Broken promises? FDA needs more power to remove drugs from marketplace, JAMA analysis finds
The FDA is struggling to remove drugs from the marketplace that don’t show effectiveness in late stage trials, new JAMA analyses found, thanks to the persistent tension between speed and confidence in early clinical data.
Congress, regulated industry and patients have urged the FDA to shorten the amount of time that the market has to wait for drugs to become available that may help severe and prevalent diseases – and the FDA has listened, offering up a quick accelerated approval pathway that’s frequently used by new cancer drugs.
But it can be a double-edged sword.
A JAMA viewpoint published this week on pre-approval promises made by drug manufacturers to the FDA found that companies can refuse to take their accelerated approval program products off of the market, and sometimes do, even after required late stage clinical trials find the drugs to be less than effective. The FDA’s reliance on companies to withdraw the drugs themselves has created a regulatory push and pull.
The saga around Amylyx’s new ALS drug Relyvrio is one of the examples cited. Data from 2020, when Amylyx published results of its Phase II CENTAUR trial, reported statistically significant improvement of the primary endpoint, the rate of decline of the total score on the amyotrophic lateral sclerosis functional rating scale-revised at 24 weeks.
The FDA wanted an additional placebo-controlled trial, but also eventually agreed to accept a marketing application before trial completion.
The problems began when the drug lacked sufficient evidentiary support to be granted traditional approval or accelerated approval, the later of which gives authority for the FDA to require postmarket studies and to invoke expedited withdrawal procedures in exchange for early market access.
Several advisory committees later, data from the drug’s extension trial did not show substantial effectiveness, Rachel Sachs and Holly Fernandez Lynch, law professors at Washington University in St. Louis and University of Pennsylvania, explained. But the company verbally promised during the adcomm to remove the drug if it wasn’t effective. The FDA approved the drug, but didn’t address the company’s removal process.
The answer moving forward, Fernandez Lynch and Sachs urged, is to match the agency’s regulatory flexibility to withdraw with its flexibility to approve.
Another more extreme example cited in a separate viewpoint published this week in JAMA Network by Harvard and Brown professors is Covis Pharma’s Makena, an injectable drug for the prevention of preterm birth. The FDA approved the drug in 2011 for accelerated approval, but 2019 end-stage trial results found the drug wasn’t effective.
Three years later, the FDA is still fighting the company to take it off the market, and the results have been disastrous.
“Makena’s adverse effects include increased risk of cancer in exposed offspring, including pediatric brain cancer. The presence of a drug like Makena on the market may also discourage other manufacturers from developing or commercializing new therapies to prevent preterm birth,” the JAMA analysis reads. “Although accelerated approval can facilitate drug development in some cases, it carries serious costs when such drugs prove ineffective or unsafe.”