title: Justification of noninferiority margin: methodology considerations in an exposure-response analysis.
abstract: The pivotal clinical trial to support the indication of liver transplantation for everolimus was based on a noninferiority trial design. The unique trial design made it impossible to estimate the noninferiority margin at the design stage. Even though the trial was conducted based on a noninferiority 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. 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.
authors: Division of Pharmacometrics, Office of Clinical Pharmacology, FDA, Silver Spring, MD.
authors: Y
authors: Y
authors: Wang
authors: Y
authors: Y
authors: Harigaya
authors: M
authors: M
authors: Cavaillé-Coll
authors: P
authors: P
authors: Colangelo
authors: K S
authors: KS
authors: Reynolds
mesh_terms: D000328:Adult; D000368:Aged; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D012107:Research Design; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus; D016559:Tacrolimus