- Email: [email protected]
Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review
IJCA-24297; No of Pages 3 International Journal of Cardiology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review Muthiah Vaduganathan a,⁎,1, Ayman Samman-Tahhan b,1, Ravi B. Patel c, Anita Kelkar b, Lampros Papadimitriou d, Vasiliki V. Georgiopoulou b, Stephen J. Greene e, Andreas P. Kalogeropoulos b, Eric Peterson e, Gregg C. Fonarow f, Mihai Gheorghiade g, Javed Butler d a
Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA, United States Cardiology Division, Emory University, Atlanta, GA, United States c Division of Cardiology, Bluhm Cardiovascular Institute at Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, United States d Division of Cardiology, Stony Brook University, Stony Brook, NY, United States e Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, United States f Division of Cardiology, University of California Los Angeles, Los Angeles, CA, United States g Center for Cardiovascular Innovation, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States b
a r t i c l e
i n f o
Article history: Received 6 September 2016 Received in revised form 15 November 2016 Accepted 17 December 2016 Available online xxxx Keywords: Cardiovascular Clinical trials Funding source Outcomes Trial design
To the Editor: Trial-level characteristics, including mechanism of funding, may shape the likelihood of trial completion, patient population enrolled, and possibly trial outcomes [1]. Concerns exist regarding the influence of funding source on clinical trial conduct and outcomes. However, limited quantitative data are available characterizing the role of funding source on trial operating characteristics, enrollment patterns, and outcomes in contemporary cardiovascular clinical trials. We evaluated cardiovascular phase II-IV randomized controlled trials published in the 8 highest Web-of-Science impact factor journals (according to the 2013 edition of the Journal Citation Reports® in the categories “General and Internal Medicine” and Cardiology”) between January 2001 to December 2012 using both a PubMed database and manual journal search. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for all ⁎ Corresponding author at: Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, 75 Francis St, Boston, MA 02115, United States. E-mail address: [email protected] (M. Vaduganathan). 1 Drs. Vaduganathan and Samman-Tahhan contributed equally to this manuscript.
procedures. We employed a previously reported algorithm to define funding source [2]. For studies registered in ClinicalTrials.gov, we used the entry provided for funding source. For trials not registered, we obtained the information from the main published article, statements of sources of support, acknowledgments, supplemental data, or online appendices. A total of 4524 studies were screened, of which, 1224 trials, cumulatively studying 2,350,632 patients from 98 countries, met the criteria for inclusion. Of these, 581 (47.5%) were funded by industry sources, 273 (22.3%) by non-profit organizations, 159 (13%) by governments, 127 (10.4%) jointly funded by a non-profit organization with industrial or governmental collaboration, and 84 (6.9%) did not report a specific funding source. From 2001–2003 to 2009–2012, the proportion of industry- and government-funded trials trended down, while the proportion of non-profit and jointly-funded trials increased over time (P b 0.001; Fig. 1). Studies funded by industry tended to have larger numbers of participants per trial, sites per trial, and countries per trial (Table 1). Fifty-six trials (4.9%) included more than 10,000 patients enrolled per trial; of these, industry funded 71.4%. The total duration of trials was shortest for industry trials (median 1.8, IQR 1.2–2.5 years). Non-profit trials had the highest enrollment rates with median of 4 (IQR 1–9.7) patients/site/month. Industry sponsors were more likely to fund trials that evaluated effects of new therapy vs. placebo, while government sponsors were more likely to fund non-drug or device trials. Positive outcomes were more likely to be reported by industry (65.6%) and non-profit (66.3%) trials compared with government (50.3%) or jointly-funded (45.7%) trials (P b 0.001). The proportion of positive trials decreased over time for industry (71.5% to 62.4%; P = 0.05) and jointly-funded (75% to 32.8%; P = 0.02) trials, while government and non-profit trials had stable rates of positive outcomes over time (P N 0.4 for both). In this systematic review of over 1200 cardiovascular clinical trials published in high impact, peer-reviewed journals from 2001 to 2012, we observed substantial variability in study type, design, intervention, enrollment rates, and outcomes among trials by primary funding
http://dx.doi.org/10.1016/j.ijcard.2016.12.119 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: M. Vaduganathan, et al., Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.119
2
M. Vaduganathan et al. / International Journal of Cardiology xxx (2016) xxx–xxx
Fig. 1. Proportion of trials stratified by funding sources over time. Proportion of trials funded by industry and government sponsors trended down over time, while there was a significant increase in the proportion of jointly-funded trials or those funded by nonprofit organizations. Temporal trends across trial time-frames were performed using non-parametric tests for trend.
mechanism. Industry-sponsored trials accounted for almost half of all trials, enrolled the highest volume of patients, completed protocols on the shortest timelines, and reported a high proportion of favorable results, but displayed poor enrollment efficiency. Slow enrollment in global industry-funded trials may be related to application of strict inclusion and exclusion criteria, need for coordination across a number of countries and sites, and adherence to country-specific enrollment thresholds and regulatory requirements. Industry-funded trials were more likely to compare the study intervention with placebo and less likely to engage in head-to-head drug or device comparisons. Non-
profit organizations tended to fund a larger proportion of trials over time and enrolled patients more efficiently [3]. Consistent with recent data [4], government-based funding of trials has significantly declined over the last decade, to less than 10% of all trials based on our contemporary estimates. Taken together with other similar aggregate trial-level experiences [5–8], our data suggest substantial variation in sources of funding of cardiovascular clinical trials, which may influence key trial characteristics and outcomes. It is difficult to dissect whether the trends towards improved outcomes in industry-funded trials are secondary to more rigorous trial conduct or systematic bias [9]. Features that may bias industryfunded trials toward favorable trial outcomes include: 1) preferential funding of trial programs more likely to translate to positive outcomes; 2) publication bias with under-publication of negative findings [6]; 3) the evaluation of second and third in class drugs similar to ones known to have favorable results; 4) selection of inappropriate or “straw-man” comparator or doses; and 5) biased interpretation of trial results [10]. Indeed, industry-funded trials may also preferentially support later-phase investigations, which set the stage for new drug/device approval, and thus incorporate certain design elements that facilitate this regulatory process. Further research is required to explore the systematic influence of funding mechanisms on contemporary cardiovascular clinical trials. Over time, the landscape of financial support of cardiovascular clinical trials is changing and key trial characteristics and outcomes may be related to primary sources of funding.
Disclosures Eric Peterson: reports significant research grant support from Eli Lilly & Company, Janssen Pharmaceuticals, Inc.; and modest consultant/advisory board support from Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Pfizer, and Genentech Inc.
Table 1 Trial characteristics stratified by funding sources.a Industry
Government
Non-profit
Jointly-funded
Number of trials Number of patients
581 1,406,221
159 357,423
273 291,217
127 266,252
Trial size Patients per trial Sites per trial Countries per trial Duration (years) Enrollment rateb
849 (303–3123) 70 (24–198) 6 (1–17) 1.75 (1.15–2.5) 0.76 (0.41–1.39)
589 (219–1869) 18 (3.75–50.5) 1 (1–2) 3.27 (2.3–4.71) 1.08 (0.45–3.2)
351.5 (161–955) 3 (1–15) 1 (1–1) 2.06 (1.36–3.59) 3.99 (1.0–9.7)
601 (195–2305) 19 (4–52) 1 (1–3) 3 (1.67–4.27) 1.12 (0.45–4.2)
Outcomes Clinical Intermediate Surrogate Positive outcomes Mortality as outcomes
315 (54.2) 37 (6.4) 229 (39.4) 381 (65.6) 225 (38.7)
99 (62.3) 5 (3.1) 55 (34.6) 80 (50.3) 70 (44)
162 (59.3) 23 (8.4) 88 (32.2) 181 (66.3) 95 (34.8)
75 (59.1) 6 (4.7) 46 (36.2) 58 (45.7) 55 (43.3)
Trial design Superiority Non-inferiority Placebo-controlled
290 (49.9) 35 (6) 256 (44.1)
102 (64.2) 2 (1.3) 55 (34.6)
167 (61.2) 18 (6.6) 88 (32.2)
82 (64.6) 3 (2.4) 42 (33.1)
Intervention Medication Invasive Testing/imaging Others Multinational Multiregional
402 (69.2) 148 (25.5) 5 (0.9) 26 (4.5) 376 (68.5) 234 (50.1)
75 (47.2) 48 (30.2) 4 (2.5) 32 (20.1) 47 (30.3) 21 (14.2)
116 (42.5) 101 (37) 14 (5.1) 42 (15.4) 44 (16.8) 21 (8.2)
56 (44.1) 41 (32.3) 13 (10.2) 17 (13.4) 42 (34.4) 26 (22)
All variables are expressed as number (%) or median (interquartile range) and either compared using chi-squared tests, Kruskal-Wallis tests, or one-way analysis of variance tests with Bonferroni correction for multiple comparisons. a P-value is b0.001 for all comparisons except Outcomes (P = 0.13) and Mortality as outcomes (P = 0.19). b Enrollment rate is expressed as number of patients enrolled per site per month.
Please cite this article as: M. Vaduganathan, et al., Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.119
M. Vaduganathan et al. / International Journal of Cardiology xxx (2016) xxx–xxx
Gregg C Fonarow: reports significant consultant support from Novartis; and modest consultant support from Amgen, AstraZeneca, Bayer, Gambro, Janssen, and Medtronic. Mihai Gheorghiade: reports relationships with Abbott, Astellas, AstraZeneca, Bayer, Cardiorentis, CorThera, Cytokinetics, CytoPherx, DebioPharm, Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Johnson & Johnson, Medtronic, Merck, Novartis, Ono Pharma, Otsuka, Palatin Technologies, Pericor Therapeutics, Protein Design, Sanofi-Aventis, Sigma Tau, Solvay, Sticares InterACT, Takeda, and Trevena. Javed Butler: reports research support from the National Institutes of Health, European Union; and is a consultant to Amgen, Bayer, BG Medicine, Celladon, Gambro, GE Healthcare, Harvest, Medtronic, Ono Pharma, Stemedica, and Trevena. All other authors have no relevant conflicts of interest to declare. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements We are grateful to Michael Lee, BS, † and Bilal Khan, MD, ‡ for their assistance with the database. † Emory Cardiovascular Clinical Research Institute, Emory University, Atlanta, GA, United States ‡ Good Samaritan Hospital (University of Cincinnati), Cincinnati, OH, United States
3
References [1] J. Butler, A.S. Tahhan, V.V. Georgiopoulou, A. Kelkar, M. Lee, B. Khan, et al., Trends in characteristics of cardiovascular clinical trials 2001–2012, Am. Heart J. 170 (2015) 263–272. [2] R.M. Califf, D.A. Zarin, J.M. Kramer, R.E. Sherman, L.H. Aberle, A. Tasneem, Characteristics of clinical trials registered in ClinicalTrials.gov, 2007–2010, JAMA 307 (2012) 1838–1847. [3] J. Butler, H. Subacius, M. Vaduganathan, G.C. Fonarow, A.P. Ambrosy, M.A. Konstam, et al., Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial, J. Am. Coll. Cardiol. 61 (2013) 571–579. [4] S. Ehrhardt, L.J. Appel, C.L. Meinert, Trends in national institutes of health funding for clinical trials registered in ClinicalTrials.gov, JAMA 314 (2015) 2566–2567. [5] P.M. Ridker, J. Torres, Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000–2005, JAMA 295 (2006) 2270–2274. [6] S. Hopewell, K. Loudon, M.J. Clarke, A.D. Oxman, K. Dickersin, Publication bias in clinical trials due to statistical significance or direction of trial results, Cochrane Database Syst. Rev. (2009) MR000006. [7] M. Bhandari, J.W. Busse, D. Jackowski, V.M. Montori, H. Schunemann, S. Sprague, et al., Association between industry funding and statistically significant proindustry findings in medical and surgical randomized trials, CMAJ 170 (2004) 477–480. [8] J. Lexchin, L.A. Bero, B. Djulbegovic, O. Clark, Pharmaceutical industry sponsorship and research outcome and quality: systematic review, BMJ 326 (2003) 1167–1170. [9] S.S. Chopra, Industry funding of clinical trials: benefit or bias? JAMA 290 (2003) 113–114. [10] B. Als-Nielsen, W. Chen, C. Gluud, L.L. Kjaergard, Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA 290 (2003) 921–928.
Please cite this article as: M. Vaduganathan, et al., Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.119
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review Muthiah Vaduganathan a,⁎,1, Ayman Samman-Tahhan b,1, Ravi B. Patel c, Anita Kelkar b, Lampros Papadimitriou d, Vasiliki V. Georgiopoulou b, Stephen J. Greene e, Andreas P. Kalogeropoulos b, Eric Peterson e, Gregg C. Fonarow f, Mihai Gheorghiade g, Javed Butler d a
Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA, United States Cardiology Division, Emory University, Atlanta, GA, United States c Division of Cardiology, Bluhm Cardiovascular Institute at Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, United States d Division of Cardiology, Stony Brook University, Stony Brook, NY, United States e Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, United States f Division of Cardiology, University of California Los Angeles, Los Angeles, CA, United States g Center for Cardiovascular Innovation, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States b
a r t i c l e
i n f o
Article history: Received 6 September 2016 Received in revised form 15 November 2016 Accepted 17 December 2016 Available online xxxx Keywords: Cardiovascular Clinical trials Funding source Outcomes Trial design
To the Editor: Trial-level characteristics, including mechanism of funding, may shape the likelihood of trial completion, patient population enrolled, and possibly trial outcomes [1]. Concerns exist regarding the influence of funding source on clinical trial conduct and outcomes. However, limited quantitative data are available characterizing the role of funding source on trial operating characteristics, enrollment patterns, and outcomes in contemporary cardiovascular clinical trials. We evaluated cardiovascular phase II-IV randomized controlled trials published in the 8 highest Web-of-Science impact factor journals (according to the 2013 edition of the Journal Citation Reports® in the categories “General and Internal Medicine” and Cardiology”) between January 2001 to December 2012 using both a PubMed database and manual journal search. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for all ⁎ Corresponding author at: Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, 75 Francis St, Boston, MA 02115, United States. E-mail address: [email protected] (M. Vaduganathan). 1 Drs. Vaduganathan and Samman-Tahhan contributed equally to this manuscript.
procedures. We employed a previously reported algorithm to define funding source [2]. For studies registered in ClinicalTrials.gov, we used the entry provided for funding source. For trials not registered, we obtained the information from the main published article, statements of sources of support, acknowledgments, supplemental data, or online appendices. A total of 4524 studies were screened, of which, 1224 trials, cumulatively studying 2,350,632 patients from 98 countries, met the criteria for inclusion. Of these, 581 (47.5%) were funded by industry sources, 273 (22.3%) by non-profit organizations, 159 (13%) by governments, 127 (10.4%) jointly funded by a non-profit organization with industrial or governmental collaboration, and 84 (6.9%) did not report a specific funding source. From 2001–2003 to 2009–2012, the proportion of industry- and government-funded trials trended down, while the proportion of non-profit and jointly-funded trials increased over time (P b 0.001; Fig. 1). Studies funded by industry tended to have larger numbers of participants per trial, sites per trial, and countries per trial (Table 1). Fifty-six trials (4.9%) included more than 10,000 patients enrolled per trial; of these, industry funded 71.4%. The total duration of trials was shortest for industry trials (median 1.8, IQR 1.2–2.5 years). Non-profit trials had the highest enrollment rates with median of 4 (IQR 1–9.7) patients/site/month. Industry sponsors were more likely to fund trials that evaluated effects of new therapy vs. placebo, while government sponsors were more likely to fund non-drug or device trials. Positive outcomes were more likely to be reported by industry (65.6%) and non-profit (66.3%) trials compared with government (50.3%) or jointly-funded (45.7%) trials (P b 0.001). The proportion of positive trials decreased over time for industry (71.5% to 62.4%; P = 0.05) and jointly-funded (75% to 32.8%; P = 0.02) trials, while government and non-profit trials had stable rates of positive outcomes over time (P N 0.4 for both). In this systematic review of over 1200 cardiovascular clinical trials published in high impact, peer-reviewed journals from 2001 to 2012, we observed substantial variability in study type, design, intervention, enrollment rates, and outcomes among trials by primary funding
http://dx.doi.org/10.1016/j.ijcard.2016.12.119 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: M. Vaduganathan, et al., Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.119
2
M. Vaduganathan et al. / International Journal of Cardiology xxx (2016) xxx–xxx
Fig. 1. Proportion of trials stratified by funding sources over time. Proportion of trials funded by industry and government sponsors trended down over time, while there was a significant increase in the proportion of jointly-funded trials or those funded by nonprofit organizations. Temporal trends across trial time-frames were performed using non-parametric tests for trend.
mechanism. Industry-sponsored trials accounted for almost half of all trials, enrolled the highest volume of patients, completed protocols on the shortest timelines, and reported a high proportion of favorable results, but displayed poor enrollment efficiency. Slow enrollment in global industry-funded trials may be related to application of strict inclusion and exclusion criteria, need for coordination across a number of countries and sites, and adherence to country-specific enrollment thresholds and regulatory requirements. Industry-funded trials were more likely to compare the study intervention with placebo and less likely to engage in head-to-head drug or device comparisons. Non-
profit organizations tended to fund a larger proportion of trials over time and enrolled patients more efficiently [3]. Consistent with recent data [4], government-based funding of trials has significantly declined over the last decade, to less than 10% of all trials based on our contemporary estimates. Taken together with other similar aggregate trial-level experiences [5–8], our data suggest substantial variation in sources of funding of cardiovascular clinical trials, which may influence key trial characteristics and outcomes. It is difficult to dissect whether the trends towards improved outcomes in industry-funded trials are secondary to more rigorous trial conduct or systematic bias [9]. Features that may bias industryfunded trials toward favorable trial outcomes include: 1) preferential funding of trial programs more likely to translate to positive outcomes; 2) publication bias with under-publication of negative findings [6]; 3) the evaluation of second and third in class drugs similar to ones known to have favorable results; 4) selection of inappropriate or “straw-man” comparator or doses; and 5) biased interpretation of trial results [10]. Indeed, industry-funded trials may also preferentially support later-phase investigations, which set the stage for new drug/device approval, and thus incorporate certain design elements that facilitate this regulatory process. Further research is required to explore the systematic influence of funding mechanisms on contemporary cardiovascular clinical trials. Over time, the landscape of financial support of cardiovascular clinical trials is changing and key trial characteristics and outcomes may be related to primary sources of funding.
Disclosures Eric Peterson: reports significant research grant support from Eli Lilly & Company, Janssen Pharmaceuticals, Inc.; and modest consultant/advisory board support from Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Pfizer, and Genentech Inc.
Table 1 Trial characteristics stratified by funding sources.a Industry
Government
Non-profit
Jointly-funded
Number of trials Number of patients
581 1,406,221
159 357,423
273 291,217
127 266,252
Trial size Patients per trial Sites per trial Countries per trial Duration (years) Enrollment rateb
849 (303–3123) 70 (24–198) 6 (1–17) 1.75 (1.15–2.5) 0.76 (0.41–1.39)
589 (219–1869) 18 (3.75–50.5) 1 (1–2) 3.27 (2.3–4.71) 1.08 (0.45–3.2)
351.5 (161–955) 3 (1–15) 1 (1–1) 2.06 (1.36–3.59) 3.99 (1.0–9.7)
601 (195–2305) 19 (4–52) 1 (1–3) 3 (1.67–4.27) 1.12 (0.45–4.2)
Outcomes Clinical Intermediate Surrogate Positive outcomes Mortality as outcomes
315 (54.2) 37 (6.4) 229 (39.4) 381 (65.6) 225 (38.7)
99 (62.3) 5 (3.1) 55 (34.6) 80 (50.3) 70 (44)
162 (59.3) 23 (8.4) 88 (32.2) 181 (66.3) 95 (34.8)
75 (59.1) 6 (4.7) 46 (36.2) 58 (45.7) 55 (43.3)
Trial design Superiority Non-inferiority Placebo-controlled
290 (49.9) 35 (6) 256 (44.1)
102 (64.2) 2 (1.3) 55 (34.6)
167 (61.2) 18 (6.6) 88 (32.2)
82 (64.6) 3 (2.4) 42 (33.1)
Intervention Medication Invasive Testing/imaging Others Multinational Multiregional
402 (69.2) 148 (25.5) 5 (0.9) 26 (4.5) 376 (68.5) 234 (50.1)
75 (47.2) 48 (30.2) 4 (2.5) 32 (20.1) 47 (30.3) 21 (14.2)
116 (42.5) 101 (37) 14 (5.1) 42 (15.4) 44 (16.8) 21 (8.2)
56 (44.1) 41 (32.3) 13 (10.2) 17 (13.4) 42 (34.4) 26 (22)
All variables are expressed as number (%) or median (interquartile range) and either compared using chi-squared tests, Kruskal-Wallis tests, or one-way analysis of variance tests with Bonferroni correction for multiple comparisons. a P-value is b0.001 for all comparisons except Outcomes (P = 0.13) and Mortality as outcomes (P = 0.19). b Enrollment rate is expressed as number of patients enrolled per site per month.
Please cite this article as: M. Vaduganathan, et al., Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.119
M. Vaduganathan et al. / International Journal of Cardiology xxx (2016) xxx–xxx
Gregg C Fonarow: reports significant consultant support from Novartis; and modest consultant support from Amgen, AstraZeneca, Bayer, Gambro, Janssen, and Medtronic. Mihai Gheorghiade: reports relationships with Abbott, Astellas, AstraZeneca, Bayer, Cardiorentis, CorThera, Cytokinetics, CytoPherx, DebioPharm, Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Johnson & Johnson, Medtronic, Merck, Novartis, Ono Pharma, Otsuka, Palatin Technologies, Pericor Therapeutics, Protein Design, Sanofi-Aventis, Sigma Tau, Solvay, Sticares InterACT, Takeda, and Trevena. Javed Butler: reports research support from the National Institutes of Health, European Union; and is a consultant to Amgen, Bayer, BG Medicine, Celladon, Gambro, GE Healthcare, Harvest, Medtronic, Ono Pharma, Stemedica, and Trevena. All other authors have no relevant conflicts of interest to declare. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements We are grateful to Michael Lee, BS, † and Bilal Khan, MD, ‡ for their assistance with the database. † Emory Cardiovascular Clinical Research Institute, Emory University, Atlanta, GA, United States ‡ Good Samaritan Hospital (University of Cincinnati), Cincinnati, OH, United States
3
References [1] J. Butler, A.S. Tahhan, V.V. Georgiopoulou, A. Kelkar, M. Lee, B. Khan, et al., Trends in characteristics of cardiovascular clinical trials 2001–2012, Am. Heart J. 170 (2015) 263–272. [2] R.M. Califf, D.A. Zarin, J.M. Kramer, R.E. Sherman, L.H. Aberle, A. Tasneem, Characteristics of clinical trials registered in ClinicalTrials.gov, 2007–2010, JAMA 307 (2012) 1838–1847. [3] J. Butler, H. Subacius, M. Vaduganathan, G.C. Fonarow, A.P. Ambrosy, M.A. Konstam, et al., Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial, J. Am. Coll. Cardiol. 61 (2013) 571–579. [4] S. Ehrhardt, L.J. Appel, C.L. Meinert, Trends in national institutes of health funding for clinical trials registered in ClinicalTrials.gov, JAMA 314 (2015) 2566–2567. [5] P.M. Ridker, J. Torres, Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000–2005, JAMA 295 (2006) 2270–2274. [6] S. Hopewell, K. Loudon, M.J. Clarke, A.D. Oxman, K. Dickersin, Publication bias in clinical trials due to statistical significance or direction of trial results, Cochrane Database Syst. Rev. (2009) MR000006. [7] M. Bhandari, J.W. Busse, D. Jackowski, V.M. Montori, H. Schunemann, S. Sprague, et al., Association between industry funding and statistically significant proindustry findings in medical and surgical randomized trials, CMAJ 170 (2004) 477–480. [8] J. Lexchin, L.A. Bero, B. Djulbegovic, O. Clark, Pharmaceutical industry sponsorship and research outcome and quality: systematic review, BMJ 326 (2003) 1167–1170. [9] S.S. Chopra, Industry funding of clinical trials: benefit or bias? JAMA 290 (2003) 113–114. [10] B. Als-Nielsen, W. Chen, C. Gluud, L.L. Kjaergard, Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA 290 (2003) 921–928.
Please cite this article as: M. Vaduganathan, et al., Association between funding sources and the scope and outcomes of cardiovascular clinical trials: A systematic review, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.119