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Cox Regression Methods for Two-Stage Randomization Designs

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Abstract:

Summary. 

Two-stage randomization designs (TSRD) are becoming increasingly common in oncology and AIDS clinical trials as they make more efficient use of study participants to examine therapeutic regimens. In these designs patients are initially randomized to an induction treatment, followed by randomization to a maintenance treatment conditional on their induction response and consent to further study treatment. Broader acceptance of TSRDs in drug development may hinge on the ability to make appropriate intent-to-treat type inference within this design framework as to whether an experimental induction regimen is better than a standard induction regimen when maintenance treatment is fixed. Recently Lunceford, Davidian, and Tsiatis (2002, Biometrics58, 48–57) introduced an inverse probability weighting based analytical framework for estimating survival distributions and mean restricted survival times, as well as for comparing treatment policies at landmarks in the TSRD setting. In practice Cox regression is widely used and in this article we extend the analytical framework of Lunceford et al. (2002) to derive a consistent estimator for the log hazard in the Cox model and a robust score test to compare treatment policies. Large sample properties of these methods are derived, illustrated via a simulation study, and applied to a TSRD clinical trial.

Keywords: Induction therapy; Intent to treat; Inverse weighting; Maintenance therapy; Potential outcomes; Survival analysis

Document Type: Research Article

DOI: http://dx.doi.org/10.1111/j.1541-0420.2007.00707.x

Affiliations: 1: Department of Biostatistics and Bioinformatics, Duke University, 2400 Pratt Street, Room 0311, Terrace Level, Durham, North Carolina 27705, U.S.A., Email: lokhn001@dcri.duke.edu 2: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, U.S.A., Email: jdhelter@gene.com

Publication date: June 1, 2007

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