Learning from failure - rationale and design for a study about discontinuation of randomized trials (DISCO study)

Abstract

BackgroundRandomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs.Methods/DesignOur aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs.We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment.DiscussionOur study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules

“…The rationale and design of the retrospective cohort as well as other results have previously been published [14,15].…”

“…The present analyses were part of a larger project investigating the prevalence and publication of discontinued RCTs in an international, multicenter cohort of RCT protocols across all medical fields [14,15]. We worked in close collaboration with RECs and had unrestricted access to their archived RCT protocols and corresponding files.…”

“…If we could not elucidate the reason for trial discontinuation or if poor participant recruitment was mentioned, we used a pre-specified cut-off of less than 90% of achieved target sample size to determine discontinuation [14,15]. We considered a trial as discontinued based on a pre-specified stopping rule if the reported reason for discontinuation matched the purpose of a planned interim analysis or stopping rule mentioned in the protocol.…”

“…Twelve investigators trained in clinical research methodology independently extracted data from eligible trial protocols including study design, number of centres, clinical field, details about the intervention arms, trial funding and initiation, planned sample size, follow-up time, and planned statistical analyses [14]. The initial 30% of the protocol extractions were completed in duplicate.…”

“…If the REC files provided no information about the publication status of a trial, we conducted comprehensive searches of electronic databases (Medline, Embase, Google Scholar, Cochrane CENTRAL register of clinical trials, trial registries such as ClincialTrials.gov and registries of sponsors, if publicly available) to find any associated publications [14]. If trial publication or completion status still remained unclear, the REC in charge conducted a survey of investigators by sending them a standardized questionnaire (see Appendix).…”