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FDA breakthrough therapy designation not associated with improved novelty, safety, efficacy

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July 2, 2018

A “breakthrough” designation led to faster FDA approval for new medications, although these agents did not show improved safety, novelty or efficacy compared with nonbreakthrough agents, study data showed.

“In July 2012, Congress established the breakthrough therapy program to expedite the development and review of new medicines,” Aaron S. Kesselheim, MD, JD, MPH, associate professor of medicine at Harvard Medical School, and colleagues wrote. “To qualify, a new medicine must be intended to treat a serious or life-threatening disease and, on the basis of preliminary clinical evidence, have the potential to offer substantial improvement over existing treatment options.”

Cancer therapies make up more than half of breakthrough-designated drugs that have been approved from the beginning of the program through 2017.

“Despite the increasing frequency of breakthrough designations and approvals in oncology, the full implications of the breakthrough therapy program are not well understood,” the researchers wrote.

Kesselheim and colleagues reviewed all new cancer drugs approved by the FDA from 2012 through 2017. The researchers compared the regulatory and therapeutic characteristics of breakthrough and nonbreakthrough designated drugs, using random-effects meta-regression to evaluate possible associations between breakthrough designation and HRs for PFS, solid tumor response rates, serious adverse events and deaths that were not attributed to disease progression.

Fifty-eight new cancer drugs were approved by the FDA during the study period. Nearly half of these (43%; n = 25) were designated as breakthrough therapies.

Breakthrough-designated drugs had a median 5.2 years to FDA approval, compared with 7.1 years for nonbreakthrough designated drugs (P = .01).

However, breakthrough-designated drugs did not provide significantly greater median PFS gains compared with nonbreakthrough drugs (8.6 vs. 4 months). The same was true of HRs for PFS (0.43 vs. 0.51) and response rates for solid tumors (37% vs. 39%).

Further, breakthrough-designated drugs were not more likely to use a novel mechanism (36% vs. 39%).

Breakthrough-designated drugs also demonstrated similar rates of death as nonbreakthrough designated drugs (6% vs. 4%) and similar rates of adverse events (38% vs. 36%).

Gary Lyman
Gary H. Lyman

The FDA should aim to simultaneously protect patients from adverse events and grant them timely access to potentially life-saving treatments, Nicole M. Kuderer, oncologist at the Advanced Cancer Research Group in Seattle, and Gary H. Lyman, MD, MPH, researcher at the Fred Hutchinson Cancer Research Center, wrote in an accompanying editorial.

“Although minimization of lengthy delays in approval of promising agents without major safety concerns is reasonable, rational drug approvals are needed to avoid future rationing of drug approvals,” Kuderer and Lyman wrote. “The development of clinically meaningful benchmarks for major disease settings will help focus FDA approvals on the most effective drugs.

“At the same time, careful ongoing evaluation of the impact of new regulatory models for expedited approval, such as presented in these studies, are essential,” they added. “Likewise, systematic engagement of regulators, clinicians, and patients is needed to jointly nd solutions to better balance access to promising new agents and better protect patients from harm. Patients deserve no less than our best collaborative efforts.” – by Andy Polhamus

Disclosures: Kesselheim reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Kuderer reports an immediate family member with a leadership role at Generex Biotechnology, a consultant/advisory role with G1 Therapeutics and research funding from Amgen. Kurderer also reports consultant/advisory roles with Celldex, Coherus Biosciences, Halozyme, Janssen, Mylan and Myriad Genetics; and travel, accommodations and expenses from Coherus Biosciences, Janssen and Mylan. Lyman reports a leadership role with Generex Biotechnology, research funding to his institution from Amgen and consultant/advisory roles with Coherus Biosciences, G1 Therapeutics and Halozyme.

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