Details
Annovera (segesterone acetate and ethinyl estradiol vaginal system) is a new molecular entity approved in 2018 for prevention of pregnancy in women of reproductive potential. During the Phase 3 clinical trial of Annovera, four venous thromboembolism (VTE) cases were observed. This resulted in a crude incidence rate of 24.1 per 10,000 woman-years (95% confidence interval 6.6, 61.7) which was higher than reported for NuvaRing (5.4 per 10,000 woman-years) or other combined oral contraceptives (6.6 per 10,000 woman-years). This prompted a question about whether the risk of VTE is greater for Annovera than for other approved combination hormonal contraceptives (CHCs) in the U.S. The U.S. Food and Drug Administration (FDA) planned this study in the Sentinel System to conduct sequential monitoring to detect any large increase in the risk of VTE or arterial thromboembolism (ATE), particularly as compared to VTE and ATE risk of other approved CHC products. At the time Annovera was approved, Sentinel’s Active Risk Identification and Analysis (ARIA) system was assessed as sufficient for conducting sequential safety monitoring for early detection of a large increase in the risk of non-fatal VTE and ATE.
Although a descriptive analysis was conducted in preparation of the sequential analysis (i.e., calculating incidence and incidence rates of VTE and ATE in new users of CHCs, including NuvaRing), the ARIA study was ultimately not conducted as planned. In parallel with post-marketing surveillance through the ARIA system, the Applicant initially planned an observational study to assess VTE risk and fulfill their postmarket requirement using electronic health record (EHR) data to account for potential confounders such as body mass index (BMI) and smoking. However, lower-than-expected utilization of Annovera limited the feasibility of this approach. As an alternative, the Applicant proposed a study using administrative claims data, supplemented with claims-EHR-linked information on BMI and smoking, and incorporating medical record validation of the outcome algorithm.
Given that the administrative claims data proposed in the revised postmarket required study were comparable to those available in the ARIA system, and claims-EHR-linked data and outcome algorithm validation were incorporated to address limitations inherent in a claims-based study such as that planned in ARIA, the FDA decided to close the sequential analysis of Annovera and VTE/ATE in Sentinel’s ARIA system.