In the US Food and Drug Administration Amendments Act of 2007, the Food and Drug Administration (FDA) was mandated to establish a postmarket active risk identification and analysis (ARIA) system that contained data from 100 million patient lives to monitor risks associated with drug and biologic products using data from disparate sources to complement the FDA’s existing postmarket capabilities. In response, FDA established the Sentinel Initiative. Within the Sentinel Initiative, a core program is the Sentinel System, a national medical product safety surveillance system with one of the largest curated multi-site distributed databases dedicated to medical product safety in the world. The Sentinel System supports the FDA’s mission to protect public health and monitor the safety of FDA-regulated medical products. The objectives of this report are to review the activities conducted within the Sentinel System spanning federal fiscal years 2018-2022, which align with the period of the sixth term of the Prescription Drug User Fee Act (PDUFA VI).