Early Detection of Cardiovascular Signals: A Simulation Study About Power Enhancement

• Activity Number: 321
• Type: Contributed
• Date/Time: Tuesday, August 6, 2013 : 8:30 AM to 10:20 AM
• Sponsor: Biometrics Section
• Author(s): Jing Huang*+ and Ouhong Wang and Mike Hale
• Companies: and Amgen and Amgen
• Keywords: safety ; simulation ; power ; early phase trial ; cardiovascular

Abstract

Due to the small size of first-in-human (FIH) trials, it has been widely accepted that safety signals are difficult to detect. The chances of recognizing early signals in cardiovascular safety have long been considered to be remote. However, much of this belief is based on analyses involving pair-wise comparisons of very small cohorts without incorporating any possible dose-response pattern. When dose is considered as a continuous variable, dose-response becomes the main focus and power can be substantially improved with appropriate testing procedures. In this project, we use simulation to describe several common dose-response relationships such as step, linear, log-linear and Emax; we quantify the power improvement in these settings by comparing the results derived from simple pair-wise tests versus more appropriate tests such as Jonckheere-Terpstra test and tests for recognizing linear and log-linear trends. We demonstrate that cardiovascular safety signals for small sized FIH studies in general have reasonable statistical power for early detection when using the appropriate statistical analysis.