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Ineffective study endpoints, poor dose selection account for most delays in FDA NDAs
Some of the most common setbacks in the FDA approval of new drugs, including suboptimal drug dose selection and unsatisfactory study endpoints, are potentially avoidable, a new study has found.
The retrospective review amassed 302 applications for new molecular entities (NMEs) submitted to the FDA between 2000 and 2012. The researchers analyzed information in the FDA’s action letters, which are sent to failed applications, as well as in-house and publicly circulated FDA evaluations and correspondence. They established the following four categories for the documented shortcomings of the applications: efficacy, safety, chemistry/manufacturing/controls (CMC) and product labeling.
The study found that of the 302 NME applications, 151 (50%) were approved upon initial submission and 222 (73.5%) were eventually approved. One or more resubmissions were necessary for 71 applications prior to ultimate approval, with a median delay to approval of 435 days after the first failed submission. Of the applications that failed to secure initial approval, 24 (15.9%) included ambiguities involving dose selection, 20 (13.2%) used study endpoints that did not yield a clinically meaningful result, 20 (13.2%) produced inconsistent results when different endpoints were applied, 17 (11.3%) yielded inconsistent outcomes when compared to different study sites or trials, and 20 (13.2%) delivered inadequate efficacy compared to the standard of care.
The prevalence of safety inadequacies was found to be similar in the never-approved drugs vs. those eventually approved (43 of 80 never approved [53.8%] vs. 37 of 71 with delayed approval [52.1%]; difference: 1.7% [95% CI, -14.86% to 18.05%]). There was, however, a significantly higher rate of efficacy deficiencies among the never-approved drugs compared with delayed-approval drugs (61 of 80 never approved [76.3%] vs. 28 of 71 delayed approval [39.4%]; difference: 36.9% [95% CI, 20.2% to 50.86%]).
“For drug developers and clinical investigators, our findings suggest areas of deficiencies in new drug applications in which strategies for drug development could be improved,” the researchers wrote. “Early and frequent dialogue between the FDA and drug sponsors addressing critical aspects of study design has the potential to reduce delays in the approval of new drugs.”
Disclosure: The researchers report no relevant disclosures.