12 Mar Randomized Controlled Trials: 25% Discontinued, Mostly in Patient Studies
MedicalResearch.com Interview with:
Matthias Briel, MD, MSc
Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital of Basel, Basel, Switzerland
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
MedicalResearch.com: What are the main findings of the study?
Dr. Briel: Using a retrospective cohort of 1017 randomized controlled trials (RCTs) based on archived protocols approved by six research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003, we found that 25% of initiated RCTs were discontinued. While discontinuation was common with RCTs involving patients (28%), it was rare in RCTs with healthy volunteers (3%). The most commonly reported reason for RCT discontinuation was poor recruitment (10% of included RCTs). We found that trials with investigator sponsor (versus industry) and those with smaller planned sample sizes were at higher risk of discontinuation due to poor recruitment. Of discontinued RCTs, up to 60% remained unpublished. Trial investigators rarely informed research ethics committees about trial discontinuation and publication.
MedicalResearch.com: Were any of the findings unexpected?
Dr. Briel: We did not expect such a poor reporting to ethics committees. Overall, only 96 of 253 discontinuations (38%) were reported to research ethics committees. For randomized controlled trials discontinued due to poor recruitment discontinuation was reported in 24 of 101 RCTs (24%), for RCTs discontinued due to futility it was 16 of 37 RCTs (43%), and for RCTs discontinued due to harm it was 13 of 24 RCTs (54%).
MedicalResearch.com: What should clinical researchers and patients take away from your report?
Dr. Briel: Our findings indicate that ethical obligations of RCTs are frequently not met. Failure to report premature discontinuation to ethics committees limits the ethics committees’ ability to carry out their mandate of ensuring ethical trial conduct and to monitor problematic randomized controlled trials. Not sharing with the scientific community the challenges resulting in RCT discontinuation removes any opportunity for learning within the trialist community, including identifying risks and instituting preventative action. Non-publication of inconclusive results leads to loss of valid evidence that could contribute to systematic reviews and meta-analyses. Our findings also highlight the necessity of current efforts to enhance the transparency, quality, and accessibility of trial protocols and results such as the ‘Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)’ and ‘AllTrials’ (www.alltrials.net) initiatives. Patient recruitment to trials should be closely monitored and contingency plans should be in place if it is lower than expected.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Briel: For investigator-initiated RCTs, stakeholders including trial investigators, funding agencies, and ethics committees need to develop strategies to prevent trial discontinuation. Based on our data retrospective or prospective screening of patients appears to hold little promise in estimating recruitment rates, but conducting a pilot study including patients’ consent to check that recruitment strategies are adequate might be effective. Further research is necessary to determine the optimal length of pilot trials and to develop reliable prediction models for recruitment performance.
Citation:
Prevalence, Characteristics, and Publication of Discontinued Randomized Trials
Last Updated on March 12, 2014 by Marie Benz MD FAAD