A Novel Framework to Assess Reproductive Toxicity: Pregnancy Outcomes Intensive Monitoring (PRIM)

Background: As few as 5% of authorized medicines have been adequately monitored, tested and labelled with safety information for use during pregnancy. Pregnancy registries often suffer from poor recruitment and many never reach an adequate sample size. Alternative strategies are needed to gather evidence related to safety during pregnancy.

Objectives: The objective of this work is to develop a scientifically rigorous framework to assess drug safety during pregnancy faster than a pregnancy registry, while maintaining precision. The framework extends from initial work with fingolimod and takes into account previous learnings.

Methods: PRegnancy outcomes Intensive Monitoring (PRIM) is a framework to evaluate risk of drug exposure during pregnancy on pregnancy and infant outcomes. PRIM involves improving data collection, quality, and processing of pregnancies spontaneously reported by healthcare professionals (HCPs) or consumers to a marketing authorization holder. PRIM uses targeted follow-up questionnaires sent to the reporter or HCP at structured follow-up time points, rigorous data entry and quality control, and provides an end-to-end process from data extraction to analyses. PRIM data collection and processing involves information relative to all pregnancies whether with normal or abnormal outcomes, enabling the calculation of prevalence estimates (with 95% confidence intervals (CI)) of adverse outcomes, such as major congenital malformations (MCM). Prospective cases are focused on to reduce reporting bias.
PRIM is classified as a non-interventional post-authorization safety study and transcends pharmacovigilance activities in several ways: (1) at least two external, independent experts adjudicate malformation cases based on data provided by the reporter or HCP; (2) an enhanced data quality control and correction system ensures data rigor; (3) PRIM uses pre-specified programs to extract and analyze aggregate data as defined a priori in a statistical analysis plan.

Results: Gilenya/fingolimod was the first clinical program to apply a PRIM framework and served as a pilot. From 1-Mar-2014 to 28-Feb-2021, PRIM enrolled 698 prospective cases with known pregnancy outcome, resulting in a MCM prevalence in live births of 2.2% (95% CI: 1.1-3.9). Conversely, from 1-Oct-2011 to 28-Feb-2021, the Gilenya pregnancy registry enrolled 297 women, with a MCM prevalence of 6.0% (95% CI: 3.3-9.8).
To date, five products use the PRIM framework. The European Medicines Agency accepted PRIM as an alternative to a pregnancy registry and US Food and Drug Administration accepted it as an adjunct strategy.

Conclusions: With PRIM, Novartis is able to provide consumers and HCPs with crucial information on safety during pregnancy faster compared to a pregnancy registry.