@article {9672,
title = {Adjusting for unknown bias in non-inferiority clinical trials.},
journal = {Statistics in biopharmaceutical research},
volume = {5},
year = {2013},
month = {2013 Jan 1},
abstract = {Evaluation of non-inferiority is based on ruling out a threshold for what would constitute unacceptable loss of efficacy of an experimental treatment relative to an active comparator "Standard". This threshold, the "non-inferiority margin", is often based on preservation of a percentage of Standard{\textquoteright}s effect. To obtain an estimate of this effect to be used in the development of the "non-inferiority margin", data are needed from earlier trials comparing Standard to placebo if the non-inferiority trial does not have a placebo arm. This approach often provides a biased over-estimate of Standard{\textquoteright}s true effect in the setting of the current non-inferiority study. We describe two commonly used non-inferiority margin methods that adjust for this bias, the two-confidence interval (95-95) and the Synthesis margins. However, the added {\textquoteright}variance inflation{\textquoteright} adjustment made by 95-95 margin diminishes with increasing information from historical trial(s), and the Synthesis margin is based on a strong assumption that the relative bias is known. We introduce an alternative "Bias-adjusted" margin addressing vulnerabilities of each by attenuating the estimate and by accounting for uncertainty in the true level of bias. Examples and asymptotic estimates of non-inferiority hypothesis rejection rates in the proportional hazards setting are used to compare methods.},
keywords = {2013, December 2013, Public Health Sciences Division},
issn = {1946-6315},
doi = {10.1080/19466315.2013.795910},
author = {Odem-Davis, Katherine and Fleming, Thomas R}
}