Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012

Study Questions:

What are the reasons that Food and Drug Administration (FDA) marketing approval for new drugs was delayed or denied?


This was a retrospective review of FDA documents and extraction of data was performed. The investigators 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, the authors investigated the reasons NMEs failed to obtain FDA approval. The main outcomes measures were reasons for delayed FDA approval or nonapproval of NME applications.


Of the 302 identified NME applications, 151 (50%) were approved when first submitted and 222 (73.5%) were ultimately approved. Seventy-one applications required one 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 endpoints that failed to adequately reflect a clinically meaningful effect, 20 (13.2%) inconsistent results when different endpoints 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% confidence interval, −14.86% to 18.05%]; p = 0.87). 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% confidence interval, 20.25%-50.86%]; p < 0.001).


The authors concluded that several potentially preventable deficiencies accounted for significant delays in the approval of new drugs.


This study suggests that potentially preventable deficiencies, including failure to select optimal drug doses and suitable study endpoints, accounted for significant delays in the approval of new drugs. Failure to determine the most appropriate dose for clinical use was a major reason for nonapproval. These findings may be helpful to clinicians and policy makers in interpreting the extensive literature reporting the design and outcome of clinical trials, which in turn may have an effect on practice. For drug developers and clinical investigators, these findings suggest areas of deficiencies in new drug applications in which strategies for drug development and trial design could be improved.

Keywords: Drug Approval, United States Food and Drug Administration, Marketing

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