Challenges and Insights from the Mepolizumab Pregnancy Exposure Study.

Pregnant women are often excluded from clinical trials owing to uncertainty about fetal safety and adverse pregnancy complications. As such, little is known about the effect of medications on pregnancy at the time of marketing. Post-marketing data are therefore important for establishing the safety of treatments in pregnancy, particularly in chronic diseases requiring long-term therapy. Mepolizumab (NUCALA), a first-in-class biologic treatment for patients with severe eosinophilic asthma, was first approved in the United States (US) and European Union (EU) in 2015 as an add-on maintenance treatment for adult and adolescent patients. At the time of marketing, pregnancy safety data for mepolizumab was limited. To address this gap, a Post-Authorization Safety Study (PASS) was conducted-a pregnancy registry to monitor pregnancies exposed to mepolizumab and evaluate the possible teratogenic effect of this medication compared with women treated with other anti-asthmatics and those without asthma. The Mepolizumab Pregnancy Exposure Study (GSK ID: 200870; EU PAS Number: EUPAS13772), a phase IV, prospective, observational exposure registry, was initiated in 2016 by the Organization of Teratology Information Specialists (OTIS) Research Center. Despite extensive recruitment efforts, enrollment into the mepolizumab-exposed cohort remained low during the 5-year enrollment period. In contrast, robust enrollment in the anti-asthmatic comparison cohort was achieved, suggesting both the ability to recruit pregnant women with asthma and the limited use of mepolizumab in pregnancy. The Mepolizumab Pregnancy Exposure Study was ultimately closed in 2024 due to inadequate recruitment. This commentary presents the challenges experienced in the Mepolizumab Pregnancy Exposure Study and describes a pragmatic decision-making framework aimed at mitigating similar issues in future post-marketing pregnancy safety studies, particularly in the context of low treatment exposure in individual population-level data sources. This framework considers important inputs such as prior experience with treatment in the same therapeutic area, background maternal and fetal risks, and potential treatment utilization in the population of interest. A principal recommendation stemming from this framework is the implementation of enhanced worldwide pharmacovigilance, which offers a more robust and structured approach to data collection than standard pharmacovigilance methods, thereby improving information quality and enabling the capture of important variables and confounders, when the exposure rate is low in a population and registry or other database studies cannot reasonably be conducted. However, given the inherent limitations of pharmacovigilance in generating definitive safety conclusions, enhanced data collection methods serve as a pragmatic and necessary tool for ongoing surveillance, to aid in providing information until other types of study designs becoming feasible.