FDA analysis of the characteristics and relevance of serious adverse events that are Grade 1 or 2 in severity.

Abstract

2538 Background: In New Drug Approval (NDA) applications, sponsors must provide an integrated summary of the safety of the drug product, including serious adverse events (SAEs), defined as adverse events (AE) resulting in death, life-threatening AEs, inpatient hospitalization or prolongation of hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grades the severity of AEs from 1 (mild) to 5 (death). This analysis attempts to quantify and characterize Grade 1-2 toxicities reported as SAEs. Methods: We reviewed SAEs from registrational trials submitted in nine NDAs for new molecular entities approved by FDA in 2014. Results: A total of 28,467 AEs were reported in 1,699 patients, of which 2,073 (7.3%; range 3.2- 10.9) were reported as SAEs. Of these 2,073 SAEs, 528 (25.5%; range 15.5-37.5) were Grade 1-2. Of 1,489 hospitalizations reported as SAEs, 93 (7.6%) reported no Grade 3-5 toxicities. Forty-four (8.3%) Grade 1 or 2 SAEs were not listed in the CTCAE dictionary, including dosing errors, catheter placement, and hospitalization for observation. A total of 65 (12.3%) Grade 1-2 SAEs were reported concomitantly with Grade 3-5 SAEs (e.g., Grade 2 fever with Grade 4 pneumonia). Of all Grade 1-2 SAEs, 24 (4.5%) were related to medication errors not resulting in toxicity; 57 (10.8%) were infections; 51 (9.6%) were neurologic complications; 44 (8.3%) were pyrexia; 28 (5.3%) were metabolic disturbances and 16 (3%) were abnormal laboratory findings; 12 (2.2%) were related to device/catheter complications. Fourteen SAEs were erroneously reported as Grade 1-2; i.e., CTCAE only defined the events as Grade 3 to 5 in severity (e.g., septic shock). Conclusions: A significant amount of time is spent by applicants, investigators, cooperative groups, and FDA conducting analyses of both SAEs and AEs by CTCAE grade. In most cases, this is a duplication of efforts. Most reported Grade 1-2 events were, by definition, non-severe. Minor changes in the CTCAE definition and/or SAE definition could serve to streamline clinical trial processes.