Drugs Approved Under the Breakthrough Therapy Pathway Lack Basic Features of High-Quality Trials

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Close postmarketing monitoring will be especially crucial for drugs approved with a breakthrough therapy designation, as many of them were approved on the basis of a single pivotal trial.
Close postmarketing monitoring will be especially crucial for drugs approved with a breakthrough therapy designation, as many of them were approved on the basis of a single pivotal trial.

More than half (58.7%) of all drug approvals under the US Food and Drug Administration's (FDA's) breakthrough therapy pathway were made on the basis of a single pivotal trial, according to a research letter published in JAMA.1

From 2012 to 2017, the FDA approved a total of 46 therapies with a breakthrough therapy designation on the basis of 89 total pivotal trials. And, as the letter highlighted, these 89 pivotal trials often lacked “basic features of high-quality trials, such as randomization, blinding, and concurrent controls,” said to Bishal Gyawali, MD, PhD, a physician from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, who was not involved in the study.

Though it may not be surprising that the authors found that clinical testing periods for breakthrough therapy drugs are typically much faster than those for non-breakthrough therapy-designated drugs — expediency is why the pathway was created — the researchers also found that these trials used surrogate markers as primary end points and enrolled very small numbers of patients (the median number of patients across all breakthrough therapy trials was 222).

Some could argue that because nearly two-thirds of the drugs that followed this approval journey were orphan products (30 of 46), many of the trials would be expected to enroll lower numbers of patients by default (as the total population affected by one of these conditions is likely small). “A trial's sample size should be determined based on the presumed rate at which the outcome events will occur in the trial population, as well as what power investigators want to have in the trial,” explained Dr Gyawali.

Although small trials are hallmarks of drugs developed for rare diseases, as Dr Gyawali told Cancer Therapy Advisor, the breakthrough therapy designation can apply to both rare and common diseases. “So one would expect that breakthrough therapy drugs for common diseases would be tested in more patients … However, all breakthrough therapy drugs are being tested in small numbers of patients, which makes active postapproval monitoring even more important.”

Dr Gyawali and his colleagues have conducted similar analyses of breakthrough therapy designations. He and his colleagues showed that cancer drugs approved through this pathway were associated with faster times to approval, but there was no evidence that these cancer drugs were more novel or provided “improvements in safety or a statistically significant efficacy advantage when compared with non–breakthrough-designated drugs.”2

Though the authors of the letter, who are from the Yale School of Medicine, wrote that it will be critical to confirm the clinical benefit of the drugs approved with breakthrough status, there is no safety mechanism built into the pathway to guarantee these activities occur — and that they occur in a timely fashion.

“Drugs approved on the basis of less rigorous preapproval testing … should be more actively followed up after approval to evaluate their adverse events or clinical outcomes, but that is not a required part of the process,” Dr Gyawali noted.

A little more than half of the breakthrough therapies (54.3%) approved since the inception of this expedited pathway were for cancer.1 This matches up closely with the findings of another study, which determined nearly all of the drugs that were approved within the accelerated approval pathway between 2009 and 2013 were for cancer indications.3 That study also determined that postmarketing examination of anticancer drugs approved with an accelerated approval label commonly languish on the market for at least 5 years before manufacturers release any data validating the safety and efficacy of the medications.


  1. Puthumana J, Wallach JD, Ross JS. Clinical trial evidence supporting FDA approval of drugs granted Breakthrough Therapy designation. JAMA. 2018;320(3):301-303.
  2. Hwang TJ, Franklin JM, Chen CT, et al. Efficacy, safety, and regulatory approval of Food and Drug Administration–designated Breakthrough and nonbreakthrough cancer medicines. J Clin Onc. 2018;36(18):1805-1812. doi: 10.1200/JCO.2017.77.1592
  3. Zettler M, Nabhan C. Fulfillment of postmarketing requirements to the FDA for therapies granted oncology indications between 2011 and 2016 [published online May 10, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.0610

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