Mehta-StoppingBoundaries2007教程.pdfVIP

Efficacy, Safety and Futility Stopping Boundaries ExL Pharma Workshop Philadelphia, PA Feb 25-26, 2007 Cyrus R. Mehta President, Cytel Inc. email: mehta@ – web: – tel: 617-661-2011 1 ExL Pharma. Feb 25-26, 2008. Philadelphia Contents of the Talk • Three Real Examples with Early Stopping Boundaries – Efficacy boundaries alone (CHARM trial) – Efficacy and safety boundaries (CRASH trial) – Efficacy and futility boundaries (COMET trial) • Acknowledgement: I thank Professor Stuart Pocock for providing me with these examples 2 ExL Pharma. Feb 25-26, 2008. Philadelphia 1. Tough Efficacy Boundaries: CHARM Trial • Candersartan vs. placebo for reducing mortality in heart failure patients (CHARM). American Heart Journal (Pocock, 2005) • Primary endpoint is all causes mortality • Require 85% power to detect a 14% reduction in annual mortality from 8% in the placebo group, with a 2-sided level-0.05 test 3 ExL Pharma. Feb 25-26, 2008. Philadelphia How Many Events Needed? • Number of events needed to achieve 1 − β power is D = 4 zα/2 + zβ 2 = 1570 ln(HR) • Investigators want a 4 year study – Enroll for 2 years – Follow up for 2 additional years after last patient enrolled • What sample size will produce 1570 events in 4 years? 4 ExL Pharma. Feb 25-26, 2008. Philadelphia Sample Size Calculation • Patients enroll at the rate of A per month for Sa months and are followed for an additional Sf months Accrual Period Accru