Cancer drugs approved as FDA breakthrough therapies are not necessarily better than those approved through the traditional pathway: Although breakthrough-designated cancer drugs were approved in less time, a recent study reported, they were not associated with gains in progression-free survival or response rates, nor were they safer or more novel than non–breakthrough-designated drugs.

In 2012, the FDA created the breakthrough therapy designation to speed up the development and review of drugs intended to treat serious or life-threatening diseases when preliminary clinical evidence indicates a possible substantial improvement over existing therapies. However, a recent analysis of breakthrough-designated cancer drugs indicates that although they are approved more quickly, they are no more effective, safe, or novel than drugs approved via the traditional pathway.

Because 59% of cancer medicines approved since 2014 have received that designation, researchers wanted to assess the value of these drugs, explains Jonathan Darrow, SJD, JD, MBA, of Harvard Medical School and Brigham and Women's Hospital in Boston, MA, and senior author of the study (J Clin Oncol 2018 Apr 24 [Epub ahead of print]).

Darrow and his colleagues analyzed 58 cancer drugs approved by the FDA between January 2012 and December 2017, 25 of which had received breakthrough therapy designation. The median time to FDA approval was 5.2 years for breakthrough therapies, versus 7.1 years for drugs without the designation. There was no significant difference between the two categories of drugs in median progression-free survival gains (8.6 vs. 4 months) or response rates (37% vs. 39%). Nor were breakthrough drugs more likely to have a novel mechanism of action (36% vs. 39%). Further, rates of death (6% vs. 4%) and serious adverse events (38% vs. 36%) were similar.

“The take-home message is that there's no statistically significant difference in patient benefit between the breakthrough and non-breakthrough cancer medicines,” Darrow says. The findings, he adds, raise two main concerns: that patients and clinicians may have unrealistically high expectations about breakthrough therapies, and that patients and insurers are spending large amounts of money on breakthrough drugs that, in some cases, may not be any better than other available treatments (N Engl J Med 2018;378:1444–53).

In response, three physicians at the FDA penned a letter defending the program (N Engl J Med 2018;378:1457–8).

“The FDA needs the tools to identify and accelerate the approval of drugs that can substantially improve the lives of patients with serious or life-threatening diseases who have inadequate options,” they wrote. “Fast-track and breakthrough-therapy designations have done just that—while not without challenges, certainly without compromising the thoroughness of our review or the standards of evidence to support approval.”

They note that “not all drugs with the breakthrough-therapy designation ultimately deliver on their promise.” In those cases, the designation can be withdrawn.

“All of us want really good drugs to become available to patients really quickly, and it's obviously the intention of this mechanism to make that happen,” says Leonard Saltz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who was not involved in the study. Yet he wonders if the expedited approvals of breakthrough-designated drugs result in slower approvals of other drugs. “If the goal is to identify and bring the substantially better drugs to market faster, these data would suggest that that's not being accomplished.”

Saltz thinks more stringent criteria that clearly define what is required of a drug to become a breakthrough therapy could help ensure that the designation is given only to the most promising drugs.

“The concept is valid, and it's well intentioned,” he says. “I think we should be objectively evaluating, ‘Is it serving its intended purpose, or do we need to recalibrate’ ” –Catherine Caruso

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