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A gatekeeping procedure to test a primary and a secondary endpoint in a group sequential design with multiple interim looks

Tamhane, Ajit C., Gou, Jiangtao, Jennison, Christopher, Mehta, Cyrus R., Curto, Teresa
Biometrics 2018 v.74 no.1 pp. 40-48
biometry, clinical trials, computer software, data analysis, experimental design
Glimm et al. (2010) and Tamhane et al. (2010) studied the problem of testing a primary and a secondary endpoint, subject to a gatekeeping constraint, using a group sequential design (GSD) with K=2 looks. In this article, we greatly extend the previous results to multiple (K>2) looks. If the familywise error rate (FWER) is to be controlled at a preassigned α level then it is clear that the primary boundary must be of level α. We show under what conditions one α‐level primary boundary is uniformly more powerful than another. Based on this result, we recommend the choice of the O'Brien and Fleming (1979) boundary over the Pocock (1977) boundary for the primary endpoint. For the secondary endpoint the choice of the boundary is more complicated since under certain conditions the secondary boundary can be refined to have a nominal level α′>α, while still controlling the FWER at level α, thus boosting the secondary power. We carry out secondary power comparisons via simulation between different choices of primary–secondary boundary combinations. The methodology is applied to the data from the RALES study (Pitt et al., 1999; Wittes et al., 2001). An R library package gsrsb to implement the proposed methodology is made available on CRAN.