Prevalence, characteristics, and predictors of early termination of cardiovascular clinical trials due to low recruitment: Insights from the ClinicalTrials.gov registry

doi:10.1016/j.ahj.2014.04.013

American Heart Journal

Volume 168, Issue 2, August 2014, Pages 213-219.e1

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https://doi.org/10.1016/j.ahj.2014.04.013 Get rights and content

Background

Early termination of clinical trials due to low recruitment represents an understudied challenge for clinical research. We aimed to describe characteristics of cardiovascular trials terminated because of low recruitment and identify the major predictors of such early termination.

Methods

We reviewed all cardiovascular clinical trials (7,042 studies) registered in ClinicalTrials.gov from February 29, 2000, to January 17, 2013, and assessed information about trials that were completed and those that were terminated early. Logistic regression models were developed to identify independent predictors of early termination due to low recruitment.

Results

Our search strategy identified 6,279 cardiovascular clinical trials, of which 684 (10.9%) were terminated prematurely. Of these halted trials, the main reason for termination was lower than expected recruitment (278 trials; 53.6%). When comparing trials that terminated early because of low recruitment with those that were completed, we found that studies funded by the National Institutes of Health or other US federal agencies (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.14-0.89), studies of behavior/diet intervention (OR 0.35, 95% CI 0.19-0.65), and single-arm design studies (OR 0.57, 95% CI 0.42-0.78) were associated with a lower risk of early termination. University/hospital-funded (OR 1.52, 95% CI 1.10-2.10) and mixed-source–funded studies (OR 2.14, 95% CI 1.52-3.01) were associated with a higher likelihood of early termination due to lower than expected recruitment rates.

Conclusions

Low recruitment represents the main cause of early termination of cardiovascular clinical trials. Funding source, type of intervention, and study design are factors associated with early termination due to low recruitment and might be good targets for improving enrollment into cardiovascular clinical trials.

Section snippets

ClinicalTrials.gov

The methods and quality assurance strategies used by ClinicalTrials.gov to register trials have been described in detail previously.5, 6 ClinicalTrials.gov was developed and is maintained by the National Library of Medicine on behalf of the National Institutes of Health (NIH). ClinicalTrials.gov uses a Web-based system to facilitate registration of clinical trials by the study sponsor or the principal investigator and includes both mandatory and optional data elements.⁷

Eligibility criteria and search strategy

We searched the

Results

Our search strategy retrieved 7,042 trials, from which we were able to identify 6,279 studies that met the inclusion criteria of cardiovascular clinical trials registered in ClinicalTrials.gov between February 29, 2000, and January 17, 2013. From the eligible trials, 5,595 (89.1%) were classified as completed and 684 (10.9%) trials as terminated.

From the total of terminated trials, 165 trials (24.1%) did not report the reason for their early termination. After performing a Medline search, we

Discussion

Our study showed that, among a contemporary cohort of cardiovascular clinical trials registered in ClinicalTrials.gov, more than 10% were terminated prematurely. The most common reason for early termination was lower than expected recruitment rates. Factors associated with lower risk of early termination due to low recruitment were funding by the NIH or other US federal agencies as well as trials assessing behavioral or dietary interventions and those with a single-arm design. On the other

Disclosures

Sources of funding: No extramural funding was used to support this work.

Acknowledgements

We thank Peter Hoffmann of the Duke Clinical Research Institute for his editorial contribution to this manuscript.

References (24)

Centers for Disease Control and Prevention
Compressed mortality file: underlying cause of death, 1979 to 2005
A. Avenell et al.
The effects of an open design on trial participant recruitment, compliance and retention—a randomized controlled trial comparison with a blinded, placebo-controlled design
Clin Trials
(2004)
R.M. Califf et al.
Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010
JAMA
(2012)
D.A. Zarin et al.
The ClinicalTrials.gov results database—update and key issues
N Engl J Med
(2011)
D.A. Zarin et al.
Trial registration at ClinicalTrials.gov between May and October 2005
N Engl J Med
(2005)
D.A. Zarin et al.
Issues in the registration of clinical trials
JAMA
(2007)
ClinicalTrials.gov protocol Data Element Definitions (DRAFT)
National Center for Biotechnology Information
MeSH terms: cardiovascular diseases
R Core Team
R: a language and environment for statistical computing
AACT Database
Clinical Trials Transformation Initiative Web site

P.D. Allison

Logistic regression using the SAS system: theory and application

(2001)

D.W. Hosmer et al.

Applied logistic regression

(2000)

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: Charles Maynard, PhD, served as guest editor for this article.

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Clinical InvestigationCardiovascular EpidemiologyPrevalence, characteristics, and predictors of early termination of cardiovascular clinical trials due to low recruitment: Insights from the ClinicalTrials.gov registry

Background

Methods

Results

Conclusions

Section snippets

ClinicalTrials.gov

Eligibility criteria and search strategy

Results

Discussion

Disclosures

Acknowledgements

Compressed mortality file: underlying cause of death, 1979 to 2005

The effects of an open design on trial participant recruitment, compliance and retention—a randomized controlled trial comparison with a blinded, placebo-controlled design

Clin Trials

Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010

JAMA

The ClinicalTrials.gov results database—update and key issues

N Engl J Med

Trial registration at ClinicalTrials.gov between May and October 2005

N Engl J Med

Issues in the registration of clinical trials

JAMA

ClinicalTrials.gov protocol Data Element Definitions (DRAFT)

MeSH terms: cardiovascular diseases

R: a language and environment for statistical computing

Clinical Trials Transformation Initiative Web site

Logistic regression using the SAS system: theory and application

Applied logistic regression

Clinical Investigation
Cardiovascular Epidemiology
Prevalence, characteristics, and predictors of early termination of cardiovascular clinical trials due to low recruitment: Insights from the ClinicalTrials.gov registry