{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T17:15:42Z","timestamp":1772212542502,"version":"3.50.1"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T00:00:00Z","timestamp":1633910400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["681044"],"award-info":[{"award-number":["681044"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>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\u2019s 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\u2019s ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial\u2019s 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0258093","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T16:58:21Z","timestamp":1633971501000},"page":"e0258093","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["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"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8938-2284","authenticated-orcid":true,"given":"Jean-Pierre","family":"Boissel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"P\u00e9rol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herv\u00e9","family":"D\u00e9cousus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid","family":"Klingmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Hommel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,10,11]]},"reference":[{"key":"pone.0258093.ref001","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1056\/NEJM198707163170304","article-title":"Equipoise and the ethics of clinical research","volume":"317","author":"B Freedman","year":"1987","journal-title":"N Engl J Med"},{"key":"pone.0258093.ref002","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrclinonc.2017.8","article-title":"Precision medicine needs randomized clinical trials","volume":"14","author":"ED Saad","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"pone.0258093.ref003","doi-asserted-by":"crossref","first-page":"e0173042","DOI":"10.1371\/journal.pone.0173042","article-title":"Worldwide trends in volume and quality of published protocols of randomized controlled trials","volume":"12","author":"BV van Rosmalen","year":"2017","journal-title":"PLoS One"},{"key":"pone.0258093.ref004","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1002\/cpt1979255part2728","article-title":"Some ethical considerations in clinical trials","volume":"25","author":"R Levine","year":"1979","journal-title":"Clin Pharmacol Ther"},{"key":"pone.0258093.ref005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.publhealth.031308.100223","article-title":"Adaptive designs for randomized trials in public health","volume":"30","author":"CH Brown","year":"2009","journal-title":"Annu Rev Public Health"},{"key":"pone.0258093.ref006","doi-asserted-by":"crossref","first-page":"457","DOI":"10.2147\/CLEP.S242097","article-title":"Synthetic and External Controls in Clinical Trials\u2013A Primer for Researchers","volume":"12","author":"K Thorlund","year":"2020","journal-title":"Clin Epidemiol"},{"key":"pone.0258093.ref007","first-page":"244","article-title":"Design, and management of large multicenter clinical trials","volume":"60","author":"RD Remington","year":"1978","journal-title":"Clin Pharmacol Ther"},{"key":"pone.0258093.ref008","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0895-4356(94)00150-O","article-title":"Large-scale randomized evidence: large simple trials and overviews of trials","volume":"48","author":"R Peto","year":"1995","journal-title":"J Clin Epidemiol"},{"key":"pone.0258093.ref009","unstructured":"Statistical Principals for Clinical Trials. 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