Essentials of Regulatory: Noninferiority Clinical Trials: Practical Issues and Challenges

Noninferiority (NI) clinical trials are increasing in prevalence. There are several disease states (e.g., cancer, pneumonia, complicated skin and skin structure infections) where placebo-controlled superiority trials are not feasible and an active controlled NI trial must be conducted instead. Likewise, comparative effectiveness trials such as NI trials, can be highly beneficial for purposes of labeling or supporting reimbursement negotiations. Each NI trial has a myriad of challenges for the sponsor to overcome (choice of margin, choice of type of statistical NI method to use, etc.). As an aid to the regulatory professional, this article reviews the high-level requirements and challenges of NI trial designs and provides some recommendations for sidestepping pitfalls. It also discusses NI trial objectives, the challenges of assay sensitivity, the NI margin, and why NI clinical trials are of increasing concern to the regulatory professional.