Single-center trials show larger treatment effects than multicenter trials: evidence from a meta-epidemiologic study

Ann Intern Med. 2011 Jul 5;155(1):39-51. doi: 10.7326/0003-4819-155-1-201107050-00006.


Background: A recent study suggested that results of single-center trials are frequently contradicted when similar trials are performed in multicenter settings.

Purpose: To perform a meta-epidemiologic study to evaluate whether estimates of treatment effect differ between single-center and multicenter randomized, controlled trials (RCTs).

Data sources: MEDLINE was searched via PubMed for meta-analyses of RCTs with binary outcomes that were published between August 2008 and January 2009 and in the first 6 months of 2010 in the 10 leading journals of each medical specialty. One issue of the Cochrane Database of Systematic Reviews was also searched.

Study selection: All individual RCTs included in the meta-analyses were selected.

Data extraction: Data were extracted and their quality was assessed by use of the risk of bias tool of the Cochrane Collaboration.

Data synthesis: The primary outcome was the ratio of odds ratios (ROR), used to quantify the difference in estimated intervention effect between single-center and multicenter RCTs. An ROR less than 1 would indicate larger estimates of the intervention effect in single-center trials. Sensitivity analyses were performed with adjustment for sample size, risk of bias within RCTs, and variance of the log odds ratio to take publication bias into account. Forty-eight meta-analyses were selected, including 421 RCTs (223 were single-center and 198 were multicenter). Single-center RCTs showed a larger intervention effect than did multicenter RCTs (combined ROR, 0.73 [95% CI, 0.64 to 0.83]), with low heterogeneity across individual meta-analyses (I(2) = 12.0%; P = 0.24). Adjustment for sample size yielded consistent results (ROR, 0.85 [CI, 0.74 to 0.97]), as did adjustment for risk of bias within RCTs, such as allocation concealment (ROR, 0.76 [CI, 0.67 to 0.86]), and variance of log odds ratio (ROR, 0.83 [CI, 0.72 to 0.96]).

Limitation: Despite sensitivity analyses, meta-confounding cannot be fully excluded.

Conclusion: Single-center RCTs showed larger treatment effects than did multicenter RCTs, a finding that was consistent in all sensitivity analyses. These results suggest that this item should be considered when the results of RCTs and meta-analyses are interpreted.

Primary funding source: Academic grant Recherche sur la Recherche from the Délégation Interrégionale à la Recherche Clinique (DIRC), Ile de France, Assistance Publique-Hôpitaux de Paris (APHP).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bias
  • Epidemiologic Research Design
  • Humans
  • Meta-Analysis as Topic
  • Multicenter Studies as Topic / standards*
  • Odds Ratio
  • Randomized Controlled Trials as Topic / standards*
  • Sample Size
  • Sensitivity and Specificity
  • Treatment Outcome