Non-Constancy Adjustment for Non-Inferiority Testing in Active-Controlled Clinical Trials

• Activity Number: 452
• Type: Topic Contributed
• Date/Time: Wednesday, August 1, 2012 : 8:30 AM to 10:50 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Carl Dicasoli*+ and Emily Martin and Cynthia Desouza
• Companies: Vertex Pharmaceuticals and Vertex Pharmaceuticals and Vertex Pharmaceuticals
• Keywords: covariate adjustment ; non-inferiority ; constancy ; risk difference ; adaptive ; interim analysis

Abstract

In new studies of oral regimens for the treatment of Hepatitis C, a potential challenge is to derive a valid method for testing non-inferiority. One critical assumption in non-inferiority trials is constancy; that is, the effect of the active control in the historical trial population is similar to the effect in the active control trial population. This assumption is at risk due to the potential heterogeneity between trial populations primarily related to subject characteristics, and secondarily to other sources of heterogeneity resulting from differences in patient management (e.g., usage of concomitant medications). To investigate the impact of the constancy assumption, we propose an adaptive two-stage method for non-inferiority testing based on a constancy adjustment followed by sample size re-estimation. We will evaluate the overall magnitude of the alpha and beta errors when implementing this two-step approach for non-inferiority testing, compared to the standard synthesis and confidence-interval approaches.