When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable Conclusions: Three Examples

Abstract: Journal of Clinical Medicine Opinion When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable Conclusions: Three Examples David E. Scheim 1, * , Colleen Aldous 2 , Barbara Osimani 3 , Edmund J. Fordham 4 1 2 3 4 5 * Citation: Scheim, D.E.; Aldous, C.; Osimani, B.; Fordham, E.J.; Hoy, W.E. When Characteristics of Clinical and Wendy E. Hoy 5 US Public Health Service, Commissioned Corps, Inactive Reserve, Blacksburg, VA 24060, USA College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa Center for Philosophy, Science, and Policy, Faculty of Medicine, Marche Polytechnic University, 60121 Ancona, Italy EbMCsquared CIC, Bath BA2 4BL, UK Centre of Chronic Disease, Faculty of Medicine, University of Queensland, Brisbane 4072, Australia Correspondence: dscheim@alum.mit.edu Abstract: Under exceptional circumstances, including high rates of protocol non-compliance, perprotocol (PP) analysis can better indicate the real-world benefits of a medical intervention than intention-to-treat (ITT) analysis. Exemplifying this, the first randomized clinical trial (RCT) considered found that colonoscopy screenings were marginally beneficial, based upon ITT analysis, with only 42% of the intervention group actually undergoing the procedure. However, the study authors themselves concluded that the medical efficacy of that screening was a 50% reduction in colorectal cancer deaths among that 42% PP group. The second RCT found a ten-fold reduction in mortality for a COVID-19 treatment drug vs. placebo by PP analysis, but only a minor benefit by ITT analysis. The third RCT, conducted as an arm of the same platform trial as the second RCT, tested another COVID-19 treatment drug and reported no significant benefit by ITT analysis. Inconsistencies and irregularities in the reporting of protocol compliance for this study required consideration of PP outcomes for deaths and hospitalizations, yet the study coauthors refused to disclose them, instead directing inquiring scientists to a data repository which never held the study’s data. These three RCTs illustrate conditions under which PP outcomes may differ significantly from ITT outcomes and the need for data transparency when these reported or indicated discrepancies arise. Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Keywords: intention-to-treat; per-protocol; colonoscopy; fluvoxamine; ivermectin; COVID-19 Reliable Conclusions: Three Examples. J. Clin. Med. 2023, 12, 3625. https://doi.org/10.3390/jcm12113625 Academic Editor: Giuseppe Migliaretti Received: 4 April 2023 Revised: 10 May 2023 Accepted: 19 May 2023 Published: 23 May 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).