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The assessment of non‐inferiority in a gold standard design with censored, exponentially distributed endpoints
Author(s) -
Mielke Matthias,
Munk A.,
Schacht A.
Publication year - 2008
Publication title -
statistics in medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.996
H-Index - 183
eISSN - 1097-0258
pISSN - 0277-6715
DOI - 10.1002/sim.3348
Subject(s) - censoring (clinical trials) , sample size determination , type i and type ii errors , statistics , wald test , nominal level , replication (statistics) , statistical hypothesis testing , placebo , test (biology) , mathematics , sample (material) , computer science , econometrics , medicine , confidence interval , paleontology , chemistry , alternative medicine , pathology , chromatography , biology
The objective of this paper is to develop statistical methodology for non‐inferiority hypotheses to censored, exponentially distributed time to event endpoints. Motivated by a recent clinical trial in depression, we consider a gold standard design where a test group is compared with an active reference and with a placebo group. The test problem is formulated in terms of a retention of effect hypothesis. Thus, the proposed Wald‐type test procedure assures that the effect of the test group is better than a pre‐specified proportion Δ of the treatment effect of the reference group compared with the placebo group. A sample size allocation rule to achieve optimal power is presented, which only depends on the pre‐specified Δ and the probabilities for the occurrence of censoring. In addition, a pretest is presented for either the reference or the test group to ensure assay sensitivity in the complete test procedure. The actual type I error and the sample size formula of the proposed tests are explored asymptotically by means of a simulation study showing good small sample characteristics. To illustrate the procedure a randomized, double blind clinical trial in depression is evaluated. An R‐package for implementation of the proposed tests and for sample size determination accompanies this paper on the author's web page. Copyright © 2008 John Wiley & Sons, Ltd.