Study: 1/3 of Cancer Accelerated Approval Indications Remain Despite Lack of Confirmation

The U.S. Food and Drug Administration (FDA) developed its Accelerated Approval Program in 1992, with the intention of moving certain new drugs to the market faster.

An Accelerated Approval typically leans on a surrogate endpoint, basically a marker, such as a laboratory value, radiographic image, physical sign or other measures that can be used to predict clinical benefit but isn’t by itself a measure of clinical benefits.

Typically, a drug approved under an Accelerated Approval pathway requires confirmatory trials or the drug’s approval for that indication will be rescinded.

A study published in the BMJ suggests that about one-third of cancer indications receiving approval under an Accelerated Approval pathway are still on product labels even after follow-up studies did not confirm their benefits. This is consistent with a study published in 2019 in the INFORMS journal Manufacturing & Service Operations Management, which reported the same proportion. That study evaluated drugs approved from 1992 to 2008 under the accelerated pathway, showing 36% of post-market studies had not been completed and that 50% of the uncompleted studies took an average of five years to even start.

The BMJ study analyzed data from the Drugs@FDA database for cancer drugs that received accelerated approval from the beginning of the program in 1992 to December 2020. They then verified the status of post-approval trials through a variety of databases.

The researchers then identified a study cohort of 18 indications for 10 cancer drugs that had received accelerated approval but did not improve the primary endpoint in post-approval trials. Of these, 11, or 61%, were voluntarily withdrawn by the pharmaceutical company. One was revoked by the FDA— Genentech’s Avastin (bevacizumab). It was withdrawn in 2011.

Of the 11 withdrawals, six were in 2021. The remaining six, or 33%, are still on the labels.

The authors note, “The law mandates that drugs granted accelerated approval be tested in post-approval trials showing the putative clinical benefit expected from improvement in surrogate measures. The rationale for such a requirement is to ensure that all drugs granted accelerated approval eventually have their clinical benefit established for the patients relying on them.”

Their analysis found that the most common type of cancer was urothelial cancer (four), small cell lung cancer, hepatocellular cancer, and breast cancer (two each). Of the study cohort, 15 (83%) of the indications received accelerated approval based on studies demonstrating a change in tumor response rate, with the rest granted based on progression-free survival (PFS) (two) and overall survival (OS) (one) from a Phase II trial.

In the 16 indications that completed post-approval studies, the primary efficacy endpoint was either overall survival alone or overall survival as a co-primary endpoint with progression-free survival. In all, the post-approval studies demonstrated that the drugs did not improve overall survival. And in four indications, the studies showed the drug improved PFS but failed to improve the co-primary endpoint of OS. Seven studies’ post-approval trials failed to improve PFS and OS. The effect on PFS was worse in two cases, olaratumab (Eli Lilly’s Lartruvo) in sarcoma and durvalumab (AstraZeneca’s Imfinzi) in urothelial cancer.

The authors do note that “the most common outcome for cancer drugs that received accelerated approval but failed to improve the primary endpoint in post-approval trials was the voluntary withdrawal of the indication.” However, they added, “Even in cases in which the indication was withdrawn, the withdrawal was sometimes delayed for several years after initial approval and after the results of post-approval trial were announced. These indications also frequently continue to be recommended in clinical practice guidelines, sometimes after the manufacturer has withdrawn the indication from the FDA.”

They conclude, “Our results also show that the FDA often does not take immediate action on accelerated approval cancer drugs even when post-approval trials are negative. Without proactive steps from the FDA, drugs that have no proven clinical benefit and known toxicities will continue to be used by patients and clinicians who rely on the FDA to assess the risks and benefits of drugs.”

However, the FDA reported it was running an industry-wide evaluation of its accelerated approvals earlier this year. And there is some evidence the agency was taking a tougher stance on accelerated approvals in general, although the conclusions are a bit murky. Even the BMJ study indicates that more than half of the withdrawals were this year.