve clinical endpoints like survival, which can take years to read out. Although drug developers are supposed to provide confirmatory evidence of these drugs' clinical benefits to maintain their market access, companies don't always complete these studies. In recent years, critics have accused the FDA of bringing treatments to market through the accelerated approval pathway based on what they consider insufficient surrogate data and not removing therapies from the market when sponsors fail to produce confirmatory evidence in the post-market setting.
Only 20, or fewer than half, of 46 cancer drugs that received accelerated approval between 2013 and 2017 demonstrated a clinical benefit in confirmatory trials, according to a paper published in JAMA last month. Still, the FDA converted 29 drugs' accelerated approval to traditional approval, while sponsors had to withdraw 10 agents from the market.
Despite the critical focus on the accelerated approval pathway of late, Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, on Wednesday reaffirmed that he considers the accelerated approval pathway a critical avenue to shepherd gene therapies for rare diseases to market.
"Accelerated approval has obviously been pretty controversial," Marks said at a fireside chat Wednesday morning at the American Society of Gene & Cell Therapy's annual meeting. He acknowledged that there are debates among stakeholders over when it's appropriate to grant accelerated approval but said he would focus his comments on rare disease therapeutics, a key area where he believes this pathway can be particularly beneficial.
"We can leave the controversy for large population oncology products for another day," he said, adding, "there are people who think that we were using accelerated approval too much, or too little."
There are often very few treatments available for rare diseases, in part because it's challenging to study therapeutic candidates in small patient populations. In the absence of comprehensive natural history studies or external control arms, the surrogate biomarkers or intermediate endpoints the FDA uses to grant accelerated approvals to drugs can be a "powerful way to get [them] over the finish line," Marks said.
Biomarkers are an attractive type of endpoint for gene therapies in particular, since researchers may be able to report evidence of gene replacement or its effects, such as enzyme activity or protein expression, which can be studied on a shorter time frame than many clinical outcomes.
Still, Marks acknowledged that accelerated approval isn't always the right avenue. If drugmakers are able to study a validated surrogate endpoint or clinical outcomes within a reasonable time frame, they should consider pursuing traditional approval. Moreover, there are drawbacks to accelerated approval. Confirmatory studies can be expensive, for example, and health insurers don't always cover treatments approved through the accelerated approval pathway.
However, for smaller companies and startups that aren't yet generating revenue from a commercialized product, biomarker studies might be the only way to get a product to market, Marks said, since they often lack the finances for the longer studies needed to monitor a clinical endpoint.
Ultimately, Marks said he would rather approve a product based on a review of preclinical and clinical evidence available, even if it later must be withdrawn from the market, than leave patients without options. "I would much rather take the chance that we're occasionally going to make an error and give something an accelerated approval than have people so desperate that they're going out and either going overseas to get unproven therapies, which happens, or using other pathways in which the FDA doesn't have much regulatory oversight," Marks said.
He stressed that in granting accelerated approval based on a surrogate biomarker, the agency's goal is "to get it right 90 percent of the time or more."
It could be helpful for industry to have more guidance on using the accelerated approval pathway specifically for gene therapies, Marks acknowledged, but did not say whether that guidance would be forthcoming.
As part of the Consolidated Appropriations Act of 2023, Congress gave the FDA new authorities for overseeing the accelerated approval pathway, such as provisions that the agency specify post-approval study requirements before an accelerated approval and set up an expedited withdrawal procedure for products approved through the pathway. In 2022, the US Department of Health and Human Services' Office of Inspector General had found that more than one-third of drugs with accelerated approval did not complete confirmatory trials.
Even though the FDA might have more authority to rescind market access to drugs it granted accelerated approval, the agency doesn't take such decisions lightly, according to Marks. "We're going to only do that when it's pretty clear," he said of withdrawals, such as in cases where there are minimal benefits to patients but significant side effects.
In cases where there are side effects observed, researchers will need to investigate them and tease out if the adverse events are attributed to the gene therapy, conditioning regimen, or the underlying disease. And, should a gene therapy product fail a confirmatory trial, the agency will look carefully at whether it's a problem with the gene therapy itself or something else. A failed trial doesn't necessarily mean that the treatment isn't benefiting patients, Marks said, adding that the failure may be due to a clinical trial design flaw, such as not selecting an appropriate endpoint or study period.
The FDA will want to make sure that there "isn't something in the confirmatory trial that led us astray, … if we think we've leveraged the science correctly for the initial accelerated approval," Marks said. "There's nothing wrong with having to do a second confirmatory trial, if you think it's the trial design and not the product itself."