Clinical trials are constantly evolving, especially in the context of rare or serious drug indications where uncontrolled trials are common. These trials often use single-arm designs, which can introduce bias due to the lack of randomization. To mitigate this, sponsors may use Synthetic Control Arms (SCAs), which utilize patient-level data from external sources to enhance trial interpretation and support product development. SCAs have become a valuable tool in clinical research, offering cost reduction and faster results by leveraging real-world data. This white paper discusses the principles, benefits, and challenges of SCAs, particularly in real-world evidence studies.