As part of the 2012 US Food and Drug Administration (FDA) Safety and Innovation Act, Section 9021 created a new regulatory review designation—breakthrough therapy—that would expedite the development and FDA review of as-yet unapproved drugs and biologic agents intended to treat serious or life-threatening diseases and for which preliminary clinical evidence indicates that the drugs may offer substantial improvement over existing therapies. This legislation was likely enacted to promote innovative drug development and to respond to critics of the FDA regulatory review process, who criticize it as being slow despite research demonstrating the opposite.2 Reflecting these intentions, the term developed by Congress and adopted by the FDA for this new review designation—breakthrough therapy—is aspirational.
In this issue of JAMA Internal Medicine, Krishnamurti et al3 examine the impact of this terminology. They report a randomized controlled trial testing how healthy volunteers responded to 5 different vignettes describing a drug to treat lung cancer newly approved as a breakthrough therapy, modeled from current FDA press releases. Not surprisingly, inclusion of the terms breakthrough or promising without any other change in vignettes led to higher ratings of the drug’s effectiveness and perceptions of the strength of supporting evidence. It is entirely reasonable to expect that patients, as well as health care professionals, will similarly perceive drugs as more promising based on this terminology. When patients learn about “breakthrough therapies” from FDA press releases, should we not expect them to request that their physicians prescribe these therapies instead of other available therapies, even if the evidence to support their use is less robust? Similarly, should we not expect physicians to preferentially adopt their use? Moreover, and not studied by Krishnamurti et al,3 it is likely that drug and device manufacturers will use this intentionally exciting terminology for direct-to-consumer and health care professional advertising.
According to the FDA, there have been 267 requests for breakthrough therapy designation from drug and biologic agent manufacturers, 95 (35.6%) of which were granted.4 While some of these therapies may actually be “breakthroughs,” most are not likely to be. Breakthrough designation is based on preliminary evidence, which can include changes in surrogate markers of disease, such as laboratory measurements, that do not always translate into meaningful clinical benefit.5 Even when based on clinical outcomes, many of these benefits will not be confirmed in subsequent, larger-scale clinical trials. Moreover, the 21st Century Cures Act recently passed by the US House of Representatives includes Section 2201,6 a provision for a similar priority regulatory review designation for breakthrough medical devices, about which we have the same concerns. To protect patients from spurious hopes for miracle cures, Congress and the FDA should abandon the adoption of terminology like breakthrough and focus on strengthening the evidentiary requirements for meaningful clinical data to ensure the promise of new drugs and devices.
Conflict of Interest Disclosures: Dr Ross receives research grant funding through Yale University from the US Food and Drug Administration to develop methods for postmarket medical device surveillance and from Medtronic Inc and Johnson & Johnson to develop methods for clinical trial data sharing. No other disclosures are reported.
Ross JS, Redberg RF. Would a Breakthrough Therapy by Any Other Name Be as Promising?. JAMA Intern Med. 2015;175(11):1858-1859. doi:10.1001/jamainternmed.2015.5311