The use of observed-to-expected analyses as a signal detection tool in COVID-19 vaccine safety surveillance: lessons learned from an industry perspective.

During the pandemic, the accelerated review and authorization of coronavirus disease 19 (COVID-19) vaccines by regulatory authorities elicited the need for rapid and thorough worldwide signal detection and evaluation. To meet this need, the European Medicines Agency and other health authorities expected that, in addition to routine signal detection, COVID-19 vaccine manufacturers should leverage observed-to-expected (O/E) analyses unconventionally as a quantitative method for signal detection of adverse events of special interest (AESIs). The objective of O/E analyses in vaccine signal detection was to determine if AESIs were occurring at a higher-than-expected rate in the vaccinated population in comparison with an unexposed population. The use of O/E was intended to mitigate the challenge of analyzing large volumes of individual case safety reports (ICSRs) received over a very short period following mass vaccination campaigns. The "Beyond COVID-19 Monitoring Excellence" (BeCOME) initiative, a non-competitive voluntary initiative launched in 2022 by COVID-19 vaccine Marketing Authorization Holders (MAHs) and key stakeholders, was established to align systems, enhance processes, and foster innovation in post-marketing vaccine monitoring, building on lessons from the pandemic. A dedicated working group was created to review and share MAHs' experience on O/E analyses used as an additional tool for signal detection during the COVID-19 pandemic. This review presents the industry perspective on using O/E analyses for COVID-19 vaccine signal detection, including challenges and limitations encountered, and proposes best practices for future improvement. Despite the priority and resources devoted to O/E analyses, no