The Ethics of Early Stopping Rules

Decision making in adjuvant trials in breast cancer: the NCIC CTG MA.17 trial as an example

“…We have previously stated our agreement with this position [9], since patients clearly do want to avoid the morbidity of disease recurrence [20]. If this view were generally accepted it would call into question the suggestion that it is ethical to ask patients to remain on study when a clinically meaningful difference in DFS has been observed [5].…”

“…The controversy has, to a large extent, focused on the question of whether such a trial should have been stopped early because of results related to DFS when an improvement in overall survival (OS) had not been demonstrated. Positions expressed have ranged from advocating that DFS should never be used as a primary endpoint [4] through arguing that while observing differences in DFS outcomes could be a legitimate reason for early publication, patients might not need to be unblinded if a benefit in OS had not been found [5] to stating that DFS is both a legitimate surrogate for OS in this setting and a valid endpoint in and of itself [9]. In general, the arguments took a dichotomous and conventional perspective: DFS was either the correct primary endpoint or it was not, and, if it was, the statistical methods that formed the basis for an early termination decision were correct [3].…”

“…This early ''termination'' or ''stopping'' of a large adjuvant trial has been the subject of considerable controversy [3][4][5][6][7][8][9]. The controversy has, to a large extent, focused on the question of whether such a trial should have been stopped early because of results related to DFS when an improvement in overall survival (OS) had not been demonstrated.…”

The capture–mark–recapture technique can be used as a stopping rule when searching in systematic reviews

“…Stopping trials based on accumulation of ''enough'' data is important and contentious and all decisions need to be strongly based on evidence [5]. Stopping rules for searching would be ideal in the production of systematic reviews, but no empirically derived stopping rules exist for this purpose.…”

“…Stopping rules have been used to decide when clinical trials should stop once benefit or harm has been identified [1,5]. Stopping trials based on accumulation of ''enough'' data is important and contentious and all decisions need to be strongly based on evidence [5].…”