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The design of the best possible clinical trials of adjuvant interventions in colorectal cancer will entail the use of both time-tested and novel methods that allow efficient, reliable and patient-relevant therapeutic development. The ultimate goal of this endeavor is to safely and expeditiously bring to clinical practice novel interventions that impact patient lives. In this paper, we discuss statistical aspects and provide suggestions to optimize trial design, data collection, study implementation, and the use of predictive biomarkers