Non-inferiority Trial Design in Drug Development: A Primer for Cardiovascular Healthcare Professionals

Noninferiority trials, in which a new treatment is compared with a standard active treatment, are becoming increasingly popular in cardiovascular medicine. A noninferiority trial seeks to test whether the effect of a new drug is not unacceptably worse than that of an active comparator by more than a predefined noninferiority margin. Noninferiority trials are typically used when a new drug is anticipated to have an efficacy profile similar to its comparator and offers advantages over the existing drug (better toxicity profile, less expensive, less invasive, simpler regimen, shorter treatment duration, different resistance profile). Given the high number of noninferiority trials, it is vital that clinicians fully understand the clinical impacts of the results. Nonetheless, assessing noninferiority in a trial is complex, in both the design and the analysis phases. The crucial issue in the design of a noninferiority trial is the definition of the noninferiority margin, accounting for both statistical (summarizing the historical evidence of the active comparator from randomized controlled trials) and clinical (choosing the fraction of the effect of the old drug that should be “preserved” by the new drug) considerations. We review the role of noninferiority trials in the development of new cardiovascular treatments and discuss a variety of key issues involved in the design and conduction of noninferiority trials, using some examples from real clinical trials in cardiovascular medicine.