Background Incidence Rates from Electronic Healthcare Databases for Vaccine Safety Monitoring: Review of Challenges from the COVID-19 Vaccination Campaign and Proposal for Best Practices

Sonja Banga^1*Laurence Serradell²Deborah Layton³Jill Dreyfus⁴Nicolas Praet⁵Diana C. Garofalo⁴Vincent Bauchau⁶Scott Kelly⁴Lin Li^7*

• ¹Epidemiology and Real-World Sciences, Quantitative Sciences, Astra Zeneca Alexion, Mississauga, ON, Canada
• ²Epidemiology and Benefit Risk, Patient Safety & Pharmacovigilance, Sanofi, Lyon, France
• ³PEPI Consultancy Limited, Southampton, United Kingdom
• ⁴Global Medical Epidemiology, Pfizer, Inc., New York, NY, United States
• ⁵Global Epidemiology Organization, Johnson & Johnson, Beerse, Belgium
• ⁶Independent, Previously Vaccine Safety, GlaxoSmithKline (GSK), Wavre, Belgium
• ⁷Epidemiology and Benefit Risk, Patient Safety & Pharmacovigilance, Sanofi, Morristown, NJ, United States

Background incidence rates (BIRs) are essential for contextualizing adverse event rates in vaccine safety monitoring, particularly through observed-to-expected (O/E) analyses. The unprecedented rapid development of vaccines during the coronavirus disease 2019 (COVID-19) pandemic necessitated rigorous and continuous safety monitoring. While BIRs are traditionally obtained from literature reviews, the pandemic accelerated the large-scale generation of BIRs from electronic healthcare databases through various initiatives such as the vACCine covid-19 monitoring readinESS (ACCESS) and the Biologics Effectiveness and Safety (BEST) to support COVID-19 vaccine safety surveillance strategies. The Beyond COVID-19 Monitoring Excellence (BeCOME) initiative, launched in 2022, established seven working groups, including one focused on best practices for BIR generation and utilization in pharmacovigilance activities. The BeCOME BIR working group conducted a targeted literature review to enable focused analysis of challenges that emerged during large-scale vaccination campaigns through December 2023. The group also used structured group discussion following the nominal group technique over 10 months to develop consensus-based judgments on critical factors for BIR best practices. The findings were organized into four domains: key initiatives summary, pandemic-related challenges, implications for O/E analyses, and best practice recommendations. To identify key BIR initiatives supporting COVID-19 vaccine safety assessment, the review employed multiple strategies including scientific literature examination, public health authority website reviews, and reference list searches; data on study characteristics, limitations, challenges, and recommendations were extracted. The targeted review focused on five major initiatives, such as ACCESS and BEST, that generated BIRs for adverse events of special interest (AESIs) during the pandemic. The group identified persistent challenges during the vaccination campaign including timeliness constraints during rapid vaccine deployment, substantial heterogeneity across data sources, inconsistent case definitions, limited information for key subpopulations, and difficulties addressing emerging AESIs. These challenges directly impacted O/E analyses, potentially leading to biased safety signal assessments. We propose a coordinated action plan among key stakeholders to establish sustainable mechanisms for regular BIR delivery with methodological improvements, develop consensus on best practices for BIR selection, and secure resources to ensure pandemic preparedness. Implementing these recommendations will strengthen vaccine safety monitoring systems for both routine vaccination programs and future public health emergencies.