I’ve been hearing a lot of complaints about this lately. A JAMA manuscript is on point this week:
Importance Some new drug applications fail because of inadequate drug performance and others are not approved because the information submitted to the US Food and Drug Administration (FDA) is unsatisfactory to make that determination. Resubmission of failed applications is costly, delaying marketing approval and the availability of new drugs to patients.
Objective To identify the reasons that FDA marketing approval for new drugs was delayed or denied.
Design, Setting, and Participants A retrospective review of FDA documents and extraction of data were performed. We examined all drug applications first submitted to the FDA between 2000 and 2012 for new molecular entities (NMEs), which are active ingredients never before marketed in the United States in any form. Using FDA correspondence and reviews, we investigated the reasons NMEs failed to obtain FDA approval.
Main Outcomes and Measures Reasons for delayed FDA approval or nonapproval of NME applications.
Results Of the 302 identified NME applications, 151 (50%) were approved when first submitted and 222 (73.5%) were ultimately approved. Seventy-one applications required 1 or more resubmissions before approval, with a median delay to approval of 435 days following the first unsuccessful submission. Of the unsuccessful first-time applications, 24 (15.9%) included uncertainties related to dose selection, 20 (13.2%) choice of study end points that failed to adequately reflect a clinically meaningful effect, 20 (13.2%) inconsistent results when different end points were tested, 17 (11.3%) inconsistent results when different trials or study sites were compared, and 20 (13.2%) poor efficacy when compared with the standard of care. The frequency of safety deficiencies was similar among never-approved drugs compared with those with delayed approval (43 of 80 never approved [53.8%] vs 37 of 71 eventually approved [52.1%]; difference, 1.7% [95% CI, −14.86% to 18.05%]; P = .87). However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals (61 of 80 never approved [76.3%] vs 28 of 71 eventually approved [39.4%]; difference, 36.9% [95% CI, 20.25% to 50.86%]; P < .001).
Please recognize that this study looked at ALL drugs from 2000 through 2012. So please don’t come at me with an anecdote; it’s included in this study.
Were drugs sometimes not approved on the first pass? Sure. But the reasons why seem legitimate to me. Uncertainties related to dose selection? Study end points not reflecting a clinically meaningful effect? Inconsistent results? Poor efficacy? All of them seem reasonable.
Moreover, some of this stuff is terrible. More than half of drugs refused approval had safety deficiencies? More than three quarters of them had efficacy deficiencies? Yeah, I’m glad the FDA was checking.
I imagine it’s possible to interpret these results as an over-zealous regulatory body at work. But I don’t think that would be easy. Prove me wrong.
