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August 15, 2001

Comparison of Evidence of Treatment Effects in Randomized and Nonrandomized Studies

Author Affiliations

Author Affiliations: Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina (Drs Ioannidis and Contopoulos-Ioannidis, and Ms Haidich), Department of Hygiene and Epidemiology, University of Athens School of Medicine (Ms Pappa and Mr Pantazis) and Laikon General Hospital (Drs Kokori and Tektonidou), Athens, Greece; Department of Pediatrics, George Washington University School of Medicine, Washington, DC (Dr Contopoulos-Ioannidis); and Division of Clinical Care Research, Department of Medicine, Tufts University School of Medicine, Boston, Mass (Drs Ioannidis and Lau).

JAMA. 2001;286(7):821-830. doi:10.1001/jama.286.7.821

Context There is substantial debate about whether the results of nonrandomized studies are consistent with the results of randomized controlled trials on the same topic.

Objectives To compare results of randomized and nonrandomized studies that evaluated medical interventions and to examine characteristics that may explain discrepancies between randomized and nonrandomized studies.

Data Sources MEDLINE (1966–March 2000), the Cochrane Library (Issue 3, 2000), and major journals were searched.

Study Selection Forty-five diverse topics were identified for which both randomized trials (n = 240) and nonrandomized studies (n = 168) had been performed and had been considered in meta-analyses of binary outcomes.

Data Extraction Data on events per patient in each study arm and design and characteristics of each study considered in each meta-analysis were extracted and synthesized separately for randomized and nonrandomized studies.

Data Synthesis Very good correlation was observed between the summary odds ratios of randomized and nonrandomized studies (r = 0.75; P<.001); however, nonrandomized studies tended to show larger treatment effects (28 vs 11; P = .009). Between-study heterogeneity was frequent among randomized trials alone (23%) and very frequent among nonrandomized studies alone (41%). The summary results of the 2 types of designs differed beyond chance in 7 cases (16%). Discrepancies beyond chance were less common when only prospective studies were considered (8%). Occasional differences in sample size and timing of publication were also noted between discrepant randomized and nonrandomized studies. In 28 cases (62%), the natural logarithm of the odds ratio differed by at least 50%, and in 15 cases (33%), the odds ratio varied at least 2-fold between nonrandomized studies and randomized trials.

Conclusions Despite good correlation between randomized trials and nonrandomized studies—in particular, prospective studies—discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common.

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