Scientific Publications by FDA Staff

Clin Pharmacol Ther 2014 Nov 29 [Epub ahead of print]

Justification of non-inferiority margin: Methodology considerations in an exposure response analysis.

Wang Y, Harigaya Y, Cavaille-Coll M, Colangelo P, Reynolds KS

The pivotal clinical trial to support the indication of liver transplantation for everolimus was based on a non-inferiority trial design. The unique trial design made it impossible to estimate the non-inferiority margin at the design stage. Even though the trial was conducted based on a non-inferiority margin of 12% for the primary efficacy endpoint, the lack of consensus on this margin made the efficacy results difficult to interpret. A novel pharmacometric approach was applied to derive a new margin. Even though it was smaller than 12%, the new margin was large enough so that the observed efficacy results became interpretable and supported the efficacy of everolimus. This novel analysis was an important contributor to the "totality of evidence" approach that led to the approval of everolimus for the new indication. This approval represents the approval of a new drug in more than 10 years for the indication of liver transplantation.