The Ethics of Early Stopping Rules: Who Is Protecting Whom?

Well-conducted clinical investigation, in concert with basic laboratory research, is the cornerstone for progress in medicine. Without it, we are forced to depend solely on experience and bias in the choice of proper treatment, which can sometimes be misleading. Our well-intended predecessors from the time of Hippocrates would envy our analytic approach to clinical investigation, releasing them from the limitations of leeches, bad humors, and evil spirits inthemanagementofpatientswithlife-threateningdisease. Giventheimportanceoftheclinicaltrialprocess,ourgreatest challenge as clinical investigators is to ensure that trials yield interpretable results while preserving the safety of study participants. For phase III randomized trials, these issues are typically under the purview of an independent Data and Safety Monitoring Board (DSMB), composed of statisticians and clinical investigators not directly involved with the study. The DSMB is responsible for reviewing the data, performing interim analyses when the study reaches its specified number of events, and deciding whether or not to close the study on the basis of predetermined early stopping rules that relate to toxicity or outcome. If excess harm is observed, or if a statistically significant benefit is observed, the study is stopped early and the patient is informed of the results. If treatment is ongoing, the patient is