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When clinical research fails: A study of controlled trials that were discontinued

English title When clinical research fails: A study of controlled trials that were discontinued
Applicant Briel Matthias
Number 133540
Funding scheme Project funding
Research institution Institut für klinische Epidemiologie Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Methods of Epidemiology and Preventive Medicine
Start/End 01.02.2011 - 31.03.2013
Approved amount 276'667.00
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Keywords (13)

clinical research; randomized controlled trials; clinical trial recruitment; research ethics; dissemination of research; medical research methodology; clinical trial units; Clinical trials Switzerland; study protocols; research ethics committee; trial discontinuation; insufficient recruitment; publication history

Lay Summary (English)

Lead
Lay summary
Clinical trials may be discontinued for different reasons, for example when it becomes apparent that a clinically relevant treatment effect will not be seen; when unanticipated adverse effects occur; or when outcomes are clearly superior in one study group. In addition, many trials are discontinued due to insufficient recruitment (slow accrual) of participants. This has ethical implications because participants consent on the premise of contributing to the advancement of medical knowledge, research ethics committees and funding agencies spend considerable resources on reviewing protocols of planned studies, and finite resources for research are wasted. Little is known about the epidemiology of discontinued trials in Switzerland. We propose to assemble a cohort of clinical trials based on protocols approved by ethics committees in Lausanne, Basel, Lucerne, and Zurich between 2000 to 2004. We will explore other sources of trials, for example trials funded by the Swiss National Science Foundation. We will analyze this cohort to determine the risk of discontinuation of trials for different reasons. In a case-control study, we will focus on trials that were discontinued due to insufficient recruitment. We will compare these trials with trials that were completed and thus identify characteristics of study protocols associated with discontinuation due to poor recruitment. Finally, we will examine the publication history of trials that were discontinued, and assess to what extent lessons learnt have been disseminated. We will extract relevant data from the files of the collaborating ethics committees and from published trial reports, and through a survey of trialists. The study will be based on over 1000 protocols of clinical trials, and about 150 trials that were discontinued due to poor recruitment. The proposed research is timely: recruitment of participants has repeatedly been identified as a serious "bottleneck" in clinical research. The planning of effective recruitment strategies and anticipation of problems will be a core task of the Clinical Trial Units (CTUs) that have been established in Switzerland with the support of SNSF. Our study will provide important insights into the problems with recruitment of participants that were encountered in randomized trials conducted in Switzerland in the recent past. It will identify modifiable barriers to successful study completion and inform future recommendations to individual trialists, research groups and units providing methodological support.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Premature Discontinuation of Pediatric Randomized Controlled Trials: A Retrospective Cohort Study
Schandelmaier Stefan, Tomonaga Yuki, Bassler Dirk, Meerpohl Joerg J., von Elm Erik, You John J., Bluemle Anette, Lamontagne Francois, Saccilotto Ramon, Amstutz Alain, Bengough Theresa, Stegert Mihaela, Olu Kelechi K., Tikkinen Kari A.O., Neumann Ignacio, Carrasco-Labra Alonso, Faulhaber Markus, Mulla Sohail M., Mertz Dominik, Akl Elie A., Sun Xin, Busse Jason W., Ferreira-González Ignacio, Nordmann Alain, et al. (2017), Premature Discontinuation of Pediatric Randomized Controlled Trials: A Retrospective Cohort Study, in The Journal of Pediatrics, 184, 209-214.e1.
Premature Discontinuation of Prospective Clinical Studies Approved by a Research Ethics Committee - A Comparison of Randomised and Non-Randomised Studies
Blümle Anette, Schandelmaier Stefan, Oeller Patrick, Kasenda Benjamin, Briel Matthias, von Elm Erik (2016), Premature Discontinuation of Prospective Clinical Studies Approved by a Research Ethics Committee - A Comparison of Randomised and Non-Randomised Studies, in PLOS One, 11(10), e0165605.
Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials
Kasenda Benjamin, von Elm Erik, You John J., Blümle Anette, Tomonaga Yuki, Saccilotto Ramon, Amstutz Alain, Bengough Theresa, Meerpohl Joerg J., Stegert Mihaela, Olu Kelechi K., Tikkinen Kari A. O., Neumann Ignacio, Carrasco-Labra Alonso, Faulhaber Markus, Mulla Sohail M., Mertz Dominik, Akl Elie A., Bassler Dirk, Busse Jason W., Ferreira-González Ignacio, Lamontagne Francois, Nordmann Alain, Gloy Viktoria, et al. (2016), Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials, in PLOS Medicine, 13(6), e1002046-e1002046.
Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials.
Briel Matthias (2016), Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials., in PLOS Medicine, 13(6), e1002046.
An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules
Stegert Mihaela, Kasenda Benjamin, von Elm Erik, You John J., Blümle Anette, Tomonaga Yuki, Saccilotto Ramon, Amstutz Alain, Bengough Theresa, Briel Matthias (2016), An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules, in Journal of Clinical Epidemiology, 69, 152-60.
Premature Discontinuation of Randomized Trials in Critical and Emergency Care: A Retrospective Cohort Study
Schandelmaier Stefan, von Elm Erik, You John J., Blümle Anette, Tomonaga Yuki, Lamontagne Francois, Saccilotto Ramon, Amstutz Alain, Bengough Theresa, Meerpohl Joerg J., Stegert Mihaela, Olu Kelechi K., Tikkinen Kari A. O., Neumann Ignacio, Carrasco-Labra Alonso, Faulhaber Markus, Mulla Sohail M., Mertz Dominik, Akl Elie A., Sun Xin, Bassler Dirk, Busse Jason W., Ferreira-González Ignacio, Kasenda Benjamin, Briel Matthias (2016), Premature Discontinuation of Randomized Trials in Critical and Emergency Care: A Retrospective Cohort Study, in Critical Care Medicine, 44, 130-137.
Completion and publication rates of randomized controlled trials in surgery: An empirical study
Rosenthal Rachel, Kasenda Benjamin, Dell-Kuster Salome, Von Elm Erik, You John, Blümle Anette, Tomonaga Yuki, Saccilotto Ramon, Amstutz Alain, Bengough Theresa, Meerpohl Joerg J., Stegert Mihaela, Tikkinen Kari A O, Neumann Ignacio, Carrasco-Labra Alonso, Faulhaber Markus, Briel Matthias (2014), Completion and publication rates of randomized controlled trials in surgery: An empirical study, in Annals of Surgery, 262(1), 68-73.
Planning and reporting of quality-of-life outcomes in cancer trials
Schandelmaier S., Conen K., von Elm E., You J. J., Blümle A., Tomonaga Y., Amstutz A., Briel M., Kasenda Benjamin, Saccilotto R., Bengough T., Meerpohl J. J., Stegert M., Olu K. K., Tikkinen K. A O, Neumann I., Carrasco-Labra A. (2014), Planning and reporting of quality-of-life outcomes in cancer trials, in Annals of Oncology, 26(9), 1966-1973.
Subgroup analyses in randomised controlled trials: Cohort study on trial protocols and journal publications (BMJ (Online) (2014) 349 (g4539) DOI: 10.1136/bmj.g4539)
Kasenda Benjamin, Schandelmaier Stefan, Sun Xin, Von Elm Erik, You John, Blümle Anette, Tomonaga Yuki, Saccilotto Ramon, Amstutz Alain, Bengough Theresa, Meerpohl Joerg J., Stegert Mihaela, Olu Kelechi K., Tikkinen Kari A O, Neumann Ignacio, Carrasco-Labra Alonso, Faulhaber Markus, Mulla Sohail M., Mertz Dominik, Akl Elie A., Bassler Dirk, Busse Jason W., Ferreira-González Ignacio, Lamontagne Francois, Nordmann Alain (2014), Subgroup analyses in randomised controlled trials: Cohort study on trial protocols and journal publications (BMJ (Online) (2014) 349 (g4539) DOI: 10.1136/bmj.g4539), in BMJ (Online), 349, g4539.
Prevalence, characteristics, and publication of discontinued randomized trials
Kasenda Benjamin, Von Elm Erik, You John, Blümle Anette, Tomonaga Yuki, Saccilotto Ramon, Amstutz Alain, Bengough Theresa, Meerpohl Joerg J., Stegert Mihaela, Tikkinen Kari A O, Neumann Ignacio, Carrasco-Labra Alonso, Faulhaber Markus, Mulla Sohail M., Mertz Dominik, Akl Elie A. (2013), Prevalence, characteristics, and publication of discontinued randomized trials, in JAMA - Journal of the American Medical Association, 311(10), 1045-1051.
Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study).
Kasenda Benjamin, von Elm Erik B, You John, Blümle Anette, Tomonaga Yuki, Saccilotto Ramon, Amstutz Alain, Bengough Theresa, Meerpohl Jörg, Stegert Mihaela, Tikkinen Kari A O, Neumann Ignacio, Carrasco-Labra Alonso, Faulhaber Markus, Mulla Sohail, Mertz Dominik, Akl Elie A, Bassler Dirk, Busse Jason W, Ferreira-González Ignacio, Lamontagne Francois, Nordmann Alain, Rosenthal Rachel, Schandelmaier Stefan, Sun Xin (2012), Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study)., in BMC medical research methodology, 12, 131-131.

Collaboration

Group / person Country
Types of collaboration
McMaster University, Hamilton Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Ethikkommission Luzern Switzerland (Europe)
- Research Infrastructure
Ethikkommission Zürich Switzerland (Europe)
- Research Infrastructure
IUMSP Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Deutsches Cochrane Zentrum Freiburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ethikkommission Lausanne Switzerland (Europe)
- Research Infrastructure
Ethikkommission beider Basel Switzerland (Europe)
- Research Infrastructure
ISPM Zürich Switzerland (Europe)
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
23rd Cochrane Colloquium Talk given at a conference Agreements on publication rights: an investigation of protocols and publications of randomized clinical trials 03.10.2015 Vienna, Austria Briel Matthias; Burnand Bernard; Tomonaga Yuki; Kasenda Benjamin; Bucher Heiner C.; Von Elm Erik; Bengough Theresa;
23rd Cochrane Colloquium 2015 Talk given at a conference Premature discontinuation of studies approved by research ethics committees - a comparison of randomized and non-randomized clinical studies 03.10.2015 Vienna, Austria Kasenda Benjamin; Briel Matthias;
23rd Cochrane Colloquium 2015 Talk given at a conference Quality of life after cancer treatment is at high risk of reporting bias - a retrospective cohort study 03.10.2015 Vienna, Austria Kasenda Benjamin; Von Elm Erik; Briel Matthias;
REWARD/EQUATOR Meeting 2015 Poster Premature discontinuation of studies: A comparison of randomized and non-randomized clinical studies 28.09.2015 Edinburgh, Great Britain and Northern Ireland Briel Matthias; Kasenda Benjamin; Von Elm Erik;
OMU Séminaire sur les Politiques Pharmaceutiques à l'attention des experts francophones 2015 Individual talk Discontinuation and selection of outcomes: how medicine effects can be overpuffed eluding moral and scientific obligations 15.09.2015 Geneva, Switzerland Briel Matthias;
36th Annual Conference of the International Society of Clinical Biostatistics 2015 Individual talk "Believe it or not" - Empirical research on credibility criteria for subgroup analyses 24.08.2015 Utrecht, Netherlands Briel Matthias;
SGIM Congress 2015 Talk given at a conference Planning and reporting of quality of life outcomes in cancer trials 20.05.2015 Basel, Switzerland Briel Matthias; Von Elm Erik; Kasenda Benjamin; Tomonaga Yuki; Bucher Heiner C.;
11. Berner Nuklearmedizin Symposium 2014 Individual talk Abgebrochene Studien - zu früh gefreut? 15.11.2014 Bern, Switzerland Briel Matthias;
European and Swiss Congress of Internal Medicine 2014 Poster Subgroup analyses in randomized trials - the illusion of pre-specification 14.05.2014 Geneva, Switzerland Von Elm Erik; Kasenda Benjamin; Tomonaga Yuki; Briel Matthias;
European and Swiss Congress of Internal Medicine 2014 Talk given at a conference Reporting of interim analyses, stopping rules and Data Safety and Monitoring Boards in protocols and publications of discontinued randomized trials 14.05.2014 Geneva, Switzerland Tomonaga Yuki; Kasenda Benjamin; Bengough Theresa; Von Elm Erik; Briel Matthias;
Canadian Association of Research Ethics Boards Annual Meeting 2014 Poster Prevalence, characteristics and publication of discontinued randomized trials 25.04.2014 Montreal, Canada Kasenda Benjamin; Briel Matthias;
11th Annual Research Day McMaster University 2014 Talk given at a conference Prevalence, Characteristics, and Publication of Discontinued Randomized Trials 27.03.2014 Hamilton, Canada Briel Matthias; Kasenda Benjamin; Burnand Bernard; Bucher Heiner C.; Von Elm Erik; Tomonaga Yuki; Bengough Theresa; Saccilotto Ramon;
Continuing education session at the Swiss National Science Foundation & article in "Horizonte" Individual talk Prevalence, doscontinuation, and publication of randomized controlled trials 19.03.2014 Bern, Switzerland Briel Matthias;
21st Cochrane Colloquium 2013 Talk given at a conference Epidemiology and publication of discontinued randomized trials - the DISCO study 19.09.2013 Quebec City, Canada Von Elm Erik; Bengough Theresa; Kasenda Benjamin; Saccilotto Ramon; Briel Matthias; Tomonaga Yuki;
21st Cochrane Colloquium 2013 Poster Reporting of interim analyses, stopping rules, and Data Safety and Monitoring Boards in protocols and publications of discontinued randomized trials 19.09.2013 Quebec City, Canada Kasenda Benjamin; Briel Matthias; Von Elm Erik; Saccilotto Ramon; Tomonaga Yuki; Bengough Theresa;
21st Cochrane Colloquium 2013 Talk given at a conference Planning and reporting of subgroup analyses in randomized trials - between confidence and delusion 19.09.2013 Quebec City, Canada Bengough Theresa; Tomonaga Yuki; Kasenda Benjamin; Briel Matthias; Von Elm Erik; Saccilotto Ramon;
7th Peer Review and Biomedical Publication Congress 2013 Talk given at a conference Publication of randomized controlled trials that were discontinued - An international multicenter cohort study 08.09.2013 Chicago, United States of America Kasenda Benjamin; Von Elm Erik; Tomonaga Yuki; Bengough Theresa; Briel Matthias;
SGIM Congress 2013 Talk given at a conference Reporting of randomized controlled trials that were discontinued - An international multicenter empirical study 29.05.2013 Basel, Switzerland Kasenda Benjamin; Von Elm Erik; Briel Matthias; Tomonaga Yuki; Bengough Theresa;
4th EQUATOR International Scientific Symposium 2012 Poster Reporting of randomized controlled trials that were discontiued - An international multicenter empirical study 11.10.2012 Freiburg, Germany Briel Matthias; Tomonaga Yuki; Kasenda Benjamin; Von Elm Erik;
SGIM Congress 2012 Poster Studying discontinued randomised controlled trials in Switzerland and abroad: protocol of an empirical research project 23.05.2012 Basel, Switzerland Kasenda Benjamin; Von Elm Erik; Saccilotto Ramon; Tomonaga Yuki; Briel Matthias;
Colloque Lausannois d'Epidémiologie Clinique, CHUV Individual talk Discontinuation of clinical trials – can we prevent it? 16.12.2011 Lausanne, Switzerland Von Elm Erik;
19th Cochrane Colloquium 2011 Poster Epidemiology and publication history of randomized clinical trials that were stopped early 19.10.2011 Madrid, Spain Von Elm Erik; Saccilotto Ramon; Kasenda Benjamin; Briel Matthias;
Grand Rounds in Medicine, University Hospital Basel Individual talk Trials stopped early 25.08.2011 Basel, Switzerland Briel Matthias;
Canadian Association of Research Ethics Boards Annual Meeting 2011 Poster When clinical research fails: a research protocol for a study of discontinued controlled trials 28.04.2011 Halifax, Canada Kasenda Benjamin; Von Elm Erik; Briel Matthias;


Awards

Title Year
David Sackett Prize of the German Network of Evidence-based Medicine 2015

Associated projects

Number Title Start Funding scheme
149496 Learning from failure - Understanding the mechanisms of trial discontinuation 01.12.2013 Project funding
114142 Selective reporting of clinical trials? Multicentre study of protocols and published articles 01.06.2007 Project funding
188802 Making clinical trials more affordable - systematic investigation of trial costs and tool development 01.11.2019 Project funding

Abstract

Clinical trials may be discontinued for different reasons, for example when it becomes apparent that a clinically relevant treatment effect will not be seen; when unanticipated adverse effects occur; or when outcomes are clearly superior in one study group. In addition, many trials are discontinued due to insufficient recruitment (slow accrual) of participants. This has ethical implications because participants consent on the premise of contributing to the advancement of medical knowledge, research ethics committees and funding agencies spend considerable resources on reviewing protocols of planned studies, and finite resources for research are wasted. Little is known about the epidemiology of discontinued trials in Switzerland. We propose to assemble a cohort of clinical trials based on protocols approved by research ethics committees in Lausanne, Basel, Lucerne, and Zurich between 2000 and 2004. We will explore other sources of trials, for example trials funded by the Swiss National Science Foundation. We will analyze this cohort to determine the risk of discontinuation of trials for different reasons. Using a case-control design, we will focus on trials that were discontinued due to insufficient recruitment. We will compare these trials with trials that were completed and thus identify characteristics of study protocols associated with discontinuation due to poor recruitment. Finally, we will examine the publication history of trials that were discontinued, and assess to what extent any lessons learned have been disseminated. We will extract relevant data from the files of the collaborating ethics committees and from published trial reports, and through a survey of trialists. The study will be based on over 1000 protocols of clinical trials, and about 150 trials that were discontinued due to poor recruitment. The proposed research is timely: recruitment of trial participants has repeatedly been identified as a serious “bottleneck” in clinical research. The planning of effective recruitment strategies and anticipation of problems is a core task of the Clinical Trial Units (CTUs) that have been established in Switzerland with the support of SNF. Our study will provide important insights into the problems with recruitment of participants that were encountered in randomized trials conducted in Switzerland in the recent past. It will identify modifiable barriers to successful study completion and inform future recommendations to individual trialists, research groups and units providing methodological support.
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