Outcomes of post-approval non-interventional safety studies in pregnancy: wide variation demonstrates need for...

Upon product approval, sponsors are often required by regulatory authorities (e.g., the United States [US] Food and Drug Administration [FDA] or the European Medicines Agency [EMA]) to conduct post-approval safety studies in pregnant populations. Existing guidance from regulatory authorities provide important recommendations of study outcomes to evaluate in such studies, however harmonized guidance on a priority list of outcomes that all studies must evaluate is currently lacking. This creates inefficiencies in study conduct and limits comparability.

The article aims to summarize outcomes that are currently being studied across post-approval safety studies in pregnancy and assess the influence of study-related factors on the evaluated outcomes.

A query of post-approval non-interventional pregnancy safety studies registered on the Heads of Medicines Agency [HMA]-EMA Catalogue of Real-world Data [RWD] Studies was conducted, and relevant studies and their protocols were extracted for evaluation. Outcomes were summarized overall and by factors such as data collection method, product type, protocol year, and regulatory agency commitment.

Among approximately 3100 studies identified in the catalogue, 30 studies met eligibility criteria for inclusion. The most common outcomes were stillbirth (N = 25 studies), congenital malformations (major or minor) (N = 24), spontaneous abortion (N = 22), small for gestational age or fetal growth restriction (N = 21), and preterm birth or labor (N = 21). Some differences in evaluated outcomes were observed by study characteristics (e.g., regulatory agency commitment, data collection methods, type of active substance, date of protocol). No outcomes were evaluated in all of the studies and none of the studies evaluated all FDA or EMA-recommended outcomes. Sample sizes from completed studies were generally low (median: 110) and few studies had sufficient power to examine commonly evaluated outcomes such as stillbirth and congenital malformations.

There was a wide variety of outcomes examined across post-marketing safety studies in pregnancy. Additional harmonized regulatory guidance on required outcomes will improve consistency across studies, allowing for meaningful comparisons and for the more efficient use of existing data.