Original Investigation |

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

Leonard V. Sacks, MBBCh1; Hala H. Shamsuddin, MD2; Yuliya I. Yasinskaya, MD2; Khaled Bouri, PhD, MPH3; Michael L. Lanthier, BA4; Rachel E. Sherman, MD, MPH1
[+] Author Affiliations
1Office of Medical Policy, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
2Office of Antimicrobial Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
3Office of Critical Path Programs, Office of the Commissioner, US Food and Drug Administration, Silver Spring, Maryland
4Office of the Commissioner, US Food and Drug Administration, Silver Spring, Maryland
JAMA. 2014;311(4):378-384. doi:10.1001/jama.2013.282542.
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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).

Conclusions and Relevance  Several potentially preventable deficiencies, including failure to select optimal drug doses and suitable study end points, accounted for significant delays in the approval of new drugs. Understanding the reasons for previous failures is helpful to improve the efficiency of clinical development for new drugs.

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Flow Diagram of Outcomes for New Molecular Entities Submissions to the Center for Drug Evaluation and Research of the US Food and Drug Administration Between 2000 and 2012

FDA indicates US Food and Drug Administration.

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