Challenges and Opportunities for Signal Detection During Public Health Emergencies: An Historical Re-evaluation of the Disproportionality Analysis of the ADR Reporting of Anti-COVID-19 Monoclonal Antibodies in Vigibase

Introduction: Anti-spike monoclonal antibodies (mAbs) for early treatment of COVID-19 represented a significant improvement in the pharmacological management of the SARS-COV-2 pandemic, especially in early phases, but the continuous emergence of novel virus variants of concern (VoC) required a rapid and continuous benefit-risk assessment. Objective: To identify possible unexplored safety signals of anti-SARS-CoV-2 mAbs through disproportionality analysis using VigiBase, the World Health Organization (WHO) global pharmacovigilance database. Methods: We conducted a disproportionality analysis of VigiBase (February 2020-December 2023). All de-duplicated individual case safety reports (ICSRs) for bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, regdanvimab, sotrovimab, and tixagevimab/cilgavimab were retrieved. Descriptive analyses of ICSRs and distribution of suspected adverse drug reactions across VoC-defined periods (Alpha, Delta, Omicron) were performed. Disproportionality analysis was conducted and reported in accordance with the READUS-PV guideline. Reporting odds ratios (RORs) with 95% confidence intervals (CI) were calculated at the MedDRA Preferred Term (PT) level, using the entire database as reference (excluding vaccines). Statistically significant drug-adverse reaction pairs included in the EMA Important Medical Event (IME) list and not described in the Summary of Product Characteristics (SmPC) were identified as potential safety signals. Results: Among 15,250 de-duplicated ICSRs, casirivimab/imdevimab accounted for the majority of reports (33.5%). Most cases involved female patients aged 45-64 years, predominantly reported from the Americas. Overall, 42,799 drug-adverse reaction pairs were identified, 33,948 (79.3%) of which were identified after filtering out, and 3047 (9.0%) were IMEs. Eighty-three unique drug-adverse reaction pairs had a statistically significant RORs, among which 56 (67.5%) were not listed in the SmPC. Bamlanivimab, as both monotherapy and in combination with etesevimab, showed increased reporting of several cardiac adverse events, including acute myocardial infarction (MI) and cardiac arrest. For tixagevimab/cilgavimab, disproportionality was found for acute MI (N = 6; ROR 12.7, 95% CI 5.7-28.4) and atrial fibrillation (N = 29; ROR 9.0, 95% CI 6.2-13.0). For regdanvimab, disproportionality emerged for hypokalemia (N = 13; ROR 5.8, 95% CI 3.4-10.1). For casirivimab/imdevimab, 5 out of 15 PTs were classified as adverse event of special interest: seizure-like phenomena (N = 8; ROR, 44.2; 95% CI 21.9-89.1), Guillain-Barré syndrome (N = 6; ROR 13.4, 95% CI 6.0-30.0), encephalopathy (N = 13; ROR 5.4, 95% CI 3.1-9.3), generalized tonic-clonic seizure (N = 9; ROR 5.0, 95% CI 2.6-9.7), and seizure (N = 57; ROR 3.1, 95% CI 2.4-4.0). Conclusion: This analysis identified potential cardiovascular and neurological safety signals, which will remain unexplored by longitudinal pharmacoepidemiologic studies due to the withdrawal of these agents from clinical use. Overall, this case study supported the full implementation of near real-time multimodal approaches to efficiently perform actionable signal management during public health emergencies.