ABSTRACT
This chapter considers phase III clinical trials to conˆrm treatment efˆcacy based on a single predictive biomarker or signature that is analytically validated and completely speciˆed. When evidence from biological or early trial data suggests that the biomarker is so reliable and the use of the treatment for biomarker-negative patients predicted by the biomarker not to beneˆt from the treatment is considered unethical at the initiation of a phase III trial, an enrichment or targeted design that randomizes only a subgroup of biomarker-positive patients (predicted to beneˆt from the treatment) can be an efˆcient trial design (e.g., Simon and Maitournam, 2005; see also Chapters 8 and 9). However, it is more common that, at the initiation of phase III trials, there is no compelling evidence regarding the capability of the biomarker in
CONTENTS
10.1 Introduction ................................................................................................ 165 10.2 Approaches to Statistical Analysis Plan ................................................. 166
10.2.1 Fixed-Sequence Approaches ........................................................ 168 10.2.2 Fallback Approach ......................................................................... 169 10.2.3 Treatment-by-Biomarker Interaction Approach ........................ 170
10.3 Comparison of the Approaches ............................................................... 171 10.3.1 Criteria: Probabilities of Asserting Treatment Efˆcacy ............ 171 10.3.2 Numerical Evaluations .................................................................. 172 10.3.3 Discussion ....................................................................................... 178
10.4 Sample Size Calculation ............................................................................ 180 10.5 Clinical Validation of Predictive Biomarkers......................................... 182 10.6 Concluding Remarks ................................................................................. 183 References ............................................................................................................. 184
predicting treatment effects or there is uncertainty about a cut-point of an analytically validated predictive assay. In such situations, it is generally reasonable to include all patients as eligible for randomization as done in traditional clinical trials, but to plan for prospective subgroup analysis based on the biomarker (Pusztai and Hess, 2004; Sargent et al., 2005; Simon and Wang, 2006; Simon, 2008; Wang et al., 2007; Mandrekar and Sargent, 2009; Freidlin et al., 2010, 2013; Buyse et al., 2011; Freidlin and Korn, 2014; Matsui et al., 2014).
