Sequential Analysis (Group Sequential Design)

O'Brien–Fleming uses very strict (large) boundaries at early interim looks and progressively relaxes them as the study approaches its maximum sample size. This makes accidental early stopping unlikely unless the evidence is overwhelming, and the final boundary is close to the unadjusted significance level. Pocock uses the same boundary at every look, which means each individual test uses a more conservative threshold but the study has a higher probability of stopping early. In practice O'Brien–Fleming is preferred for confirmatory trials because it preserves most of the nominal significance level for the final analysis.

Not necessarily. If a true effect exists and is large, early stopping can substantially reduce the expected total sample size. However, the maximum sample size — the number needed if the study runs to completion — is slightly larger than for a fixed design, because the boundary adjustments use a small portion of the alpha budget at interim looks.

Only with an alpha-spending function, which can accommodate unscheduled looks by allocating alpha based on the information fraction accumulated so far. Adding an unplanned look without formal alpha spending is a protocol violation that inflates the Type I error rate and will typically be rejected by regulators.

The naive point estimate is biased upward when the study stops early due to a boundary crossing. Bias-adjusted estimators — such as the median unbiased estimate or a shrinkage approach — are recommended alongside confidence intervals that properly account for the sequential stopping rule. Always report these alongside the raw estimate.