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Learning from failure - Understanding the mechanisms of trial discontinuation

English title Learning from failure - Understanding the mechanisms of trial discontinuation
Applicant Briel Matthias
Number 149496
Funding scheme Project funding (Div. I-III)
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 01.12.2013 - 31.12.2016
Approved amount 260'089.00
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Keywords (6)

randomized controlled trials; clinical research; research ethics; clinical trial units; medical research methodology; participant recruitment

Lay Summary (German)

Lead
Randomisierte klinische Studien (RCTs) sind die Methode der Wahl zur Evaluierung von Therapien. Ein Viertel aller RCTs werden vorzeitig abgebrochen, v.a. wegen ungenügende Patientenrekrutierung. Industrie-initiierte RCTs werden weniger häufig abgebrochen, was die Relevanz einer professionellen Studienplanung und einer ausreichenden Finanzierung nahelegt. Häufiges Nicht-Publizieren von abgebrochenen RCTs führen zu Datenverlust und Verschwendung von knappen Forschungsresourcen.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Wir planen 3 komplementäre Studien, um zugrundeliegende Ursachen und Mechanismen von Studienabbrüchen wegen ungenügender Patientenrekrutierung besser zu verstehen, Wege zu finden wie vorhandene Barrieren überwunden und ethische Standards gewahrt werden können, und Leitlinien für beteiligte Entscheidungsträger zu entwickeln. Hierfür werden wir eine Kombination aus quantitativen und qualitativen Forschungsmethoden einsetzen. In einem ersten Teilprojekt werden wir semi-strukturierte Interviews sowohl mit Studienleitern von randomisierten Studien, die wegen ungenügender Patientenrekrutierung abgebrochen wurden, als auch mit Schlüsselakteuren der klinischen Forschung in der Schweiz (Swissmedic, pharmazeutische Industrie, Schweizer Nationalfonds, Clinical Trial Units, Ethikkommissionen) durchführen. Ein zweites Teilprojekt wird SNF-geförderte randomisierte klinische Studien untersuchen, ob ein kompetitives Auswahlverfahren und eine SNF Teil- oder Vollfinanzierung das Risiko eines vorzeitigen Studienabbruchs senken kann. Ein drittes Teilprojekt beinhaltet eine umfassende Analyse von Rekrutierungsmustern zu komplettierten und abgebrochenen randomisierten Studien aus verschiedenen Ländern in unterschiedlichen kinischen Kontexten. Diese Studie untersucht, ob es möglich ist, eine ungenügende Patientenrekrutierung frühzeitig vorauszusagen, und versucht optimale Untersuchungszeitpunkte und Kriterien zur Beurteilung des Rekrutierungsverlaufs zu identifizieren.   

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Arbeit wird die komplexen Mechanismen, die zu einer ungenügenden Patientenrekrutierung und zu frühzeitigen Abbrüchen von klinischen Studien führen, verständlicher machen und Ansatzpunkte für gezielte Interventionen identifizieren. Aussagekräftige Studienresultate sind eine unabdingbare Voraussetzung für eine  wirkungsvolle patienten-orientierte Medizin.   

Direct link to Lay Summary Last update: 14.11.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Funding characteristics of randomised clinical trials supported by the Swiss National Science Foundation: a retrospective cohort study
Amstutz Alain, Schandelmaier Stefan, Frei Roy, Surina Jakub, Agarwal Arnav, Alturki Reem, von Niederhäusern Belinda, von Elm Erik, Briel Matthias (2018), Funding characteristics of randomised clinical trials supported by the Swiss National Science Foundation: a retrospective cohort study, in Swiss Medical Weekly, 148(34), w14587.
Insufficient recruitment and premature discontinuation of clinical trials in Switzerland: qualitative study with trialists and other stakeholders
Briel Matthias, Elger Bernice, von Elm Erik, Satalkar Priya (2017), Insufficient recruitment and premature discontinuation of clinical trials in Switzerland: qualitative study with trialists and other stakeholders, in Swiss Medical Weekly, 147(4546), w14556.
Discontinuation and non-publication of randomised clinical trials supported by the main public funding body in Switzerland: a retrospective cohort study
Amstutz Alain, Schandelmaier Stefan, Frei Roy, Surina Jakub, Agarwal Arnav, Olu Kelechi Kalu, Alturki Reem, Von Niederhäusern Belinda, Von Elm Erik, Briel Matthias (2017), Discontinuation and non-publication of randomised clinical trials supported by the main public funding body in Switzerland: a retrospective cohort study, in BMJ Open, 7(7), e016216-e016216.
Premature trial discontinuation often not accurately reflected in registries: comparison of registry records with publications.
Alturki Reem, Schandelmaier Stefan, Olu Kelechi K., von Niederhäusern Belinda, Agarwal Arnav, Frei Roy, Bhatnagar Neera, Hooft Lotty, von Elm Erik, Briel Matthias (2016), Premature trial discontinuation often not accurately reflected in registries: comparison of registry records with publications., in Journal of Clinical Epidemiology, 56-63.
A systematic review of discontinued trials suggested that most reasons for recruitment failure were preventable.
Briel Matthias, Olu Kelechi K., von Elm Erik, Kasenda Benjamin, Alturki Reem, Agarwal Arnav, Bhatnagar Neera, Schandelmaier Stefan (2016), A systematic review of discontinued trials suggested that most reasons for recruitment failure were preventable., in Journal of Clinical Epidemiology, 8-15.

Collaboration

Group / person Country
Types of collaboration
SPIRIT initiative Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
Swiss Clinical Trial Organization (SCTO) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Department of Clinical Epidemiology and Biostatistics, McMaster University (Canada) Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
swissethics Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Health Services Research Unit, University of Aberdeen Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
IMPACT investigators Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Assistance publique – hôpitaux de Paris (Paris Hospital Research Network, France) France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Division of Public Health, University of Liverpool (UK) Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Department of Medical Biometry and Statistics, University Medical Center Freiburg (Germany) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Stanford Prevention Research Center, Stanford University (US) United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Centre for Statistics in Medicine, University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Swiss Group for Clinical Cancer Research (SAKK) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SGAIM Congress 2018 Poster Prediction of recruitment in randomized clinical trials 31.05.2018 Basel, Switzerland Kasenda Benjamin; Von Elm Erik; Briel Matthias;
25th Cochrane Colloquium 2017 Talk given at a conference Funding characteristics of Randomized Clinical Trials supported by the Main Public Funding Body in Switzerland: a Retrospective Cohort Study 12.09.2017 Cape Town, South Africa Briel Matthias; Von Elm Erik; Amstutz Alain;
25th Cochrane Colloquium 2017 Poster Understanding the mechanisms of trial discontinuation due to poor recruitment: Interviews with stakeholders in clinical trials 12.09.2017 Cape Town, South Africa Von Elm Erik; Briel Matthias; Satalkar Priya; Elger Bernice;
18.Jahrestagung des Deutschen Netzwerks Evidenz-basierte Medizin 2017 Talk given at a conference Routinely collected health data (RCD) for randomized controlled trials (RCT) 09.03.2017 Hamburg, Germany Briel Matthias;
18. Jahrestagung des Deutschen Netzwerks Evidenz-basierte Medizin 2017 Talk given at a conference Discontinuation and publication of randomized clinical trials supported by the main public funding body in Switzerland: a retrospective cohort study 09.03.2017 Hamburg, Germany Amstutz Alain; Von Elm Erik; Briel Matthias;
18. Jahrestagung des Deutschen Netwerks Evidenz-basierte Medizin 2017 Talk given at a conference Risikofaktoren für Rekrutierungsprobleme - Vergleich von wegen Rekrutierungsproblemen abgebrochenen und nicht-abgebrochenen randomisierten Studien zur gleichen Fragestellung 09.03.2017 Hamburg, Germany Speich Benjamin; Gloy Viktoria; Briel Matthias;
24th Cochrane Colloquium 2016 Talk given at a conference Discontinuation and publication of randomized clinical trials supported by the Swiss National Science Foundation 24.10.2016 Seoul, Korean Republic (South Korea) Amstutz Alain; Von Elm Erik; Kalu Olu Kelechi; Schandelmaier Stefan; Briel Matthias;
SGAIM Congress 2016 Poster Discontinuation and publication of randomized clinical trials supported by the Swiss National Science Foundation 25.05.2016 Basel, Switzerland Briel Matthias; Amstutz Alain; Schandelmaier Stefan;
Grand Rounds, Department of Cardiology, Vall d'Hebron Hospital 2016 Individual talk Discontinued randomized trials: a challenge for the interpretation 22.04.2016 Barcelona, Spain Briel Matthias;
32. Deutscher Krebskongress 2016 Talk given at a conference Abgebrochene Studien in der Onkologie - Einzelschicksal oder Systemfehler? 24.02.2016 Berlin, Germany Briel Matthias; Kasenda Benjamin;
27th Annual National Forum on Quality Improvement in Health Care 2015 Poster Prematurely discontinued randomized trials are frequently labelled "completed" in trial registries - a systematic review 07.12.2015 Orlando, United States of America Briel Matthias; Schandelmaier Stefan; Kalu Olu Kelechi;
23rd Cochrane Colloquium 2015 Talk given at a conference Prematurely discontinued randomized trials are frequently labelled "completed" in trial registries - a systematic review 03.10.2015 Vienna, Austria Briel Matthias; Kalu Olu Kelechi; Schandelmaier Stefan;
SGIM Congress 2015 Talk given at a conference Prematurely discontinued randomized trials are frequently labelled "completed" in registries - systematic review 20.05.2015 Basel, Switzerland Kalu Olu Kelechi; Briel Matthias; Schandelmaier Stefan;
11. Berner Nuklearmedizin Symposium 2015 Individual talk Abgebrochene Studien - zu früh gefreut? 15.11.2014 Bern, Switzerland Briel Matthias;
22nd Cochrane Colloquium 2014 Talk given at a conference Reporting of randomized clinical trials discontinued due to poor recruitment: a literature review 21.09.2014 Hyderabad, India Von Elm Erik; Briel Matthias; Schandelmaier Stefan; Kalu Olu Kelechi;
European and Swiss Congress of Internal Medicine 2014 Talk given at a conference Reporting of randomized controlled trials discontinued due to poor recruitment: Systematic review 14.05.2014 Geneva, Switzerland Briel Matthias; Von Elm Erik; Schandelmaier Stefan; Kalu Olu Kelechi;
Careum Kongress/2nd ENOPE Conference 2014 Poster Ethical and practical implications of insufficient patient recruitment to clinical trials 17.03.2014 Basel, Switzerland Briel Matthias;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Meeting of the European Commission for Research in the Health Sciences - How to handle problems in the conduct of investigator-initiated clinical trials? Talk 30.05.2018 Brussels, Belgium Briel Matthias;
Nursing Sciences Research Meeting - Discontinued Clinical Trials Talk 14.11.2017 Basel, Switzerland Briel Matthias;
CTU rounds Zurich - Abgebrochene Klinische Studien und Ursachen Talk 26.01.2017 Zurich, Switzerland Briel Matthias;
Swiss National Science Foundation Council Meeting - Discontinuation and non-publication of randomized clinical trials supported by the Swiss National Science Foundation Talk 06.12.2016 Bern, Switzerland Briel Matthias; Amstutz Alain;
Cantonal Ethics Committee (KEK) Zurich Continuous Education Session - Abgebrochene Klinische Studien: Vermeidbar oder Schicksal? Talk 25.10.2016 Zurich, Switzerland Briel Matthias;
CTU lectures Bern - Abgebrochene Klinische Studien: Vermeidbar oder dumm gelaufen? Talk 12.04.2016 Bern, Switzerland Briel Matthias;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Unterschlagenes Wissen schadet SRF1 German-speaking Switzerland 2019

Awards

Title Year
Best poster award (2nd prize) - SGAIM Congress 2018

Associated projects

Number Title Start Funding scheme
133540 When clinical research fails: A study of controlled trials that were discontinued 01.02.2011 Project funding (Div. I-III)
114142 Selective reporting of clinical trials? Multicentre study of protocols and published articles 01.06.2007 Project funding (Div. I-III)
173043 Investigating the interplay of job exposures, ambient air pollution and living environment as drivers of the chronic lung disease epidemic The Large-scale LuftiBus-SNC Cohort 01.01.2018 Project funding (special)
188802 Making clinical trials more affordable - systematic investigation of trial costs and tool development 01.11.2019 Project funding (Div. I-III)

Abstract

One out of four randomized controlled trials (RCTs) is discontinued; insufficient recruitment of participants is the most frequent reason, in particular in investigator-initiated RCTs. Trials initiated by commercial sponsors are less likely to be discontinued suggesting that professional planning and conduct as well as sufficient funding of RCTs help complete recruitment as planned. Currently, the mechanisms and specific root causes of trial discontinuation remain unclear. Evidence-based guidance for trialists and other stakeholders on how to plan and assess recruitment in RCTs is lacking. In most cases, participants and research ethics committees (RECs) are not informed about discontinuation or publication of trial results. Accounts of the work done so far are not disseminated to the scientific community in up to 60% of discontinued RCTs. This entails ethical problems: The patients’ and the public’s trust in clinical research is undermined, and finite research resources are wasted. It is unknown to what extent trialists are aware of the ethical implications with trial discontinuation and what their attitudes and views are. We propose three complementary projects that will use both qualitative and quantitative methods to better understand the mechanisms that lead to RCT discontinuation, find ways to meet the associated ethical challenges, and develop guiding principles for involved stakeholders. In Project A we will conduct semi-structured interviews with principal investigators of RCTs discontinued for insufficient recruitment and with key stakeholders of clinical research in Switzerland representing Clinical Trial Units, RECs, the Swiss National Science Foundation (SNSF), the pharmaceutical industry, and Swissmedic. Project B will empirically examine all health-care RCTs funded by the SNSF to explore whether a rigorous selection of trials for funding and monitoring decreases the risk of trial discontinuation including potential effects of full versus partial funding. In Project C we will perform a comprehensive analysis of recruitment patterns from about 500 completed and discontinued RCTs conducted in different countries and settings. It will explore whether insufficient recruitment can reliably be identified at an early stage and determine optimal time points and criteria for the assessment of recruitment progress in RCTs.Using a mixed methods approach, the proposed study will further our understanding of the complex mechanisms leading to failure in trial recruitment and identify potential lever points for targeted interventions. Following on the successfully completed DISCO study it will continue a line of methodological research that is of high relevance to clinical researchers and trial participants in Switzerland and abroad. At a time in which the legal framework of research involving humans is being revised, the study will provide a most needed empirical base for the elaboration of guidance documents to be used by trialists and other stakeholders.
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