Quantifying over-estimation in early stopped clinical trials and the "freezing effect" on subsequent research

Background:Despite the wide use of the design with statistical stopping guidelines to stop a randomized clinical trial early for efficacy, there are unsettled debates of potential harmful consequences of such designs. These concerns include the possible over-estimation of treatment effects in early stopped trials and a newer argument of a “freezing effect” that will halt future randomized clinical trials on the same comparison since an early stopped trial represents an effective declaration that randomization to the unfavored arm is unethical. The purpose of this study is to determine the degree of bias in designs that allow for early stopping and to assess the impact on estimation if indeed future experimentation is “frozen” by an early stopped trial.Methods:We perform simulations to study the effect of early stopping. We simulate a collection of trials and contrast the treatment-effect estimates (risk differences and ratios) with the simulation truth. Simulations consider various scenarios of between-st...