Abstract The expanding availability of real-world data (RWD) has led to an increase in both the interest and possibilities for using this information in postmarketing safety analyses and signal management. While there is enormous potential value from the safety insights generated through RWD, the analysis preparation, execution, and communication required to reliably deliver the evidence can be time consuming. Since the safety signal assessment process is a regulated and timebound process, any supporting RWD analyses require a rapid turnaround of well-designed and informative results. To address this challenge, a TransCelerate BioPharma working group was formed and developed a framework to help teams responsible for safety signal assessment overcome the challenges of working with RWD rapidly to deliver analyses within regulatory timelines. Here, a previously performed safety assessment was evaluated within the context of the developed framework to illustrate how the framework may be adopted in practice.