(309) Retrospective Application of the FDA Preliminary Pregnancy Safety Studies Framework to an Ongoing Pregnancy-Related Commitment

Background: Pregnant women are often excluded from clinical trials which generally leads to limited information on the safety of medications during pregnancy at the time of drug approval. To fill this gap, regulators require observational studies, such as pregnancy registries or database studies, as a condition of drug approval. Historically, these studies have had feasibility challenges. In an FDA analysis, 23% (24/103) of completed/terminated FDA-required pregnancy studies were infeasible. Recently the FDA presented a preliminary framework aimed at optimizing post approval pregnancy safety studies. This publication examines how the framework may have improved the design/execution of an ongoing FDA pregnancy commitment while highlighting what gaps remain.

Objectives: To retrospectively apply the FDA’s preliminary framework to an ongoing pregnancy commitment, which includes a pregnancy registry and a database study, and to compare the designs of the existing studies to the improved study design selection path identified from the framework.

Methods: The FDA’s preliminary framework was applied to a sponsor’s experience designing and executing two complementary FDA pregnancy study commitments. Improvements and gaps after application of the framework were highlighted.

Results: Two pregnancy studies, one registry and one database study, were initiated prior to the development of the FDA preliminary framework. Per FDA requirements, both studies were designed with specific pre-specified outcomes, appropriate signal evaluation (hypothesis testing) methods and outcome adjudication. Currently, neither study is on target to reach the sample size required to meet the objectives of signal evaluation. Retrospective application of the framework showed that neither study would have been executed at the time of drug approval. Instead, the commitment would have taken a signal detection (hypothesis generation) path allowing for more study design flexibility and more timely results. This exercise also identified gaps that can be considered in future framework updates. For example, the framework does not provide a mechanism to update available information, such as information on pregnancy drug exposure, nor a method to align on subsequent downstream paths.

Conclusions: The preliminary FDA framework is a useful step toward selecting study designs that support timely delivery of pregnancy safety data. Once finalized, the framework may reduce unnecessary signal evaluation studies, resulting in fewer non-feasible studies and more timely data. However, gaps in the framework exist, specifically related to mechanisms for updating information and alignment on downstream paths.