Sense and avoid is the primary technical barrier to increased unmanned aircraft system airspace access. A safety assessment driven approach to sense and avoid system design and requirements validation is being employed to ensure safety and operational suitability. The foundation of this approach is a fast-time modeling and simulation architecture originally used to support the certification of the Traffic Alert and Collision Avoidance System. This paper describes the safety assessment methodology, including the architecture and evaluation metrics, and presents preliminary results for key system architecture and design tradeoffs.