This document provides guidance to sponsors and applicants submitting investigational drug applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or supplemental applications on the appropriate use of non-inferiority (NI) study designs to provide evidence of the effectiveness of a drug or biologic, usually because a superiority study design (drug versus placebo, dose response, or superiority to an active drug) cannot be used. The guidance gives advice on when NI studies intended to demonstrate effectiveness of an investigational drug can provide interpretable results, how to choose the NI margin, and how to test the NI hypothesis.