Long-term post-marketing safety monitoring is crucial for understanding the risks of new therapies in real-world settings, yet current registries often create considerable burdens without delivering robust, actionable data in a reasonable timeframe. For registries like those in place for cell and gene therapies and pregnancy outcomes, fragmented drug-specific data collection, cumbersome follow-up, and inconsistent quality, limit effectiveness. Patients deserve safety strategies that protect them and provide timely and meaningful information. This session will highlight the need for harmonized approaches to safety monitoring that are disease or mechanism focused, rather than drug focused. Through stakeholder perspectives, this session will aim to elucidate pragmatic approaches to generating essential data necessary for safety monitoring. Case studies will be leveraged to demonstrate where low patient accrual led to innovative solutions to obtain data to inform patient safety.