Hidden changes to prespecified primary outcomes of clinical trials completed between 2009 and 2017 in German University Medical Centres: A meta-research study

Abstract

AbstractObjectivesTo assess how often clinical trials exhibit primary outcome discrepancies within registry records that would not be caught by comparing results publications to the latest registry entry, but would require analysing the registration history.DesignMeta-research study.SettingAll 1746 randomised clinical trials with published results, registered inClinicalTrials.govor Deutsches Register Klinischer Studien (DRKS), completed at German University Medical Centres between 2009 and 2017. We analysed registry entries for all trials and publications for a random sample of 292 trials.ParticipantsNot applicable.InterventionsNot applicable.Main outcome measures[1] Primary outcome discrepancies between registry entries at key study milestones and [2] the first results publication. [3] ‘Hidden’ discrepancies, i.e., only reported in the registry before the last entry, meaning they would only be detected by assessing the full registry change history. We considered discrepancies major if primary outcomes were newly added, dropped, or changed to or from secondary outcomes. [4] Proportion of publications transparently reporting discrepancies. [5] Characteristics associated with ‘open’ and ‘hidden’ discrepancies.ResultsOf all 1746 trials, 23% (n=393) had primary outcome discrepancies between trial start and latest registry entry, with 8% (n=142) being major. Primary outcomes in publications were different from the latest registry entry in 41% of trials (120 of the 292 sampled trials; 95% CI [35%, 47%]), with major discrepancies in 18% (54 of 292; 95% CI [14%, 23%]). ‘Hidden’ discrepancies were observed in 14% of trials (41/292; 95% CI [10%, 19%]). Only 1% of discrepancies were reported in the publications (2/161, 95% CI [0%, 4%]). Trials were more likely to have a within-registry discrepancy if they had an earlier registration year (OR 0.74; 95% CI [0.69, 0.80]), were registered onClinicalTrials.gov(OR 0.41; 95% CI [0.23, 0.70]), or had been industry-sponsored (OR 0.29; 95% CI [0.21, 0.41]).ConclusionsChanges to primary trial outcomes are common, often have major relevance, are rarely transparently reported and typically not detectable with an inspection of the latest registry entry. Authors need to be more transparent and registry entries of published trials need to require more in-depth analysis to reveal potentially misleading reporting practices.Protocol registrationOpen Science Framework (https://osf.io/t3qva; amendment inhttps://osf.io/qtd2b).