About half of the drugs approved under the Food and Drug Administrations’s Breakthrough Therapy designation have lacked the gold-standard evidence of a double-blind, randomized, placebo-controlled trial, according to a new JAMA report.
“This study of all FDA approvals granted Breakthrough Therapy designation from 2012 through 2017 suggests that pivotal trials supporting these approvals commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary end points, and enrolled small numbers of patients,” wrote Jeremy Puthumana and his coauthors. “Furthermore, more than half were based on a single, pivotal trial.”
The average premarket development time was about 5 years, but regulatory review of these agents took less than 7 months on average, the report found.
Mr. Puthumana, of Yale University, New Haven, Conn., and his coauthors, reviewed all 46 of the drugs and biologics approved by the FDA from 2012 to 2017 under the designation. The Breakthrough Therapy designation allows for the rapid review of drugs and biologics for serious or life-threatening conditions where there is preliminary evidence demonstrating a substantial improvement over existing therapies. The researchers identified all pivotal trials supporting approval, looking at randomization, blinding, comparator group, primary endpoint, and patient numbers.
Of these drugs, most (25) were oncologic agents. Other indications were infectious disease (8), genetic or metabolic disorders (5), and other unspecified purposes (8). The median number of patients enrolled among all pivotal trials supporting an indication approval was 222.
Most of the approvals (27) were based on randomized trials, 21 (45.7%) were based on double-blind randomization, 25 (54.3%) employed an active or placebo comparator group, and 10 (21.7%) used a clinical primary endpoint.
Compared with drugs without accelerated approval, drugs with accelerated approval status were less likely to be examined in randomized or double-blinded trials(24 vs. 3 and 20 vs. 1, respectively), and were less likely to include a control group (32 vs. 3).
However, all drugs with Accelerated Approval status underwent at least one clinical safety or efficacy-focused postmarketing requirement, as did 64.3% of those without that status.
“Patients and physicians may have misconceptions about the strength of evidence supporting breakthrough approvals,” the authors wrote. “FDA-required postmarketing studies will be critical to confirm the clinical benefit and safety of these promising, newly approved therapies.”
Mr. Puthumana reported having no financial disclosures.
SOURCE: Puthumana J et al. .