Continuous safety monitoring for randomized controlled clinical trials with blinded treatment information. Part 1: Ethical considerations.

ABSTRACT

The protection of patient safety is the principal responsibility of clinical trial investigators, and must be assured even if that were to prevent successful completion of a trial. Yet, the decision to prematurely stop a blinded, randomized controlled clinical trial can be extremely complicated, involving a tangle of ethical, statistical, and practical issues. Questions are quickly answered when conclusive evidence of harm has been established for trial participants, or when the potential for harm exceeds an acceptable limit of comfort for an oversight body. Less readily addressed are those situations in which early alarms warn of possible harm, but the data are too preliminary or incomplete to reach a satisfactory decision as to whether or not to stop the study. Early study termination without sufficient evidence disallows the study question from being answered and may allow an inferior treatment to remain in use, or prevent a superior one from being discovered. Even without early stopping, as a study proceeds, worrisome trends may lead to overzealous (or overly cautious) looks at study data which could jeopardize the integrity of the findings. Trial investigators and safety monitoring groups, aided by objective statistical rules and thoughtful deliberations, share responsibility for patient welfare. Statistical guidelines must not frustrate ethical concerns, but, rather, should be designed to promote the highest ethical and scientific outcomes possible, safeguarding both trial participants and the public - the ultimate beneficiaries of clinical trials.