The program has recently become controversial as a number of high-profile advanced approvals were granted only for the drugs to fail a confirmatory trial later on. Now, the FDA has clearly laid out expectations.
As the Biden administration winds down, the FDA is setting out guidance on its current thinking around accelerated approvals, an issue that rose to the top of Commissioner Robert Califf’s to-do list amid a flurry of controversy around a handful of such drug approvals.
Accelerated approvals are granted to drugs that address an unmet medical need for serious or life-threatening conditions. Sponsors can get a drug approved based on a surrogate endpoint such as a biomarker that is reasonably likely to predict clinical benefit. They must also conduct a confirmatory trial to turn the accelerated approval into a regular approval.
The program has been around for decades, but has recently become controversial as a number of high-profile advanced approvals were granted, only for the drugs to fail a confirmatory trial later on.
During his tenure, Califf has overseen some changes to the accelerated review program. He set out the expectation that drug sponsors must have the confirmatory trial underway at the time of accelerated approval, or at least have a plan to get one started swiftly. That directive is codified in the new guidance, although the document is nonbinding.
The guidance also says that the label for the drug will include “a succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits.”
If an adequate and well-controlled trial cannot be conducted, accelerated approval should not be considered, the guidance explains.
The FDA also defines surrogate endpoints and provides examples of recent ones that have been used to support an accelerated approval, such as a decrease in iron stores for patients with iron overload caused by beta thalassemia. The agency also recommends that sponsors intending to seek accelerated approval start regulatory conversations early in the drug development process to gain alignment with the FDA on a surrogate endpoint. These conversations can occur as soon as at the end of Phase I.
Once accelerated approval is granted, sponsors must conduct their confirmatory trial “with due diligence,” the guidance explains. The proposed trial protocol should be submitted to the FDA for review as early as possible, with trial timelines clearly explained.
Going forward, the FDA intends to require that these trials be underway before an accelerated approval is granted except in very limited circumstances , the guidance explains. These trials should stick close to the intended population that is already able to access treatment and can even be an extended duration of the trial that was used to support the accelerated approval.
In some cases, the FDA can withdraw an accelerated approval if certain conditions aren’t met. The guidance gives examples such as the sponsor failing to conduct the confirmatory trial with due diligence, the study failing to confirm clinical benefit, safety concernsand the sponsor disseminating false or misleading promotional materials about the product.
If a withdrawal is considered, the FDA center that approved the drug should convene an advisory committee meeting. This will allow a robust public discussion and give the sponsor an opportunity to provide evidence and data.
The FDA has rarely stepped in to request withdrawals of high profile products, even those that fail confirmatory trials, leaving the decision up to the sponsor.
For example, Pfizer recently withdrew the sickle cell disease drug Oxbryta from the market and ended ongoing clinical trials voluntarily after evidence suggested a higher risk of death and complications in treated patients. The drug received accelerated approval in November 2019.
By contrast, Elevidys, a Duchenne muscular dystrophy gene therapy by Sarepta Therapeutics, failed a confirmatory trial last year and the company opted to keep it on the market, eventually securing full approval and a label expansion, though questions remain about the treatments’ efficacy.
However, in June 2022 the FDA did withdraw an advanced nod for TG Therapeutics’ lymphoma drug Ukoniq after it showed a possible increased risk of death.
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