Clinical trials for US Food and Drug Administration (FDA)-designated Breakthrough Therapy drugs may lack the rigorous methodology of non-Breakthrough approvals, according to a study published in JAMA.
Joseph S. Ross, MD, MHS, of Yale University School of Medicine, and colleagues, conducted a study of all new drugs and biologics granted Breakthrough Therapy designation by the FDA from January 2012 through December 2017. The study identified pivotal trials supporting approval and determined the use of randomization, blinding, comparator group, primary end point, and number of patients.
Overall, 46 therapeutics were found to have been granted Breakthrough Therapy designation on the basis of 89 pivotal clinical trials, primarily in the therapeutic areas of cancer (54.3%) and infectious disease (17.4%); 54.3% of these trials were considered first-in-class.
The therapeutic agents were often designated as orphan products (65.2%) and qualified for Fast Track review (52.2%) or Accelerated Approval (39.1%), with all drugs being given Priority Review. Dr Ross and colleagues found that the median number of pivotal trials per indication approval was 1; of those, 27 approvals were made based on pivotal trials that utilized randomization or an active or placebo comparator group. Trials with Accelerated Approval status were less likely to have randomized pivotal trials, be double-blinded, and include a control group than trials without Accelerated Approval status. All 18 approvals holding Accelerated Approval status and 18 of those without Accelerated Approval status had at least 1 clinical safety post-marketing requirement.
The investigators concluded that pivotal trials supporting FDA-designated Breakthrough Therapy approvals were lacking in randomization, double-blinding, and control groups and enrolled small numbers of patients. However, the current study was limited to only new Breakthrough Therapy drugs; researchers note that prior studies show these factors lacking in the new trials were more common among non-Breakthrough Therapy drugs given FDA approval.
In addition, the study found that more than half of the new approvals were based on a single pivotal trial. The investigators found that the average pre-market development times were approximately 5 years and FDA regulatory review and approval required an average of less than 7 months. Based on this research, FDA-required post-marketing studies will be critical to determining the safety and clinical benefit of the newly-approved Breakthrough Therapy drugs.
Puthumana J, Wallach JD, Ross JS. Clinical trial evidence supporting FDA approval of drugs granted breakthrough therapy designation. JAMA. 2018;320(3), 301-303. Published July 17, 2018. Accessed July 17, 2018.