(C-184) Post-approval pregnancy safety evidence for signal identification: Comparison of preliminary results from two methodological approaches for high-efficacy drugs contraindicated during pregnancy

Background: Post-approval pregnancy safety of cladribine tablets is supported by two ongoing non-interventional studies. Given the limited data available at the time of approval, CLEAR, a multi-database, comparative cohort study, and MAPLE-MS, a worldwide enhanced pharmacovigilance program, were established to facilitate signal detection for this drug, which is contraindicated during pregnancy.

Objectives: To evaluate methodologies of both studies in detecting major congenital anomalies (MCAs).

Methods: CLEAR compares pregnancies exposed to cladribine tablets with those unexposed to disease-modifying therapies using secondary data from seven European countries, each providing an unexposed MS comparator. MAPLE-MS captures spontaneous and solicited reports of cladribine-exposed pregnancies, including prospective and retrospective cases from patients and healthcare professionals. MAPLE-MS uses external comparators from unexposed MS populations (German MS Pregnancy Registry) and the general population (European Surveillance of Congenital Anomalies and Twins [EUROCAT] and the Metropolitan Atlanta Congenital Defects Program). Both studies began in October 2017 and assess MCA prevalence in offspring exposed through the mother (maternal cohort) or father (paternal cohort). Offspring are followed for up to one year post-birth. MCA definition excludes genetic anomalies and follows EUROCAT guidelines.

Results: In CLEAR (as of November 2024), a total of 28–36 exposed, and 1632 unexposed pregnancies were recorded in the maternal cohort. In Germany, 25 exposed and 248 unexposed pregnancies were identified. MCA prevalence (95% confidence interval [CI]) in live births (LB) and stillbirths (SB) was 4.17% (0.74–20.24, n=1/24) in those exposed and 2.88% (1.40–5.83, n=7/243) in those unexposed. The paternal cohort has not been assessed yet.

In MAPLE-MS (as of April 2024), the maternal cohort included 336 cladribine-exposed pregnancies (157 [46.7%] with known outcomes). Worldwide, MCA prevalence (95% CI) in LB+SB was 1.1% (0.0–6.7; n=1/98). In the paternal cohort, 47 pregnancies were reported; 16 with known outcomes. No MCAs have been observed.

Conclusions: This work highlights different approaches in evaluating medication safety in pregnancy to inform drug use. Both studies identified the same MCA (a case of atrial septal defect) from the same source. Seven years post-launch, the larger pool of exposed cases in MAPLE-MS provides a more precise estimate of MCA prevalence. CLEAR benefits from an internal comparator. In the context of signal detection, for new drugs with scarce or uncertain use, enhanced pharmacovigilance with less controlled methods can provide early pregnancy safety evidence.