title: Designing a non-inferiority study in kidney transplantation: a case study.
abstract: In organ transplantation, placebo-controlled clinical trials are not possible for ethical reasons, and hence non-inferiority trials are used to evaluate new drugs. Patients with a transplanted kidney typically receive three to four immunosuppressant drugs to prevent organ rejection. In the described case of a non-inferiority trial for one of these immunosuppressants, the dose is changed, and another is replaced by an investigational drug. This test regimen is compared with the active control regimen. Justification for the non-inferiority margin is challenging as the putative placebo has never been studied in a clinical trial. We propose the use of a random-effect meta-regression, where each immunosuppressant component of the regimen enters as a covariate. This allows us to make inference on the difference between the putative placebo and the active control. From this, various methods can then be used to derive the non-inferiority margin. A hybrid of the 95/95 and synthesis approach is suggested. Data from 51 trials with a total of 17,002 patients were used in the meta-regression. Our approach was motivated by a recent large confirmatory trial in kidney transplantation. The results and the methodological documents of this evaluation were submitted to the Food and Drug Administration. The Food and Drug Administration accepted our proposed non-inferiority margin and our rationale.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. steffen.witte@novartis.com
authors.forename: Steffen
authors.initials: S
authors.lastname: Witte
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmidli
authors.forename: Anthony
authors.initials: A
authors.lastname: O'Hagan
authors.forename: Amy
authors.initials: A
authors.lastname: Racine
mesh_terms: D001499:Bayes Theorem; D016001:Confidence Intervals; D035061:Control Groups; D015507:Drugs, Investigational / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D016030:Kidney Transplantation / Q000706:statistics & numerical data*; D016013:Likelihood Functions; D015201:Meta-Analysis as Topic; D015233:Models, Statistical; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D012107:Research Design / Q000706:statistics & numerical data*; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration / Q000706:statistics & numerical data
chemical_list: D015507:Drugs, Investigational; D007166:Immunosuppressive Agents; D010919:Placebos