(SLC-017) Trends in FDA Comments on the Design, Conduct, and Analysis of Pregnancy Exposure Registries: A Summary of Findings at a Clinical Research Organization (CRO)

Background: Sponsors of pregnancy exposure registries, required by the FDA as part of post-marketing requirements or post-marketing study commitments, must submit study protocols for FDA review and approval. Conducting pregnancy exposure registries utilizing formal, robust protocols and statistical analysis plans (SAPs) ensures consistency in data collection, analysis, and data interpretation.

Objectives: To summarize the FDA’s comments and recommendations on the design, conduct, and analysis of prospective pregnancy exposure registries protocols and SAPs, highlighting trends in comments from the agency.

Methods: We reviewed FDA comments from 12 prospective pregnancy exposure registries (using primary and secondary data collection) received in 2023 and 2024. The comments, covering protocols and SAPs for both global studies (including the US) and studies based solely in the US, were categorized into the following high-level areas: awareness/enrollment, study design, data collection, statistical analysis, outcome definition and ascertainment, and other.

Results: We identified protocols and SAPs for 12 pregnancy exposure registries submitted to the FDA between 11 August 2022 and 10 October 2024, with comments received from 17 February 2023 to 24 December 2024. Of the 12 registries, 7 evaluate the safety of autoimmune and anti-inflammatory drugs, 2 of central nervous system drugs, 1 vaccine, 1 gastroenterology drug, and 1 diabetes/weight management drug. At least one round of FDA comments (with a maximum of 2 rounds) was provided for all 12 protocols and for 6 of the SAPs (voluntarily submitted to the FDA or submitted based on FDA request). The mean time between protocol submission and the first round of comment receipt was 188 days (range: 98-333 days). The FDA provided 231 unique comments on the 12 study protocols overall: 87 (37.7%) on analysis, 50 (21.6%) on data collection, 33 (14.3%) on study design, 31 (13.4%) on outcome definition and ascertainment, 17 (7.4%) on awareness and enrollment and, 13 (5.6%) on other areas. The mean time between SAP submission and first round of comment receipt was 179 days (range: 26-333 days). The 6 SAPs received 40 comments overall: 32 (80.0%) on analysis, 5 (12.5%) on data collection, and 1 each on study design, awareness and enrollment and other areas (2.5% each).

Conclusions: Our findings indicate that the FDA's expectations for pregnancy exposure registries place emphasis on rigor in analysis and data collection. By identifying common and recurring themes raised by the FDA across protocols and SAPs, sponsors can preemptively address these areas in their initial protocol design. This proactive approach can generate more robust and compliant protocols and SAPs, potentially reducing the number of comments and revision rounds.