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

• Autores: Leonard V Sacks, Hala H. Shamsuddin, Yuliya I. Yasinskaya, Khaled Bouri
• Localización: JAMA: the journal of the American Medical Association, ISSN 0098-7484, Vol. 311, Nº. 4, 2014, págs. 378-384
• Idioma: inglés
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• Resumen

  • 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.

    The road from medical product discovery to marketing is typically long and costly. The interval between initial clinical testing and product approval has been estimated to average 8 years1 and only 1 in 6 drugs entering clinical trials ultimately obtains US Food and Drug Administration (FDA) approval.2To obtain marketing approval for new drugs, developers must provide substantial evidence of safety and efficacy for the proposed indication.3 In a number of failed applications, deficiencies are successfully addressed in resubmissions resulting in delayed approval, whereas others are never approved for marketing. Nonapproval of drugs is critical to prevent the marketing of ineffective or harmful products. However, many drugs are not approved not because they are unsafe or ineffective, but because the information is unsatisfactory to make that determination. Delays and failures that occur late in development affect the availability of innovative new drugs and increase the costs of drug development.4 To avoid preventable late-stage deficiencies in drug development and their negative consequences, it is important to understand the nature of these deficiencies.

    We reviewed marketing applications for new molecular entities (NMEs) submitted to the FDA to characterize the scientific and regulatory reasons approval was delayed or denied.