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.

Jean-Pierre Boissel,David Pérol,Ingrid Klingmann,Hervé Décousus,Marc Hommel

doi:10.1371/journal.pone.0258093

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.

Highlights

Ethical loss in randomized controlled clinical trials (RCTs) is an intuitive and rather vague concept, which can be outlined at a first glance as a loss of chance, i.e. everything an individual either misses or experience as detrimental as a result of participating in a RCT
There are various types of ethical concerns linked to randomization: prior to launching a trial of a new treatment, randomizing participants to conventional treatments that is deemed less effective is a breach of the equipoise principle, just as happen with allocation to a placebo, or to a known sham treatment; once the trial is completed, if the experimental treatment turns out to be either more effective or less effective, participants in the control arm or those in the experimental arm, respectively, face a loss of chance
Several alternatives to traditional RCTs have been proposed recently to address some of these ethical concerns: adaptive designs enabling planned interim analyses that can lead to a reduction of the total number of randomized participants or to a deletion of study arms with inefficient treatment regimens and rerandomization of subjects to the more promising treatment arms; and external control arms that suppressed the need to randomize participants to the ‘conventional treatment’ [5,6]

Summary

Introduction

Ethical loss in randomized controlled clinical trials (RCTs) is an intuitive and rather vague concept, which can be outlined at a first glance as a loss of chance, i.e. everything an individual either misses or experience as detrimental as a result of participating in a RCT. RCTs remain the gold standard for evaluating the efficacy and safety of new therapies [2,3]. Despite their wide acceptance and applying the principle of ‘equipoise’, some questions of ethics in RCTs remain unanswered. Several alternatives to traditional RCTs have been proposed recently to address some of these ethical concerns: adaptive designs enabling planned interim analyses that can lead to a reduction of the total number of randomized participants or to a deletion of study arms with inefficient treatment regimens and rerandomization of subjects to the more promising treatment arms; and external control arms that suppressed the need to randomize participants to the ‘conventional treatment’ [5,6]

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Conclusion