Maturation of effect size during enrollment of prospective randomized trials

Randomized clinical trials are powered by calculating the minimum sample size required to achieve statistical significance, given an estimated effect size (ES). The ES is the raw difference between two treatment arms. ES quantifies the actual magnitude of clinical differences between cohorts and is usually reflective of the true meaning of the trial, regardless of statistical significance. Under a fixed protocol, we hypothesize that the ES may be attained at a smaller sample than predesigned. To investigate patterns of ES during enrollment, we analyzed completed trials that were completed at our institution.

Outcomes of 11 prospective randomized clinical trials from our institution were reviewed. ES was calculated at intervals throughout each trial to determine at which point a steady clinical difference was achieved between treatment cohorts.

ES stabilized at a median of 64% enrollment. All patients were needed to meet the precise ES in our smallest study, indicating the need for full enrollment in smaller studies. Otherwise, 50% of our trials required between 48% and 76% of patient enrollment to meet ES. In comparing clinical outcomes, 9 of 12 found a final difference that was nearly identical to the difference that could have been determined much earlier. Categorical outcomes met stabilized ES at 51% enrollment and continuous outcomes at 68%.

ES and final clinical outcomes were achieved before the completion of enrollment for most of our studies. This suggests that clinical differences detected by randomization may not necessarily require the robust sample size often needed to establish statistical significance. This is particularly relevant in fixed-protocol interventional trials of homogenous populations.