FDA analysis of grade 3-4 safety events.

Abstract

2544 Background: In new drug/biologics applications, safety data provided to FDA include serious adverse events (SAEs), defined as adverse events (AEs) resulting in death, life-threatening AE, inpatient hospitalization or prolongation of hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or congenital anomaly/birth defect. One limitation of the SAE definition is that hospitalization practices differ across localities and among medical practitioners. Therefore, a safety signal may not be adequately reflected when analyzing SAEs. We hypothesize that evaluating CTCAE Grade 3 (severe) and Grade 4 (life-threatening) AEs, independent of whether or not these were classified as serious, provides a more complete assessment of patient safety. Methods: We reviewed SAEs from all nine registrational trials for new molecular entities approved for the treatment of cancer by the FDA in 2014. Results: A total of 25,548 AEs were reported in 1,781 patients treated with an investigational agent. There were 2,943 Grade 3-4 AEs and 912 Grade 3-4 SAEs. Information regarding hospitalization was available in 62% of Grade 3-4 AEs. Fifty-five percent of Grade 3-4 SAEs vs. 5.5% of Grade 3-4 non-serious AEs resulted in hospitalization. Several clinically serious Grade 3-4 AEs, including sepsis and respiratory failure, were not classified as SAE. Conclusions: There is significant overlap in most common Grade 3-4 AEs and most common Grade 3-4 SAEs. Most AEs that are clinically serious were appropriately classified as SAE. However, some clinically serious AEs and some AEs resulting in hospitalization were not classified as SAE. With the exception of information regarding hospitalization, characterization of the reason why certain AEs were classified as SAEs was not possible. In this pooled analysis, data from the analysis of AEs by severity was more informative than the analyses by SAEs. [Table: see text]