Unsuccessful trial accrual and human subjects protections: An empirical analysis of recently closed trials
Background Ethical evaluation of risk–benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation. Objective To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary...
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| Published in: | Clinical trials (London, England) Vol. 12; no. 1; pp. 77 - 83 |
|---|---|
| Main Authors: | , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London, England
SAGE Publications
01.02.2015
Sage Publications Ltd |
| Subjects: | |
| ISSN: | 1740-7745, 1740-7753, 1740-7753 |
| Online Access: | Get full text |
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| Abstract | Background
Ethical evaluation of risk–benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation.
Objective
To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual.
Methods
We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual.
Results
Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001).
Conclusion
A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging. |
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| AbstractList | Ethical evaluation of risk-benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation.
To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual.
We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual.
Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001).
A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging. Background Ethical evaluation of riskbenefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation. Objective To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual. Methods We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual. Results Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p \ 0.0001), earlier trial phase (23% vs 16%, p \ 0.0001), fewer number of research sites at trial completion (p \ 0.0001) and at registration (p \ 0.0001), and an active (non-placebo) comparator (23% vs 16%, p \ 0.001). Conclusion A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging. Ethical evaluation of risk-benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation.BACKGROUNDEthical evaluation of risk-benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation.To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual.OBJECTIVETo determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual.We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual.METHODSWe used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual.Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001).RESULTSOf 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001).A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging.CONCLUSIONA total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging. Background Ethical evaluation of risk–benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation. Objective To determine the fraction and number of patients enrolled in trials that were at risk of not meaningfully addressing their primary research objective due to unsuccessful patient accrual. Methods We used the National Library of Medicine clinical trial registry to capture all initiated phases 2 and 3 intervention clinical trials that were registered as closed in 2011. We then determined the number that had been terminated due to unsuccessful accrual and the number that had closed after less than 85% of the target number of human subjects had been enrolled. Five factors were tested for association with unsuccessful accrual. Results Of 2579 eligible trials, 481 (19%) either terminated for failed accrual or completed with less than 85% expected enrolment, seriously compromising their statistical power. Factors associated with unsuccessful accrual included greater number of eligibility criteria (p = 0.013), non-industry funding (25% vs 16%, p < 0.0001), earlier trial phase (23% vs 16%, p < 0.0001), fewer number of research sites at trial completion (p < 0.0001) and at registration (p < 0.0001), and an active (non-placebo) comparator (23% vs 16%, p < 0.001). Conclusion A total of 48,027 patients had enrolled in trials closed in 2011 who were unable to answer the primary research question meaningfully. Ethics bodies, investigators, and data monitoring committees should carefully scrutinize trial design, recruitment plans, and feasibility of achieving accrual targets when designing and reviewing trials, monitor accrual once initiated, and take corrective action when accrual is lagging. |
| Author | Kimmelman, Jonathan MacKinnon, Nathalie Ramsay, Tim Carlisle, Benjamin |
| AuthorAffiliation | 2 Ottawa Hospital Research Institute, Ottawa, Canada 1 Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, 3647 Peel Street, Montréal QC H3A 1X1 |
| AuthorAffiliation_xml | – name: 2 Ottawa Hospital Research Institute, Ottawa, Canada – name: 1 Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, 3647 Peel Street, Montréal QC H3A 1X1 |
| Author_xml | – sequence: 1 givenname: Benjamin surname: Carlisle fullname: Carlisle, Benjamin – sequence: 2 givenname: Jonathan surname: Kimmelman fullname: Kimmelman, Jonathan email: jonathan.kimmelman@mcgill.ca – sequence: 3 givenname: Tim surname: Ramsay fullname: Ramsay, Tim – sequence: 4 givenname: Nathalie surname: MacKinnon fullname: MacKinnon, Nathalie |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25475878$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | The Author(s) 2014 The Author(s) 2014. SAGE Publications © Feb 2015 |
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| References | Peters-Lawrence, Bell, Hsu 2012; 33 Van der Wouden, Blankenstein, Huibers 2007; 60 Scoggins, Ramsey 2010; 102 Halpern, Karlawish, Berlin 2002; 288 Viberti, Slama, Pozza 1997; 350 Malmqvist, Juth, Lynoe 2011; 21 Cheng, Dietrich, Dilts 2010; 16 Torgerson, Arlinger, Kappi 2001; 22 Bacchetti, McCulloch, Segal 2012; 31 Korn, Freidlin, Mooney 2010; 28 Schroen, Petroni, Wang 2012; 18 Lemieux, Goodwin, Pritchard 2008; 26 Ross, Grant, Counsell 1999; 52 Prayle, Hurley, Smyth 2012; 344 bibr11-1740774514558307 bibr16-1740774514558307 bibr5-1740774514558307 bibr2-1740774514558307 bibr3-1740774514558307 bibr7-1740774514558307 bibr12-1740774514558307 bibr9-1740774514558307 bibr14-1740774514558307 bibr6-1740774514558307 bibr17-1740774514558307 bibr10-1740774514558307 bibr1-1740774514558307 bibr4-1740774514558307 bibr15-1740774514558307 bibr13-1740774514558307 bibr8-1740774514558307 |
| References_xml | – volume: 31 start-page: 4138 year: 2012 end-page: 4139 article-title: Being ‘underpowered’ does not make a study unethical publication-title: Stat Med – volume: 33 start-page: 291 year: 2012 end-page: 297 article-title: Clinical trial implementation and recruitment: lessons learned from the early closure of a randomized clinical trial publication-title: Contemp Clin Trials – volume: 28 start-page: 5197 year: 2010 end-page: 5201 article-title: Accrual experience of National Cancer Institute Cooperative Group phase III trials activated from 2000 to 2007 publication-title: J Clin Oncol – volume: 21 start-page: 51 year: 2011 end-page: 78 article-title: Early stopping of clinical trials: charting the ethical terrain publication-title: Kennedy Inst Ethics J – volume: 22 start-page: 515 year: 2001 end-page: 525 article-title: Principles for enhanced recruitment of subjects in a large clinical trial. The XENDOS (XENical in the prevention of Diabetes in Obese Subjects) study experience publication-title: Control Clin Trials – volume: 18 start-page: 256 year: 2012 end-page: 262 article-title: Achieving sufficient accrual to address the primary endpoint in phase III clinical trials from U.S. Cooperative Oncology Groups publication-title: Clin Cancer Res – volume: 26 start-page: 4458 year: 2008 end-page: 4465 article-title: Identification of cancer care and protocol characteristics associated with recruitment in breast cancer clinical trials publication-title: J Clin Oncol – volume: 102 start-page: 1371 year: 2010 article-title: A national cancer clinical trials system for the 21st century: reinvigorating the NCI Cooperative Group Program publication-title: J Natl Cancer Inst – volume: 288 start-page: 358 year: 2002 end-page: 362 article-title: The continuing unethical conduct of underpowered clinical trials publication-title: JAMA – volume: 16 start-page: 5557 year: 2010 end-page: 5563 article-title: A sense of urgency: evaluating the link between clinical trial development time and the accrual performance of cancer therapy evaluation program (NCI-CTEP) sponsored studies publication-title: Clin Cancer Res – volume: 60 start-page: 819 year: 2007 end-page: 824 article-title: Survey among 78 studies showed that Lasagna’s law holds in Dutch primary care research publication-title: J Clin Epidemiol – volume: 350 start-page: 214 year: 1997 end-page: 215 article-title: Early closure of European Pimagedine trial. Steering Committee. Safety Committee publication-title: Lancet – volume: 52 start-page: 1143 year: 1999 end-page: 1156 article-title: Barriers to participation in randomised controlled trials: a systematic review publication-title: J Clin Epidemiol – volume: 344 start-page: d7373 year: 2012 article-title: Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study publication-title: BMJ – ident: bibr9-1740774514558307 doi: 10.1016/S0197-2456(01)00165-9 – ident: bibr5-1740774514558307 doi: 10.1093/jnci/djq291 – ident: bibr11-1740774514558307 doi: 10.1158/1078-0432.CCR-11-1633 – ident: bibr16-1740774514558307 doi: 10.1136/bmj.d7373 – ident: bibr1-1740774514558307 – ident: bibr6-1740774514558307 doi: 10.1200/JCO.2010.31.5382 – ident: bibr7-1740774514558307 doi: 10.1016/j.jclinepi.2006.11.010 – ident: bibr13-1740774514558307 doi: 10.1016/S0895-4356(99)00141-9 – ident: bibr10-1740774514558307 doi: 10.1353/ken.2011.0002 – ident: bibr3-1740774514558307 – ident: bibr15-1740774514558307 doi: 10.1001/jama.288.3.358 – ident: bibr14-1740774514558307 doi: 10.1200/JCO.2007.15.3726 – ident: bibr12-1740774514558307 doi: 10.1016/S0140-6736(97)26029-0 – ident: bibr17-1740774514558307 doi: 10.1002/sim.5451 – ident: bibr2-1740774514558307 – ident: bibr4-1740774514558307 doi: 10.1158/1078-0432.CCR-10-0133 – ident: bibr8-1740774514558307 doi: 10.1016/j.cct.2011.11.018 |
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Ethical evaluation of risk–benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation.... Ethical evaluation of risk-benefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation. To... Background Ethical evaluation of riskbenefit in clinical trials is premised on the achievability of resolving research questions motivating an investigation.... Ethical evaluation of risk-benefit in clinical trials is premised on the achievability of resolving research questions motivating an... |
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| SubjectTerms | Clinical trials Clinical Trials, Phase II as Topic - statistics & numerical data Clinical Trials, Phase III as Topic - statistics & numerical data Early Termination of Clinical Trials - statistics & numerical data Human Experimentation - statistics & numerical data Human subjects Humans Medical ethics Medical research Patient Selection Research Design - statistics & numerical data Risk Assessment United States |
| Title | Unsuccessful trial accrual and human subjects protections: An empirical analysis of recently closed trials |
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