Clinical Trials

❘❙❚■ Chapter 31 | Interim Monitoring and Stopping RulesFigure 3. Standardized normal statistic two-sided 5% boundaries for two different group sequential methods ina trial with five tests. The graph shows that the Pocock method more easily results in the early termination oftrials, while the O’Brien–Fleming method results in easier rejection of the null hypothesis at the end of the trial.Standardized normal statistic5 –4 –3 –2 –1 –0 ––1 ––2 ––3 ––4 ––5 –OO|1OP P POOP POP POPOOP PO|2|3Number of tests|4|5O = the O’Brien–Fleming method.P = the Pocock method.The most common group sequential methods currently in use are attributedto Pocock [3], O’Brien and Fleming [4], and Lan and DeMets [5]. For ease ofpresentation, we will describe these methods for situations in which the teststatistic has a standard normal distribution. However, the methods aregeneralizable to other settings.Recall from Chapter 17, that for a significance threshold of P ≤0.05 the teststatistic value is 1.96. The Pocock method adjusts this critical value from the usualvalue of 1.96 to some higher number that depends on the number of tests beingperformed. The number is chosen so that the overall Type I error remains 5%despite mutiple tests.The Pocock method, although controlling the overall Type I error, creates asituation in which the power to detect the true treatment difference at the endof a trial is reduced, and this reduction is greater with higher numbers of interim358