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A review of 151 drug application rejection letters unveils the most common and problematic efficacy and safety deficiencies in new drug submissions.

The lowdown: Complete response letters — in which US drug regulators lay out their reasons for rejecting drug applications — are bad news for drug developers. But some letters are worse than others. To get a grasp on the types of issues that sink submissions, and the implications of the different problems, the FDA has now released a retrospective review of complete response letters to 151 rejected regulatory applications for new molecular entities (NMEs) issued between 2000 and 2012 (JAMA 311, 378–384; 2014). Safety issues are easier to overcome on resubmission than are efficacy issues, the agency concludes.

In their heuristic analysis, Leonard Sacks, of the FDA, and his colleagues first classified complete response letters depending on whether they flagged up efficacy deficiencies (32%), safety deficiencies (26%), efficacy and safety deficiencies (27%), or chemistry, manufacturing and controls (CMC) and/or labelling problems (15%). Of the efficacy deficiencies, the most common problem was poor dose selection, which the authors note can be avoided with adaptive trial designs or other dose optimization strategies. Poor end point selection and inconsistent results when multiple end points were used also made up a large proportion of the efficacy deficiencies. On the safety side, clinically observed adverse events were the most likely to preclude a first-round approval. Theoretical risks related to drug mechanisms of action, structure or class were noted in 7% of first-round complete response letters.

Of 151 NMEs that received first-round complete response letters, 87 were resubmitted during the study's timeline. Of these, 71 were eventually approved (78% were approved on their second review, 18% after their third review and 4% after further rounds of review). But whereas 62% of resubmitted drugs with safety concerns alone were subsequently approved, only 31% of resubmitted drugs with efficacy concerns alone ever got an eventual green light. This discrepancy could be because safety problems can be addressed by appropriate labelling and risk management strategies, the authors note. Of 11 drugs that were rejected on their first review owing to increased overall mortality, none was approved upon resubmission.

“Our findings suggest areas of deficiencies in new drug applications in which strategies for drug development could be improved,” the authors write.