Permissibility and necessity in the ethical justification of randomized controlled trials: the four quadrants framework and the case of endovascular thrombectomy trials for acute ischemic stroke.

OBJECTIVES

This study seeks to propose a novel framework for the ethical justification of randomized controlled trials (RCTs).

STUDY DESIGN AND SETTING

This paper develops a novel framework for the ethical evaluation of RCTs, explored through the example of trials on endovascular thrombectomy for acute ischemic stroke. We propose that RCTs can be categorized into four quadrants, where justification in each quadrant relates to different thresholds for permissibility (the ethical defensibility of the trial) and necessity (the social and scientific importance of conducting the trial).

RESULTS

Trials can be situated within four quadrants based on the interventions being compared: standard vs standard treatment in the alpha quadrant, standard vs novel treatment in the beta quadrant, standard vs no treatment in the gamma quadrant, and no treatment vs novel treatment in the delta quadrant. In each quadrant, the thresholds to establish permissibility and necessity will differ. The controversies that surrounded trials of thrombectomy for acute stroke can be understood as representing differing points of view about whether those trials should have been situated in the beta or delta quadrant. These differing conclusions highlight the importance of using a quadrant-based analysis in assessing the ethical permissibility and necessity of RCTs.

CONCLUSION

The proposed four quadrants framework provides a comprehensive and precise approach to assessing the ethical justification of RCTs. Implementing this framework could improve regulatory evaluations of RCTs and reduce unnecessary harm to trial participants, while balancing the objectives of scientific advancement.

PLAIN LANGUAGE SUMMARY

In medical research, randomized controlled trials (RCTs) are used to test how well treatments work. However, RCTs can place patients at risk, so they should be ethically justified. This paper introduces a "four quadrants" framework to help determine when trials are ethically justified. The method proposed in this paper divides RCTs into four categories, or quadrants, based on their epistemic circumstances, or what is known about the treatments being compared. First is the alpha quadrant, in which trials compare two standard treatments. Second is the beta quadrant, in which trials compare a standard treatment with a standard plus a new treatment. Third, the gamma quadrant includes trials that compare a standard treatment with no treatment. Fourth, the delta quadrant includes trials that compare a new treatment with no treatment. The trials matter because the strength of the case to conduct a trial in any one of these quadrants will be different based on the strength of the argument necessary to prove that it is both permissible (one could do it) and necessary (one should do it). Using this methodology, we analyzed the case of endovascular thrombectomy trials for acute ischemic stroke conducted in the 2010s. We show that analysis using the four quadrants approach helps to understand the ethical controversy that beset these trials and offers a way forward in terms of resolving future potential conflicts.