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FDA’s ‘Breakthrough Therapy’ Program a Big Success, Analyst Says

Nine drugs approved in 2014

The 2-year-old “breakthrough therapy” program initiated by the FDA to speed up the approval and availability of groundbreaking therapies has been a widespread success, according to a recent analysis.

“According to the FDA, the biggest factor in deciding to grant BTS [‘breakthrough therapy’ status] is the ‘magnitude of the treatment effect,” said Dr. Mark Schoenebaum, an analyst with Everscore ISI. In addition, the successful requests “in general” showed a reduction in the risk of the event of interest of “over 50 percent,” he said.

Schoenebaum found that the FDA’s Center for Drug Evaluation and Research has received 206 applications for BTS. Of these, 62 were granted, 101 were denied, and two were withdrawn.

“Bear in mind these stats are dynamic,” Schoenebaum said. “Thus, many of the 206 applications are presumably still being evaluated.”

Moreover, the FDA’s Center for Biologics Evaluation and Research has received 37 applications for BTS, of which seven have been granted and 27 denied so far.

In 2013, three drugs granted BTS were approved: Gazyva (obinutuzumab, Genentech) for chronic lymphocytic leukemia (CLL); Imbruvica (ibrutinib, Pharmacyclics/Janssen Biotech) for CLL; and Sovaldi (sofosbuvir, Gilead) for hepatitis C.

In 2014, there were nine approvals: Kalydeco (ivacaftor, Vertex) for cystic fibrosis; Arzerra (ofatumumab, GlaxoSmithKline) supplement for CLL; Zykadia (ceritinib, Novartis) for non–small-cell lung cancer (NSCLC); Zydelig (idelalisib, Gilead) for CLL, follicular B-cell non-Hodgkin lymphoma, and small lymphocytic lymphoma; Imbruvica supplement for CLL; Promacta (eltrombopag, GlaxoSmithKline) supplement for aplastic anemia; Keytruda (pembrolizumab, Merck) for melanoma; Ofev (nintedanib, Boehringer Ingelheim) for idiopathic pulmonary fibrosis (IPF); and Esbriet (perfenidone, InterMune) for IPF. One BTS drug –– serelaxin (Novartis) –– was denied approval for the treatment of heart failure.

“If the endpoint is survival, the FDA specifically notes that ‘lesser improvements’ could be adequate,” Schoenebaum said. “The FDA has emphasized, however, that a specific efficacy ‘bar’ probably isn’t possible to precisely identify ‘because of the wide range of conditions and endpoints studied.’ That said, the FDA has stated that ‘in general, improvements of 10 percent over comparator do not seem to be BT territory.”

According to the FDA, factors that favored the granting of BTS include higher enrollment, more and larger-phase trials, and applications that have a “genetic/targeted” component. Specifically, the median trial enrollment for granted versus denied applications was 88 vs. 51; the maximum trial phase for granted versus denied applications was 1.94 vs.1.73; the trial count was 1.53 vs. 1.23; and the granted versus denied rates for applications with or without a genetic or targeted component was 38% vs. 20%.

“Perhaps surprisingly, successful applications were more likely than denials to have some form of alternative therapy available for the disease,” Schoenebaum noted.

Factors that did not appear to influence the likelihood of BTS approval included a “rare” or “orphan” status and the existence of evidence from randomized trials.

“Most denied applications were turned down for trial design and trial data issues,” Schoenebaum said. “In 66 percent of the denials, the FDA cited lack of efficacy. In 16 percent, the agency cited lack of safety. Forty-three percent of denied applications exhibited trial-design flaws.”

Source: BioSpace; December 31, 2014.

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