Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘Figure 4. Sample P-values for two different group sequential methods in a trial with five tests. The graphshows that the Pocock method makes it easier to stop a trial early and the O’Brien–Fleming method makesit easier to reject the null hypothesis at the end.0.05 –0.04 –O0.03 –P-value0.02 –P P PP PO0.01 –O0 – OO|1|2|3|4|5Number of testsO = the O’Brien–Fleming method.P = the Pocock method.tests. The O’Brien–Fleming method uses a conservative early approach thataddresses the issue of power at the end of the trial. In other words, some of theType I error is removed from the earlier tests and moved to the later tests. TheO’Brien–Fleming method also makes it more difficult to reject the null hypothesisof no treatment effect early in the trial. Figures 3 and 4 illustrate these two groupsequential methods in a trial with four interim analyses plus a final analysis.The Lan–DeMets method generalizes the Pocock and the O’Brien–Flemingmethods in two important ways. The Pocock and O’Brien–Fleming methods relyon equally spaced intervals, in terms of number of patients, between tests. TheLan–DeMets method, also referred to as an alpha spending approach, allowsfor unequally spaced intervals. As a consequence, the Lan–DeMets method allowsfor differences between the planned and actual sample sizes during the course ofthe study, and even unplanned analyses as well. While the Pocock method spreadsthe Type I error equally throughout the study, the O’Brien–Fleming method359