Sample size calculations for time-to-event endpoints with extreme hazard ratios

Music City Center 

The Schoenfeld formula is commonly used to determine the necessary number of events for an event-driven trial under the proportional hazards assumption. It is important to note, however, that the Schoenfeld formula is derived from the score test under the null hypothesis of no treatment difference and hence may exhibit bias if the hazard ratio significantly deviates from the null value of 1. We have attempted various analytic approaches but none of them seem to work in this situation. We propose a quick and simple simulation approach that performs well under various settings. We have implemented the proposed method in the lrstat R package and illustrate the method using a rare disease study example.

proportional hazards

hazard ratio

Schoenfeld formula

power

sample size

simulation 

Biopharmaceutical Section