Background
GSD, platinum-sensitive
SMALL CELL LUNG CANCER
The high failure rate of phase III trials combined with their substantial cost makes selecting an appropriate treatment and population for evaluation of paramount importance in drug development [Considering a second line small cell lung cancer clinical trial, a platinum-sensitive sub-group yields a much greater treatment benefit. Even if the treatment benefit in the platinum-resistant sub-group is less certain, from a marketing perspective, the all-comer population with the inclusion of the platinum-resistant sub-group can give maximum patient benefit, followed by market value if the platinum-resistant sub-group also receives benefit from the experimental treatment. Under this circumstance, a direct Phase III trial with a broad population can be risky. A more efficient approach could be a seamless Phase II/III design with population selection in the Phase II portion of the trial followed by a potentially targeted Phase III enrollment with focused patient population to confirm the benefit. Benefit for either progression free survival (PFS) or overall survival (OS) could justify a new treatment paradigm. This is an extension of method for a single primary endpoint by Jenkins et al. [In clinical trials, the clinical benefit of an intervention is often characterized by multiple outcomes. For multiple hypothesis testing problems, the familywise error rate (FWER), the probability of erroneously rejecting at least one null hypothesis, needs to be bounded by a pre-specified significance level α. A sequence of methods derived from weighted Bonferroni-based closed test procedures have been proposed to control the FWER for multiple testing. Examples of such methods include Bonferroni-Holm procedure [Adaptive seamless Phase II/III designs allow Phase II assessment of whether within-trial extension to Phase III is justified. Here we consider that the adaptation includes choosing a meaningful population for an effective investment with high probability of success. A pre-defined, targeted sub-group and the full population are both studied in the first stage of the adaptive Phase II/III design. Investment in the second stage of the adaptive Phase II/III design is then focused on the population(s) most likely to provide patient benefit after the futility analysis at the end of Phase II. Due to the multiple sources potentially contributing to the decision error in this type of design, the FWER control should be studied carefully. The closed testing procedure [To improve the trial efficiency in the adaptive phase II/III design, we propose a method to combine group sequential design (GSD) with the adaptive design. With the implement of GSD, the trial can stop early to save time and resources. However, the closed testing principle between the sub-group and the full population could dramatically decrease the power of an adaptive Phase II/III design when only one group has meaningful efficacy. To improve the power while controlling FWER, we propose a gated group sequential design (