Stopping guidelines for an effectiveness trial: what should the protocol specify?

BACKGROUND: Despite long-standing problems in decisions to stop clinical trials, stopping guidelines are often vague or unspecified in the trial protocol. Clear, well-conceived guidelines are especially important to assist the data monitoring committees for effectiveness trials. MAIN TEXT: To specify better stopping guidelines in the protocol for such trials, the clinical investigators and trial statistician should carefully consider the following kinds of questions: 1. How should the relative importance of the treatment benefits and hazards be assessed? 2. For decisions to stop a trial for benefit: (a) What would be the minimum clinically important difference for the study population? (b) How should the probability that the benefit exceeds that difference be assessed? (c) When should the interim analyses include data from other trials? (d) Would the evidence meet state-of-the-art standards for treatment recommendations and practice guidelines? 3. Should less evidence be required to stop the trial for harm than for benefit? 4. When should conventional stopping guidelines for futility be used for comparative effectiveness trials? CONCLUSION: Both clinical and statistical expertise are required to address such challenging questions for effectiveness trials. Their joint consideration by clinical investigators and statisticians is needed to define better stopping guidelines before starting the trial.