Hong HL, Garcia de Albeniz X, Butler AMM, Whitaker H, Suchard MA. Methodological approaches to evaluating the safety and effectiveness of multi-dose coronavirus disease 2019 (COVID-19) vaccines series. Presented at the Virtual ICPE 2021 Conference; August 24, 2021.

BACKGROUND: Real-world utilization of COVID-19 vaccines may differ from clinical trials with respect to dosing and spacing. To study the safety and effectiveness of multi-dose COVID-19 vaccine series, investigators must consider several methodological challenges, including attributing risk or effectiveness to dose schedules, immortal-time bias, and overlapping risk windows following vaccinations. This Vaccine Special Interest Group-endorsed symposium will highlight methods to address these challenges to support regulatory decision-making.

OBJECTIVES: To illustrate challenges and propose methodologic approaches for validly assessing the real-world safety and effectiveness of multi-dose COVID-19 vaccine series in study designs of cohort, case-control, self-controlled case series (SCCS), and rapid cycle analyses.

DESCRIPTION: The symposium will include a 5-minute overview on the US Food and Drug Administration (FDA) national active surveillance systems for COVID-19 vaccines, i.e., Biologics Effectiveness and SafeTy (BEST) Initiative (Dr. Wong), four 15-minute presentations followed by 5-minute Q&A each, and a 20-minute panel discussion.

(1) Methods to assess different dosing of COVID-19 vaccines. Dr. García de Albéniz will discuss causal inference-based methodological approaches to study the effectiveness and safety of different dosing (e.g. half dose, 1 dose, and 2 doses) of COVID-19 vaccines for cohort and case-control studies.
(2) Methods to study variable spacing of COVID-19 doses. Dr. Butler will demonstrate a novel application of an inverse probability censoring-weighted estimation approach to estimate the effects of different multi-dose vaccine series, using an example from a cohort study on rotavirus vaccine schedules. The applicability of this approach to study COVID-19 vaccines and several challenges will be discussed.
(3) Heterogeneous dosing and spacing of COVID-19 vaccinations in SCCS. Dr. Whitaker will discuss methodological considerations for SCCS studies to evaluate the transient risk of adverse events following multi-dose COVID-19 vaccines, focusing on the previous extensions to SCCS to examine death or adverse events that may contraindicate vaccination.
(4) Rapid safety signal detection of multi-dose COVID-19 vaccine series. Dr. Suchard will provide an overview of methods for rapid signal detection performance (e.g., historical and contemporaneous comparators) with 1-dose versus 2-dose vaccines and compare methods performance between 1-dose vaccines (e.g., seasonal flu in adults) versus 2-dose vaccines (e.g., recombinant zoster) as examples.

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