The Food and Drug Administration appears ready to raise its approval standards for a well-known class of cancer drugs due to concerns they aren’t helping patients live longer, and may be harming them as well.
A panel of FDA outside advisers on Thursday voted 16-0, with one abstention, to recommend randomized, placebo-controlled trials for the drugs, known as PI3 kinase inhibitors, before they’re approved for broader use in blood cancers such as leukemia and lymphoma. The FDA isn’t bound to follow the advice of its advisory committees, but usually does so.
Since 2014, the FDA has granted multiple accelerated approvals to PI3K blockers, among them Gilead’s Zydelig and Bayer’s Aliqopa. Those decisions were based on biological signs of a drug response, such as a reduction in the number of cancerous cells. At the time, they hadn’t yet been tested against a placebo or proven to extend lives.
Since then, placebo-controlled trials meant to confirm the drugs’ benefits have produced results, which showed that patients didn’t live longer and, in some cases, experienced serious complications. FDA scientists hypothesized the side effects of PI3K inhibitors, when given with standard blood cancer treatments like Rituxan, can cause some patients to die when they may not have otherwise.
Three trials of Zydelig, for example, were ended in 2016 because more patients taking it died from side effects than those who didn’t receive Gilead’s drug. The side effects mostly involved infections.
“We have to have confidence that these [drugs] are safe and effective and don’t cause harm. That is the guiding principle,” Nicole Gormley, acting director of of the FDA’s Division of Hematologic Malignancies, told the advisory committee.
The advisory committee largely agreed with the FDA’s assessment. “The bottom line is, if we aren’t improving length of life with any therapy, but exposing patients to toxicity, and therefore decreasing their quality of life, are we truly helping our patients? I don’t believe so,” said committee member Christopher Lieu, a medical professor at the University of Colorado.
However, several committee members struck a cautious tone, wary of the impact their decision might have on future research into PI3K inhibitors. Gilead, for example, voluntarily withdrew Zydelig from the market in two types of lymphoma because of challenges enrolling confirmatory studies. Incyte pulled an application after deciding an additional trial wasn’t worth the investment.
Last week, TG Therapeutics withdrew its lymphoma drug Ukoniq from the market, causing the FDA to cancel a meeting, originally scheduled for Friday, to evaluate a new application from the company.
“I still feel uncomfortable labeling an entire class and requiring further drugs in that class to be supported by randomized data,” said committee member Andy Chen, an associate professor of medicine at Oregon Health and Science University.
Chen noted that many of the worrisome side effects observed with PI3K inhibitors were identified in early-stage trials. If those problems aren’t observed with future, similar drugs, demanding randomized trials could slow their development, he argued. (Oregon Health and Science is conducting a trial of Ukoniq.)
The FDA wants more early development work on PI3Ks to focus on effective, but safer doses. This type of “dose optimization” was done with older chemotherapies, for which side effects are more severe at higher doses, and it’s why drugmakers search for the “maximum tolerated dose” when advancing new treatments.
That process is harder, however, with targeted drugs like PI3K inhibitors, because their effectiveness rises more quickly than their side effects as doses are increased. However, FDA officials said a “maximum tolerated dose” isn’t always much more effective than a lower, less-toxic dose.
The agency is currently running an initiative called Project Optimus that aims to better identify effective and less-toxic doses earlier in cancer drug testing.
