Adherence To Prospective Registration Policy And Implications For Clinical Trial Endpoint Integrity

ADHERENCE TO PROSPECTIVE REGISTRATION POLICY AND IMPLICATIONS FOR CLINICAL TRIAL ENDPOINT INTEGRITY Anand D. Gopal, Joshua D. Wallach, Jenerius A. Aminawung, Gregg Gonsalves, Rafael Dal-Ré, Jennifer E. Miller, Joseph S. Ross. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT Abstract: Since implementation of the International Committee of Medical Journal Editors’ (ICMJE) prospective registration policy in 2005, trial registration has increased significantly. Registering clinical trials is critical in promoting transparency and integrity in medical research, however trials must be registered in an appropriate manner to deter unaccounted protocol modifications or selection of alternate endpoints that may enhance favorability of reported results. This thesis provides relevant background on clinical trial registration and appropriate reporting in addition to evaluating adherence with the ICMJE’s prospective trial registration policy and the implications of inappropriate adherence for the integrity of reported results. In a cross-sectional, retrospective analysis of recent trials published in the highest-impact journals associated with US professional medical societies, we identified the frequency of registrations occurring late in addition to those late enough to potentially permit protocol modifications based on premature examination of collected data. We further examined whether trials that are unregistered or registered late enough to permit interim analyses were more likely to report favorable results. We used descriptive statistics to characterize the proportions of trials that were: registered; registered retrospectively; registered retrospectively potentially after initial ascertainment of primary endpoints; and reporting favorable results, overall and stratified by journal and trial characteristics. Among 486 trials published between January 1, 2010 and December 31, 2015, 47 (10%) were unregistered. Among 439 registered trials, 340 (77%) were registered prospectively and 99 (23%) retrospectively. Sixty-seven (68%) of these 99 retrospectively registered trials, or 15% of all 439 registered trials, were registered late enough to have potentially permitted premature examination of primary endpoint Since implementation of the International Committee of Medical Journal Editors’ (ICMJE) prospective registration policy in 2005, trial registration has increased significantly. Registering clinical trials is critical in promoting transparency and integrity in medical research, however trials must be registered in an appropriate manner to deter unaccounted protocol modifications or selection of alternate endpoints that may enhance favorability of reported results. This thesis provides relevant background on clinical trial registration and appropriate reporting in addition to evaluating adherence with the ICMJE’s prospective trial registration policy and the implications of inappropriate adherence for the integrity of reported results. In a cross-sectional, retrospective analysis of recent trials published in the highest-impact journals associated with US professional medical societies, we identified the frequency of registrations occurring late in addition to those late enough to potentially permit protocol modifications based on premature examination of collected data. We further examined whether trials that are unregistered or registered late enough to permit interim analyses were more likely to report favorable results. We used descriptive statistics to characterize the proportions of trials that were: registered; registered retrospectively; registered retrospectively potentially after initial ascertainment of primary endpoints; and reporting favorable results, overall and stratified by journal and trial characteristics. Among 486 trials published between January 1, 2010 and December 31, 2015, 47 (10%) were unregistered. Among 439 registered trials, 340 (77%) were registered prospectively and 99 (23%) retrospectively. Sixty-seven (68%) of these 99 retrospectively registered trials, or 15% of all 439 registered trials, were registered late enough to have potentially permitted premature examination of primary endpoint data ascertained among participants enrolled at inception. Unregistered trials were more likely to report favorable results than registered trials (89% vs. 64%; p=0.004), irrespective of registration timing. Adherence to the ICMJE’s prospective registration policy remains sub-standard, even in the highest impact journals associated with US professional medical societies. These journals frequently published unregistered trials and trials registered late enough to have potentially experienced unaccounted protocol modifications after observation of primary endpoints. ACKNOWLEDGEMENTS The authors would like to thank Alexander R. Bazazi, BA and Joseph Herrold, MD, MPH for their efforts in drafting earlier versions of the study protocol. Funding/support and role of the sponsor: This work was supported in part by the Laura and John Arnold Foundation to support the Collaboration for Research Integrity and Transparency (CRIT) at Yale, including Drs. Wallach, Gonsalves, and Ross. Dr. Miller also receives support from the Laura and John Arnold Foundation. The Foundation played no role in the design of the study, analysis or interpretation of findings, or drafting the manuscript and did not review or approve the manuscript prior to submission. The authors assume full responsibility for the accuracy and completeness of the ideas presented.