Association between trial registration and treatment effect estimates: a meta-epidemiological study

Abstract

BackgroundTo increase transparency in research, the International Committee of Medical Journal Editors required, in 2005, prospective registration of clinical trials as a condition to publication. However, many trials remain unregistered or retrospectively registered. We aimed to assess the association between trial prospective registration and treatment effect estimates.MethodsThis is a meta-epidemiological study based on all Cochrane reviews published between March 2011 and September 2014 with meta-analyses of a binary outcome including three or more randomised controlled trials published after 2006. We extracted trial general characteristics and results from the Cochrane reviews. For each trial, we searched for registration in the report’s full text, contacted the corresponding author if not reported and searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in case of no response. We classified each trial as prospectively registered (i.e. registered before the start date); retrospectively registered, distinguishing trials registered before and after the primary completion date; and not registered. Treatment effect estimates of prospectively registered and other trials were compared by the ratio of odds ratio (ROR) (ROR <1 indicates larger effects in trials not prospectively registered).ResultsWe identified 67 meta-analyses (322 trials). Overall, 225/322 trials (70 %) were registered, 74 (33 %) prospectively and 142 (63 %) retrospectively; 88 were registered before the primary completion date and 54 after. Unregistered or retrospectively registered trials tended to show larger treatment effect estimates than prospectively registered trials (combined ROR = 0.81, 95 % CI 0.65–1.02, based on 32 contributing meta-analyses). Trials unregistered or registered after the primary completion date tended to show larger treatment effect estimates than those registered before this date (combined ROR = 0.84, 95 % CI 0.71–1.01, based on 43 contributing meta-analyses).ConclusionsLack of trial prospective registration may be associated with larger treatment effect estimates.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0639-x) contains supplementary material, which is available to authorized users.

Impact of industry collaboration on randomised controlled trials in oncology

“…Since 2005, the International Committee of Medical Journal Editors (ICMJE), on behalf of its participating journals, has required prospective registration of all clinical trials 28 ; this move was designed in part to limit publication bias that may have led to a lower likelihood of publication of negative studies in which industry collaborated or simply funded, and has been broadly supported. 29,30 Although trial registration remains incomplete 31 and its impact on publication of negative trials has been disappointing, 32 among the more recent publications we evaluated the ICMJE policy may be blunting the previously documented effect of industry collaboration on positive results. Our negative finding may also relate to other changes regarding author transparency.…”

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“…The authors could not compare effect size changes between older and newer studies, because usually the more recent publications were so few that such a comparison was underpowered. According to Dechartres et al (2016)’s meta-meta-analysis of which variables affect meta-analysis treatment effect estimates, study age was one of the very few variables which did not seem to influence results.…”

Focus on sharing individual patient data distracts from other ways of improving trial transparency

“…14 As well as the problems of selective publication of trials and outcomes, unregistered trials, or those registered after the completion date, tend to yield larger estimates of treatment effects than those registered before completion. 15 Trial registration is simple, inexpensive, and uses existing systems such as ClinicalTrials.gov. The AllTrials campaign has been championing trial registration for all trials, as well as calling for summary results and a full report (full methods, analyses, and results) to be publicly available, but the campaign has stated explicitly: "We do not call for individual patient data to be made publicly available."…”