How do clinical researchers’ and patients’ preferences influence study hypotheses and reported outcome results for clinical randomised controlled trials? A critical appraisal

ABSTRACT Background Studies designed to promote unbiased research increasingly show that human preferences exert a major influence on randomised controlled trials (RCTs) [ , , ]. More information is needed on how preferences influence clinical trial design and conduction [ , , ]. To fill the information gap between what researchers seek and report and what patients want [ , ], in this study we investigated how researchers’ and patients’ preferences influence study hypotheses and outcome results of published clinical RCTs. Because conventional critical appraisal seemed inappropriate for addressing our research question, in this pilot study we developed a novel assessment method and applied it in an RCT sample. Methods We collected 20 unselected and consecutive RCTs published in a high impact paediatric journal from July to November 2013. Two experienced reviewers identified the following five domains and a grading method to score discrepancy between what authors state in clinical trial registries (CTRs) and report in published RCTs: reported funding (1 point), study hypotheses, information on patients enrolled and study conduction (3 points); primary and secondary outcomes, early study completion, and upgrading or downgrading outcome results (5 points). Higher scores implied marked discrepancy. Two reviewers then independently applied the method on the RCT sample by mapping and coding information for the domains identified and reported discrepancies by comparing CTRs and RCTs (Table). Results Of the 20 RCTs collected and CTRs compared, 14 studies had high total preference discrepancy scores (7 scored 10-12, and 7 scored 16 or more) and 4 had discrepancy in declaring funding. In 12 studies researchers completed the study early and in 8 studies they downgraded or upgraded outcomes. Only 5 CTRs were updated but they neglected to include published RCT results. Only in 5 CTRs, dataset supervisors indicated the RCT URL. None of the 20 RCTs allowed us to assess patients’ preferences (no information reported for non-response and refusal). No difference was found in discrepancy scores among the five CTR databases. Conclusions The high discrepancy scores obtained by comparing what researchers stated in CTRs and published in RCTs suggest possible misconduct. Patients’ preferences during RCT enrolment and conduction remain undetectable owing to the lack of targeted protocols to elicit this issue. These results, if confirmed in further studies, should prompt international regulation developers [2] to encourage researchers to explore patients’ preferences as a strategy to enhance informed decision-making and to improve reporting in RCTs and CTRs.   Table. Reviewers’ estimated discrepancy score between issues reported by authors in clinical trials registries and what they report in published randomised controlled trials National Registries and number of trial registration First author and reference in RCTs published in Pediatrics Total preference discrepancy score High 10-20 Medium 5-9 Low <5 International Standard Randomised Controlled Trial Number Register, BioMed Central, UK ISRCTN 31707342 www.controlled-trials.com McCarthy LK et al. 132, 1, e135-e141 July 2013 0 Low US National Controlled Trials NCT 01822626 https://clinicaltrials.gov Davoli A.M. et al. 132, 5, e1236-e1245 Oct 2013 2 Low International Standard Randomised Controlled Trial Number Register, BioMed Central, UK ISRCTN 59061709 www.controlled-trials.com McCarthy LK et al. 132, 2, e389-e395 Aug 2013 2 Low Australian New Zealand Clinical Trial Registry ACTRN 12608000056392 https://www.anzctr.org.au Daniels LA et al. 132, 1, e109- e118 July 2013 3 Low Netherlands Trial Registry NTR1613 www.trialregister.nl Van der Veek et al. 132, 5, e1163-e1172 Nov 2013 3 Low US National Controlled Trials NCT 00409448 https://clinicaltrials.gov Kurowski et al. 132, 1, e158-e166 Jul 2013 6 Medium US National Controlled Trials NCT00548379 https://clinicaltrials.gov Aluisio A.R. et al. 132,4, e832-e840 Oct 2013 10 High International Standard Randomised Controlled Trial Number Register, BioMed Central, UK ISRCTN 72635512 www.controlled-trials.com Field 132, 5, e1247-e1256 Nov 2013 12 High US National Controlled Trials NCT 01307293 https://clinicaltrials.gov Shaw RJ et al. 132, 4, e886-e894 Oct 2013 12 High International Standard Randomised Controlled Trial Number Register, BioMed Central, UK ISRCTN 03981121 www.controlled-trials.com Wake M et al. 132, 4, e895-e904 Oct 2013 12 High Clinical Trials Registry India CTRI/2010/091/001417 www.ctri.nic.in Malik A et al. 132, 1, e46-e52 July 2013 12 High US National Controlled Trials NCT 01351064 https://clinicaltrials.gov Carroll A.E. 132, 3, e623-e 629 Sept 2013 12 High Netherlands Trial Registry NTR 2061 www.trialregister.nl and Australian New Zealand Clinical Trial Registry ACTRN 12610000230055 https://www.anzctr.org.au Kamlin COF et al. 132, 2, e381-e388 Aug 2013 12 High US National Controlled Trials NCT 01403623 https://clinicaltrials.gov Leadford AE et al. 132, 1, e128-e134 Jul 2103 16 High US National Controlled Trials NCT 01810978 https://clinicaltrials.gov Dilli D. et al. 132, 4, e932-e938 Oct 2013 17 High US National Controlled Trials NCT 00334737 https://clinicaltrials.gov/ Ohls RK et al. 132, 1, e119-e127 Jul 2013 17 High US National Controlled Trials NCT 01065272 https://clinicaltrials.gov Alansari K. et al. 132,4, e810-e816 Sept 2013 17 High Australian New Zealand Clinical Trial Registry ACTRN 12612000976886 https://www.anzctr.org.au McIntosh CG et al. 132, 2, 326-331 Aug 2013 17 High US National Controlled Trials NCT 00551642 https://clinicaltrials.gov Durrmeyer X et al. 132,3, e695-e703 Sept 2013 18 High US National Controlled Trials NCT 01604460 https://clinicaltrials.gov Belsches et al 132, 3, e656-e661 Sept 2013 18 High