Typically, clinical trials compare a new product or therapy with another that already exists to determine if the new one is as successful as, or better than, the existing one. In some studies, participants may be assigned to receive a placebo. Comparing a new product with a placebo can be the fastest and most reliable way to demonstrate the new product’s therapeutic effectiveness. However, placebos are not used if a patient would be put at risk, particularly in the study of treatments for serious illnesses by not having effective therapy. Most of non-inferiority studies compare new products with an approved therapy. The active-controlled trial with a non-inferiority design has gained popularity in recent years. They have methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how an NI trial should be conducted. In this narrative review based on scientific literature and papers, but also publications about clinical trials, we will define NI trial concepts, explain the main methodology of NI margin determination with its limitations and the potential margin of improvement.