Post-Approval Safety Studies of Vaccines in Pregnancy: Available Regulatory Guidance and Next Steps Towards the More Efficient Generation of Safety Evidence

Sarah C MacDonald^1*Adrienne Guignard²Flor M Munoz³Eileen Dareng⁴Kourtney Davis⁵Marina Amaral de Avila Machado⁶Shahar Shmuel⁷Laura Taddei⁸Lydie Marcelon⁹

• ¹Pfizer, Inc, Ottawa, Canada
• ²GlaxoSmithKline, Wavre, Belgium
• ³Baylor College of Medicine, Houston, United States
• ⁴AstraZeneca, Cambridge, United Kingdom
• ⁵Johnson & Johnson, Horsham, United States
• ⁶Sanofi, Toronto, Canada
• ⁷Pfizer Inc, New York, United States
• ⁸GlaxoSmithKline, Siena, Italy
• ⁹Sanofi, Lyon, France

Background: The “Beyond COVID-19 Monitoring Excellence” (BeCOME) initiative was established to leverage the successful multi-stakeholder collaborations achieved during the COVID-19 pandemic to increase efficiencies for future pandemic preparedness. At the first BeCOME cross-stakeholder meeting, the following key challenge was identified: Inconsistent guidance from regulatory authorities on the conduct of post-marketing safety studies in pregnant people. Objectives: This article aims to describe examples of post-approval safety studies sponsored by marketing authorization holders (MAHs) for vaccines in pregnancy, analyze existing regulatory guidelines for these studies, and identify areas warranting more detailed guidance. Example Studies: Fifteen vaccine post-approval safety studies in pregnant people with publicly available methodology were identified from the European Union (EU) Post-authorisation Study (PAS) Register and supplemented by a literature search. Studies were selected to cover both primary data collection and secondary use of data, as well as for vaccines recommended and not recommended during pregnancy. The identified studies varied in their type (active vs. passive surveillance), comparators, outcomes, exposure windows, target sample sizes, and study durations. Existing Guidance: Five applicable guidance documents were identified from two health authorities (the United States [US] Food and Drug Administration [FDA] and the European Medicines Agency [EMA]), ranging in publication date from 2005-2023. Available guidance from both agencies included robust discussions of comparator groups, outcomes, and exposure periods. However, vaccine-specific recommendations were notably lacking. Actionable Recommendations: Additional vaccine-specific guidance is needed across regulatory authorities. Key areas of focus should include: the selection of study design by vaccine type, appropriate comparators for vaccine research, vaccine-specific recommendations for ascertaining exposure, a harmonized and prioritized list of outcomes, greater understanding of the role of outcome validation, pre-defined target minimal detectable risks by priority outcomes, appropriate durations of follow-up, additional guidance regarding the implementation of multi-stakeholder collaborations, and a framework for the use of rapid cycle analyses. Conclusions: There is wide variation in study designs and approaches for assessing vaccine safety in pregnancy post-approval, influenced by differences in vaccines, target populations, sponsors, and study periods. Harmonizing regulatory guidance and standards will enhance the consistency of data collection, as well as the comparability and validity of study conclusions.