When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable Conclusions: Three Examples
David E Scheim, Colleen Aldous, Barbara Osimani, Edmund J Fordham, Wendy E Hoy
Journal of Clinical Medicine, doi:10.3390/jcm12113625
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.
Author Contributions: Methodology, B.O., C.A., E.J.F., D.E.S. and W.E.H.; formal analysis, D.E.S. and E.J.F.; writing-original draft preparation, D.E.S.; writing-review and editing, B.O., C.A., E.J.F., D.E.S. and W.E.H.; All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations The The DSS of the study as published on this date promised access to its "complete de-identified data set" at the ICODA data repository beginning "immediately after publication" [26] . 10 May 2022. A letter from 66 scientists and physicians requesting the study's four outcome numbers of key importance, PP death and hospitalization rates, IVM vs. placebo, was emailed to study coauthors, and copied to 39 scientists and science journalists [24] . 10 May 2022. TOGETHER trial coauthor David Boulware replied, declining to provide those outcome numbers and directing the letter signatories to the ICODA data repository [25] . 7 June 2022. An ICODA manager sent an email to a scientist who had inquired about this data, stating "ICODA does not hold the data and we have requested that the authors update the data sharing agreement to reflect that" [28] . 8 June 2022. Three of us (DES, CA, EJF) emailed the TOGETHER trial coauthors and cc's of the above-cited email thread, quoting the above statement from that ICODA manager, that ICODA never hosted the study's data [24] . The..
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