Benjamin Kasenda1, Erik von Elm2, John You3, Anette Blümle4, Yuki Tomonaga5, Ramon Saccilotto1, Alain Amstutz1, Theresa Bengough2, Joerg J Meerpohl4, Mihaela Stegert1, Kari A O Tikkinen6, Ignacio Neumann7, Alonso Carrasco-Labra8, Markus Faulhaber9, Sohail M Mulla10, Dominik Mertz11, Elie A Akl12, Dirk Bassler13, Jason W Busse14, Ignacio Ferreira-González15, Francois Lamontagne16, Alain Nordmann1, Viktoria Gloy17, Heike Raatz1, Lorenzo Moja18, Rachel Rosenthal19, Shanil Ebrahim20, Stefan Schandelmaier21, Sun Xin22, Per O Vandvik23, Bradley C Johnston24, Martin A Walter25, Bernard Burnand2, Matthias Schwenkglenks5, Lars G Hemkens1, Heiner C Bucher1, Gordon H Guyatt10, Matthias Briel26. 1. Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital of Basel, Basel, Switzerland. 2. Cochrane Switzerland, Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland. 3. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada14Department of Medicine, McMaster University, Hamilton, Ontario, Canada. 4. German Cochrane Centre, Institute of Medical Biometry and Medical Informatics, Freiburg University Medical Center, Freiburg, Germany. 5. Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland. 6. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada15Department of Urology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland. 7. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada16Department of Internal Medicine, Pontificia Universidad Catolica de Chile, Santiago. 8. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada25Evidence-Based Dentistry Unit, Faculty of Dentistry, Universidad de Chile, Santiago. 9. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada17Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada. 10. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. 11. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada26Michael G. DeGroote Institute for Infectious Diseases Research, McMaster University, Hamilton, Ontario, Canada. 12. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada18Department of Internal Medicine, American University of Beirut, Beirut, Lebanon19Department of Medicine, State University of New York at Buffalo, Buffal. 13. Center for Pediatric Clinical Studies, Department of Neonatology, University Children's Hospital, Tuebingen, Germany. 14. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada20Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada27Michael G. DeGroote Institute for Pain Research and Care, McMaster University. 15. Epidemiology Unit, Department of Cardiology, Vall d'Hebron Hospital and CIBER de Epidemiología y Salud Publica (CIBERESP), Barcelona, Spain. 16. Centre de Recherche Clinique Étienne-Le Bel and Department of Medicine, Université de Sherbrooke, Sherbrooke, Canada. 17. Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital of Basel, Basel, Switzerland13Institute of Nuclear Medicine, University Hospital Bern, Bern, Switzerland. 18. IRCCS Orthopedic Institute Galeazzi, Milano, Italy. 19. Department of Surgery, University Hospital Basel, Basel, Switzerland. 20. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada20Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada21Stanford Prevention Research Center, Stanford University, Stanford, California. 21. Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital of Basel, Basel, Switzerland22Academy of Swiss Insurance Medicine, University Hospital of Basel, Basel, Switzerland. 22. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada23Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China. 23. Department of Medicine, Innlandet Hospital Trust-Division Gjøvik, Oppland, Norway. 24. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada12Department of Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, Ontario, Canada24Institute of Health Policy, Management and Evaluation. 25. Institute of Nuclear Medicine, University Hospital Bern, Bern, Switzerland. 26. Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital of Basel, Basel, Switzerland3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
Abstract
IMPORTANCE: The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES: To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING: Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES: Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS: After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE: In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.
IMPORTANCE: The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES: To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING: Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES: Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS: After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE: In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.
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