Association of Funding and Conclusions in Randomized Drug Trials: A Reflection of Treatment Effect or Adverse Events? | Research, Methods, Statistics | JAMA | JAMA Network
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1.
Davidson RA. Source of funding and outcome of clinical trials.  J Gen Intern Med.1986;1:155-158.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=3772583Google Scholar
2.
Yaphe J, Edman R, Knishkowy B, Herman J. The association between funding by commercial interests and study outcome in randomized controlled drug trials.  Fam Pract.2001;18:565-568.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=11739337Google Scholar
3.
Kjaergard LL, Als-Nielsen B. Association between competing interests and authors' conclusions: epidemiological study of randomised clinical trials published in BMJ.  BMJ.2002;325:249-252.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12153921Google Scholar
4.
Rochon PA, Gurwitz JH, Simms RW.  et al.  A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis.  Arch Intern Med.1994;154:157-163.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8285810Google Scholar
5.
Djulbegovic B, Lacevic M, Cantor A.  et al.  The uncertainty principle and industry-sponsored research.  Lancet.2000;356:635-638.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10968436Google Scholar
6.
Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review.  JAMA.2003;289:454-465.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12533125Google Scholar
7.
Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review.  BMJ.2003;326:1167-1170.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12775614Google Scholar
8.
Jacobs A. Association between competing interests and conclusions [letter].  BMJ.2002;325:1420.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12484375Google Scholar
9.
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials.  JAMA.1995;273:408-412.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=7823387Google Scholar
10.
Kjaergard LL, Villumsen J, Gluud C. Reported methodological quality and discrepancies between large and small randomized trials in meta-analyses.  Ann Intern Med.2001;135:982-989.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=11730399Google Scholar
11.
Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? empirical study.  Health Technol Assess.2003;7:1-76.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12583822Google Scholar
12.
Balk EM, Boris PA, Moskowitz H.  et al.  Correlation of quality measures with estimates of treatment effect in meta-analyses of randomized controlled trials.  JAMA.2002;287:2973-2982.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12052127Google Scholar
13.
 The Cochrane Database of Systematic Reviews. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
14.
Gilbert JP, McPeek B, Mosteller F. Statistics and ethics in surgery and anesthesia.  Science.1977;198:684-689.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=333585Google Scholar
15.
Altman DG. Practical Statistics for Medical ResearchLondon, England: Chapman & Hall; 1991.
16.
Hosmer D, Lemeshow S. Applied Logistic RegressionNew York, NY: Wiley & Sons; 1989.
17.
Tinnion ON, Hanlon M. Acellular vaccines for preventing whooping cough in children [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
18.
Olliaro P, Mussano P. Amodiaquine for treating malaria [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
19.
Henry DA, Moxey AJ, Carless PA.  et al.  Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
20.
French LM, Smaill FM. Antibiotic regimens for endometritis after delivery [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
21.
Roos YBWEM, Rinkel GJE, Vermeulen M, Algra A, van Gijn J. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
22.
Suarez-Almazor ME, Spooner CH, Belseck E, Shea B. Auranofin versus placebo in rheumatoid arthritis [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
23.
Kellner JD, Ohlsson A, Gadomski AM, Wang EEL. Bronchodilators for bronchiolitis [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
24.
Feigin VL, Rinkel GJE, Algra A, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
25.
Alderson P, Schierhout G, Roberts I, Bunn F. Colloids versus crystalloids for fluid resuscitation in critically ill patients [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
26.
Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Corticosteroids for preventing relapse following acute exacerbations of asthma [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
27.
Couchoud C. Cytomegalovirus prophylaxis with antiviral agents for solid organ transplantation [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
28.
Lima MS, Moncrieff J. Drugs versus placebo for dysthymia [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
29.
Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute asthma with systemic corticosteroids [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
30.
Candelise L, Ciccone A. Gangliosides for acute ischaemic stroke [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
31.
Brocklehurst P, Hannah M, McDonald H. Interventions for treating bacterial vaginosis in pregnancy [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
32.
Gibbs S, Harvey I, Sterling JC, Stark R. Local treatments for cutaneous warts [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
33.
Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
34.
Silagy C, Mant D, Fowler G, Lancaster T. Nicotine replacement therapy for smoking cessation [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
35.
Wood-Baker R, Walters E.H, Gibson P. Oral corticosteroids for acute exacerbations of chronic obstructive pulmonary disease [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
36.
Soo S, Moayyedi P, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
37.
Garner P, Gülmezoglu AM. Prevention versus treatment for malaria in pregnant women [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
38.
Martin-Hirsch PL, Jarvis G, Kitchener H, Lilford R. Progestagens for endometrial cancer [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
39.
Tan BP, Hannah ME. Prostaglandins versus oxytocin for prelabour rupture of membranes at term [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
40.
Daya S, Gunby J. Recombinant versus urinary follicle stimulating hormone for ovarian stimulation in assisted reproduction cycles [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
41.
Ioannou G, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrhage [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2001; issue 2.
42.
Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test.  BMJ.1997;315:629-634.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9310563Google Scholar
43.
Jadad AR, Cook DJ, Jones A.  et al.  Methodology and reports of systematic reviews and meta-analyses: a comparison of Cochrane reviews with articles published in paper-based journals.  JAMA.1998;280:278-280.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9676681Google Scholar
44.
Jadad AR, Moher M, Browman GP.  et al.  Systematic reviews and meta-analyses on treatment of asthma: critical evaluation.  BMJ.2000;320:537-540.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10688558Google Scholar
45.
Streiner DL, Norman GR. Health Measurement Scales: A Practical Guide to Their Development and Use2nd ed. Oxford, England: Oxford Medical Publications; 1995.
46.
 The Cochrane Library. Oxford, England: Update Software; 2003; issue 2.
47.
Zhang B, Schmidt B. Do we measure the right end points? a systematic review of primary outcomes in recent neonatal randomized clinical trials.  J Pediatr.2001;138:76-80.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=11148516Google Scholar
48.
Rossetti L, Marchetti I, Orzalesi N, Scorpiglione N, Liberati A. Is proper methodology associated with the use of a clinically relevant outcome measure? the case of randomized clinical trials on medical treatment of open-angle glaucoma.  Online J Curr Clin Trials [serial online].1993. Doc No. 100.Google Scholar
49.
Gøtzsche PC, Liberati A, Torri V, Rossetti L. Beware of surrogate outcome measures.  Int J Technol Assess Health Care.1996;12:238-246.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8707497Google Scholar
50.
Roberts L, Counsell C. Assessment of clinical outcomes in acute stroke trials.  Stroke.1998;29:986-991.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9596247Google Scholar
51.
Duncan PW, Jorgensen HS, Wase DT. Outcome measures in acute stroke trials: a systematic review and some recommendations to improve practice.  Stroke.2000;31:1429-1438.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10835468Google Scholar
52.
Pocock SJ, Hughes MD, Lee RJ. Statistical problems in the reporting of clinical trials: a survey of three medical journals.  N Engl J Med.1987;317:426-432.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=3614286Google Scholar
53.
Clarke M, Oxman A. Cochrane Reviewers' Handbook 4.1.6 [updated January 2003]. Oxford, England: Cochrane Library, Update Software; 2003; issue 2.
54.
International Conference on Harmonisation Expert Working Group.  Code of Federal Regulations & International Conference on Harmonization GuidelinesPhiladelphia, Pa: Parexel Barnett; 1997.
55.
Kjaergard LL, Nikolova D, Gluud C. Randomized clinical trials in HEPATOLOGY: predictors of quality.  Hepatology.1999;30:1134-1138.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10534332Google Scholar
56.
Huwiler-Müntener K, Jüni P, Junker C, Egger M. Quality of reporting of randomized trials as a measure of methodologic quality.  JAMA.2002;287:2801-2804.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12038917Google Scholar
57.
Colditz GA, Miller JN, Mosteller F. How study design affects outcomes in comparisons of therapy, I: medical.  Stat Med.1989;8:441-454.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=2727468Google Scholar
58.
Kjaergard LL, Als-Nielsen B. Association between competing interests and authors' conclusions: epidemiological study of randomised clinical trials published in the BMJ [authors' electronic response]. Available at: http://bmj.com/cgi/content/full/325/7358/249. Accessibility verified July 7, 2003.
59.
Adams ME, McCall NT, Gray DT, Orza MJ, Chalmers TC. Economic analysis in randomized control trials.  Med Care.1992;30:231-243.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=1538611Google Scholar
60.
Gluud C, Kjaergard LL. Quality of randomized clincial trials in portal hypertension and other fields of hepatology. In: de Franchis R, ed. Portal Hypertension III: Proceedings of the Third Baveno International Consensus Workshop on Definitions, Methodology, and Therapeutic Strategies. Oxford, England: Blackwell Science; 2001:204-218.
61.
Friedberg M, Saffran B, Stinson TJ, Nelson W, Bennett CL. Evaluation of conflict of interest in economic analyses of new drugs used in oncology.  JAMA.1999;282:1453-1457.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=10535436Google Scholar
62.
Clifford T, Barrowman N, Moher D. Funding source, trial outcome and reporting quality: are they related? results of a pilot study.  BMC Health Serv Res.2002;2:18-23.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12213183Google Scholar
63.
Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications.  BMJ.2003;326:1171-1173.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=12775615Google Scholar
64.
Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research.  Lancet.1991;337:867-872.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=1672966Google Scholar
65.
Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials.  JAMA.1991;266:93-98.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=2046134Google Scholar
66.
Freemantle N. Interpreting the results of secondary end points and subgroup analyses in clinical trials: should we lock the crazy aunt in the attic?  BMJ.2001;322:989-991.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=11312237Google Scholar
67.
Thompson DF. Understanding financial conflicts of interest.  N Engl J Med.1993;329:573-576.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=8336759Google Scholar
68.
Gøtzche PC. Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis.  Control Clin Trials.1989;10:31-56.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=2702836Google Scholar
69.
Simes RJ. Publication bias: the case for an international registry of clinical trials.  J Clin Oncol.1986;4:1529-1541.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=3760920Google Scholar
70.
Horton R. Medical editors trial amnesty.  Lancet.1997;350:756.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=9297993Google Scholar
71.
Moher D, Schulz KF, Altman DG.for the CONSORT Group.  The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials.  JAMA.2001;285:1987-1991.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=11308435Google Scholar
72.
Davidoff F, DeAngelis CD, Drazen JM.  et al.  Sponsorship, authorship, and accountability.  JAMA.2001;286:1232-1234.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=11559271Google Scholar
Original Contribution
August 20, 2003

Association of Funding and Conclusions in Randomized Drug Trials: A Reflection of Treatment Effect or Adverse Events?

Author Affiliations

Author Affiliations: The Copenhagen Trial Unit, Center for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark.

JAMA. 2003;290(7):921-928. doi:10.1001/jama.290.7.921
Abstract

Context Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions.

Objective To explore whether the association between funding and conclusions in randomized drug trials reflects treatment effects or adverse events.

Design Observational study of 370 randomized drug trials included in meta-analyses from Cochrane reviews selected from the Cochrane Library, May 2001. From a random sample of 167 Cochrane reviews, 25 contained eligible meta-analyses (assessed a binary outcome; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment). The primary binary outcome from each meta-analysis was considered the primary outcome for all trials included in each meta-analysis. The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect, adverse events, and additional confounding factors (methodological quality, control intervention, sample size, publication year, and place of publication).

Main Outcome Measure Conclusions in trials, classified into whether the experimental drug was recommended as the treatment of choice or not.

Results The experimental drug was recommended as treatment of choice in 16% of trials funded by nonprofit organizations, 30% of trials not reporting funding, 35% of trials funded by both nonprofit and for-profit organizations, and 51% of trials funded by for-profit organizations (P<.001; χ2 test). Logistic regression analyses indicated that funding, treatment effect, and double blinding were the only significant predictors of conclusions. Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with trials funded by nonprofit organizations. This association did not appear to reflect treatment effect or adverse events.

Conclusions Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results. Readers should carefully evaluate whether conclusions in randomized trials are supported by data.

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