Fast-tracked cancer drugs remain in use despite negative confirmatory trials

Some oncology drugs that are granted fast track approval continue to be used for years despite a lack of evidence from confirmatory trials, new research shows.

A third of cancer drugs given accelerated approval by the US FDA but which then fail to demonstrate benefit in confirmatory post-approval trials, stay approved regardless, according to a study published in The BMJ.

Researchers from Queens University Ontariao, Canada assessed the consequences of negative confirmatory trial results on all cancer drugs that received accelerated approval from the start of the FDA program to December 2020.

They found 18 cancer drug indications that had initially received accelerated approval but failed to improve a primary end point in confirmatory trials or were withdrawn because the studies weren’t conducted or completed.

The drug indications included bevacizumab for HER 2 negative breast cancer, fludarabine for B cell CLL, atezolizumab for urothelial cancer, gefitinib for NSCLC and gemtuzumab for AML.

For the 16 cancer drug indications with completed post-approval trials, all failed to improve overall survival. Most (n=7) failed to improve PFS and OS and four improved PFS but not OS.

“The most common outcome for cancer drugs that received accelerated approval but failed to improve the primary endpoint in post-approval trials was voluntary withdrawal of the indication (n=9; 50%),” the study authors noted.

“In two cases, after voluntary withdrawals, the FDA subsequently granted a new regular approval for the same drug for the same disease at a different dose or for a biomarker defined population.”

The only approval revoked by the FDA was bevacizumab for metastatic breast cancer.

“All of the drugs with withdrawn or revoked indications remain on the market for other indications, except for olaratumab, which had no other indication, and tositumomab, which was withdrawn from the US market for commercial reasons, citing lack of demand.”

Two drugs converted to regular approval and three remain pending with the Oncology Drug Advisory Committee (ODAC) voting against their withdrawal.

“Thus, as of July 2021, six (33%) of 18 drug indications either remain on the drug’s labelling or were converted from accelerated approval to regular approval despite the negative results from the required trial,” the study authors said.

The time from accelerated approval to a regulatory outcome was a median of 3.9 years (range 1.7-11.5 years).

The authors noted that half of all the withdrawals of approved indications for cancer drugs had occurred in the past two years – which may suggest that the FDA is taking a stronger stance in recent years in enforcing the policy compromise at the heart of the accelerated approval programme.

“However, the recent withdrawals could also simply be a result of increased numbers of accelerated approvals or relaxed standards for accelerated approval in recent years,” they said.

Also, some of the drugs were still recommended in National Comprehensive Cancer Network (NCCN) guidelines.

The investigators said their findings 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.”

“A recent flurry of regulatory action suggests that the FDA has paid greater attention to these situations in the past two years, although additional guidance and reforms of the accelerated approval pathway are needed to assure that all FDA approved drugs are shown to be safe and effective for patients,” they concluded.


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