Novel Adverse Events of Bevacizumab in the US FDA Adverse Event Reporting System Database A Disproportionality Analysis

Background: Bevacizumab is the first in its class, vascular endothelial growth factor (VEGF) inhibitor that was initially approved by the US FDA in 2004 for the treatment of metastatic colon cancer and other solid tumors. Pre-approval clinical trials, particularly for oncology drugs, are limited in their ability to detect certain adverse effects and, therefore, the FDA and pharmaceutical sponsors collect and monitor reports of adverse events (AEs) following approval. Objective: The purpose of this study was to screen the FDA's Adverse Event Reporting System (AERS) database for novel AEs that may be attributed to bevacizumab. Methods: The FDA AERS database was used to identify all AE reports for bevacizumab from February 2004 to September 2009. Disproportionality analysis was conducted for bevacizumab against all other drugs in the background by setting statistical significance at proportional reporting ratio (PRR) >= 2, observed case count >= 3 and chi-square >= 4. Subsequent clinical evaluation was performed to determine the clinical relevance of the findings and to group related events. Results: A total of 523 Preferred Terms (PTs) were disproportionally reported; following clinical review 63 (12%) were found to be both unlabelled and of clinical importance. These PTs were grouped into 15 clinical disorder groups. Among the clinical disorders, electrolyte abnormalities had the greatest number of reports (n=426) followed by cardiovascular events (n=421), gastrointestinal events (n=345), nervous system disorders (n=106) and pneumonitis (n=96). On sensitivity analysis, a number of clinically important unlabelled disorders, such as necrotizing fasciitis, vessel wall disorders, arrhythmia and conduction disorder and autoimmune thrombocytopenia still met the statistical significance criteria. Conclusions: During the study period, out of 12 010 AE reports mentioning bevacizumab, it was listed as the suspect drug in 94.2% of the reports. Our disproportionality analysis identified many events that are already recognized as AEs of bevacizumab, but it also identified a number of clinically important unlabelled terms, which if confirmed in future studies would have potential implications for use of bevacizumab in clinical practice.