Traditional confirmatory trials may not be ethical or feasible in small populations such as rare disease to demonstrate efficacy. Drug development in rare disease often faces substantial challenges, including economic, logistical, and ethical barriers. Due to small sample size and their inherent uncertainties, the design and analysis for rare disease trial require careful planning. However, the regulatory standard for approving a new drug for rare disease is no different than other disease area. They must be sufficiently well designed and appropriately analyzed to provide a reasonable measure of the benefit-risk of an intervention. Several recently released guidance by FDA shows the importance of innovative design and analysis approaches in this context. The talk will focus on a robust evidence synthesis approach that allow the use of historical control information, natural disease history, and Real-World Data (RWD) to enrich the design and analysis of clinical trial in rare disease. Different strategies of using a synthetic control in clinical trial design will be highlighted with possible pros and cons. A real-life study will be used to illustrate the methodology.