Mihaela Stegert1, Benjamin Kasenda2, Erik von Elm3, John J You4, Anette Blümle5, Yuki Tomonaga6, Ramon Saccilotto7, Alain Amstutz7, Theresa Bengough8, Matthias Briel9. 1. Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, Hebelstrasse 10, Basel 4031, Switzerland; Clinic of Internal Medicine, University Hospital Basel, Petersgraben 4, Basel 4031, Switzerland. 2. Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, Hebelstrasse 10, Basel 4031, Switzerland; Clinic of Medical Oncology, University Hospital Basel, Petersgraben 4, Basel 4031, Switzerland. 3. Cochrane Switzerland, Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la Corniche 10, Lausanne 1010, Switzerland. 4. Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, HSC-2C8, Hamilton, Ontario, Canada L8S 4K1; Department of Medicine, McMaster University, 1280 Main Street West, HSC-2C8, Hamilton, Ontario, Canada L8S 4K1. 5. German Cochrane Centre, Medical Center, University of Freiburg, Berliner Allee 29, Freiburg 79110, Germany. 6. Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, Zurich 8001, Switzerland. 7. Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, Hebelstrasse 10, Basel 4031, Switzerland. 8. Cochrane Switzerland, Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la Corniche 10, Lausanne 1010, Switzerland; Department of Health and Society, Austrian Federal Institute for Health Care, Stubenring 6, Vienna 1010, Austria. 9. Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, Hebelstrasse 10, Basel 4031, Switzerland; Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, HSC-2C8, Hamilton, Ontario, Canada L8S 4K1. Electronic address: matthias.briel@usb.ch.
Abstract
OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.
OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.
Authors: Natalie A Dilts; Frank E Harrell; Christopher J Lindsell; Samuel Nwosu; Thomas G Stewart; Matthew S Shotwell; Jill M Pulley; Terri L Edwards; Emily Sheffer Serdoz; Katelyn Benhoff; Gordon R Bernard Journal: J Clin Transl Sci Date: 2022-04-11
Authors: S D Walter; H Han; G H Guyatt; D Bassler; N Bhatnagar; V Gloy; S Schandelmaier; M Briel Journal: BMC Med Res Methodol Date: 2020-01-16 Impact factor: 4.615