Non-inferiority trials have become a major approach for evaluating the efficacy of a treatment (drug, biologic, device) when a positive active treatment exists. Recently the FDA has produced a Draft Guidance document. This highlights the issues of main concern to the FDA. In this talk we discuss and address issues seen from the experience of an academic involved in industry consultation and FDA advisory committee involvement. Attention will be given to, but not limited to, the FDA Draft Guidelines. The impact the guidelines might have on practice will be discussed.