Using numerical modeling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample

Abstract

In order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment's efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT's ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial's statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.

Fig 1. Relations between the proportion of responders in the trial sample and major features of the trial.

Panel A, shows the linear decrease of the ethical losses expressed in percentage of unnecessary patients with the increase of the percentage of responders. Panel B, keeping the number of responders in the T group constant at n = 121, the sample size drops abruptly from more than 7,000 to less than 1,000 when the responder percentage increases up to about 20% to then flatten until the “perfect” trial status is reached, meaning that only responders are enrolled. Panel C, the relative risk decreases rapidly until the responder percentage reaches about 40%, from less than 0.8 to about 0. Panel D, the chi-square value of the comparison test of mortality rates between placebo and treatment groups increases linearly as the percentage of responders increases. The probability of ascertaining significance increases as well.