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It is widely accepted that, due to the small size of first-in-human (FIH) trials, safety signals are difficult to detect. The chances of detecting early signals in cardiovascular safety, including heart rate, blood pressure, QT prolongation, etc., have long been considered to be remote. However, much of this belief is based on an analysis involving pair-wise comparisons of very small cohorts. When dose is considered as a continuous variable, dose–response becomes the main focus and power can be significantly improved with appropriate testing procedures. In this research, we try to quantify through simulations the power in this setting and demonstrate that cardiovascular safety signals in general have reasonable statistical power for early detection when using a dose–response analysis. The simulations account for different magnitudes of effects and various scenarios including linear, log-linear, and Emax relationships between dose and safety signal, together with multiple parametric and nonparametric tests.
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Hollander, M. and Wolfe, D. A.: Nonparametric Statistical Methods, pp.120-123. Wiley, New York (1973)
Kotz, S., Read, C. B., Blakrishnan, N., and Vidakovic, Brani. (eds): Encyclopedia of Statistical Sciences 2nd Edition, Volume 9, pp. 5811-14. Wiley, New York (2006)
- Statistical Power to Detect Cardiovascular Signals in First-in-Human Trials: Is It Really Small?
- Springer New York