The FDA Sentinel Initiative aims to develop and implement a proactive system that will complement existing systems that the Agency has in place to track reports of adverse events linked to the use of its regulated products. One open question is how to effectively harness information in electronic medical records and claims data to improve prescription drug safety monitoring. Research conducted by OHDSI, IMEDS, and Observational Medical Outcomes Partnership (OMOP) scientists sheds light on challenges inherent in analyzing large observational datasets, such as how to appropriately handling bias stemming from treatment by indication, protopathic bias, selection bias, mismeasurement, and unmeasured confounding. Key Question: What are the relative merits of different analytical approaches that can be used either within a risk identification and analysis system or as part of a protocol-based epidemiological evaluation?