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Open Access Study protocol

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

Benjamin Kasenda1, Erik B von Elm23, John You45, Anette Blümle3, Yuki Tomonaga6, Ramon Saccilotto1, Alain Amstutz1, Theresa Bengough2, Jörg Meerpohl3, Mihaela Stegert1, Kari A O Tikkinen47, Ignacio Neumann4, Alonso Carrasco-Labra4, Markus Faulhaber4, Sohail Mulla4, Dominik Mertz4, Elie A Akl48, Dirk Bassler9, Jason W Busse104, Ignacio Ferreira-González11, Francois Lamontagne12, Alain Nordmann1, Rachel Rosenthal13, Stefan Schandelmaier14, Xin Sun15, Per O Vandvik16, Bradley C Johnston17, Martin A Walter18, Bernard Burnand2, Matthias Schwenkglenks6, Heiner C Bucher1, Gordon H Guyatt4 and Matthias Briel14*

  • * Corresponding author: Matthias Briel brielm@uhbs.ch

  • † Equal contributors

Author affiliations

1 Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Hebelstrasse 10, 4031, Basel, Switzerland

2 Cochrane Switzerland, Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland

3 German Cochrane Centre, Institute of Medical Biometry and Medical Informatics, University Medical Centre Freiburg, Freiburg, Germany

4 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

5 Department of Medicine, McMaster University, Hamilton, Ontario, Canada

6 Institute for Social and Preventive Medicine, Zurich, Switzerland

7 Department of Urology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

8 Departments of Medicine and Family Medicine, State University of New York at Buffalo, Buffalo, NY, USA

9 Department of Neonatology and Center for Pediatric Clinical Studies, University Children’s Hospital Tübingen, Tübingen, Germany

10 Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada

11 Epidemiology Unit, Department of Cardiology, Vall d'Hebron Hospital and CIBER de Epidemiología y Salud Publica (CIBERESP), Barcelona, Spain

12 Centre de Recherche Clinique Étienne-Le Bel and Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada

13 Department of Surgery, University Hospital Basel, Basel, Switzerland

14 Academy of Swiss Insurance Medicine, University Hospital Basel, Basel, Switzerland

15 Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA

16 Norwegian Knowledge Centre for the Health Services, Oslo, Norway

17 Department of Anesthesia & Pain Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada

18 Department of Nuclear Medicine, University Hospital Bern, Bern, Switzerland

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Citation and License

BMC Medical Research Methodology 2012, 12:131  doi:10.1186/1471-2288-12-131

Published: 28 August 2012

Abstract

Background

Randomized 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/Design

Our 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.

Discussion

Our 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.

Keywords:
Randomized controlled trial; Trial discontinuation; Slow recruitment; Ethics committees; Trial protocols