ZhangBoPHHSSensitivityAnalysisNon-Inferiority.pdf
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Abstract
A major issue in non-inferiority trials is the controversial assumption of constancy,
namely that the active control has the same effect relative to placebo as in previous studies
comparing the active control with placebo. The constancy assumption is often in doubt, which
has motivated various methods that ‘discount’ the control effect estimate from historical data
as well as methods that adjust for imbalances in observed covariates. We develop a new
approach to deal with residual inconstancy, i.e. possible violations of the constancy assumption
due to imbalances in unmeasured covariates after adjusting for the measured covariates. We
characterize the extent of residual inconstancy under a generalized linear model framework and
use the results to obtain fully adjusted estimates of the control effect in the current study based
on plausible assumptions about an unmeasured covariate. Because such assumptions may
be difficult to justify, we propose a sensitivity analysis approach that covers a range of situations.
This approach is developed for indirect comparison with placebo and effect retention, and
implemented through additive and multiplicative adjustments.The approach proposed is applied
to two examples concerning benign prostate hyperplasia and human immunodeficiency virus
infection, and evaluated in simulation studies.Keywords: Putative placebo, Conditional effect, Discounting, Active control, Effect retention, ConstancyKeywords: Putative placebo, Conditional effect, Discounting, Active control, Effect retention, Constanc