Over the past two decades or more, few drug development issues have been as challenging as the design, analysis and interpretation of non-inferiority trials. Even today, despite the best efforts of regulatory agencies on both sides of the Atlantic and industry and academic statisticians, there are still very fundamental issues remaining. In this presentation I’ll discuss some of these issues, including: What is the null hypothesis being tested? Under what circumstances should approval of a new drug be based on a comparative efficacy requirement? Do we have a logically consistent approach to demonstrate preservation of effect?