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Many multicenter randomized controlled trials do not account for center effect: a methodological review
Mohamad Ossman1, Primael Megninou1, Florian Lejeune1
1Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, UMR-S 1136, AP-HP, Hôpital Pitié-Salpêtrière, Département de Santé Publique, Paris, France.
Journal of Clinical Epidemiology
|June 30, 2026
Summary
Few recent multicenter randomized controlled trials adequately address center effects in randomization and statistical analysis. Subgroup analyses by center are rarely performed, impacting the reliability of medical intervention evaluations.
Area of Science:
- Clinical Trials Methodology
- Biostatistics
- Health Services Research
Background:
- Multicenter randomized controlled trials (RCTs) are crucial for evaluating medical interventions.
- Center effects, variations in outcomes across different study sites, pose methodological challenges in multicenter RCTs.
- Standardization and appropriate statistical handling of center effects are essential for robust trial results.
Purpose of the Study:
- To evaluate how center effects are managed during randomization and statistical analysis in recent multicenter RCTs.
- To determine the frequency and outcomes of subgroup analyses conducted by center in these trials.
Main Methods:
- Methodological review of primary reports from multicenter RCTs published in 2024 in five major general medical journals.
- Searched MEDLINE via PubMed for relevant studies.
- Data extraction performed in duplicate.
Main Results:
- Out of 188 included multicenter RCTs, 49% used center stratification/minimization in randomization, more common in non-pharmacological trials (75%) than pharmacological (27%).
- Only 20% reported accounting for center in primary statistical analysis, and 36% accounted for center effect post-stratification/minimization.
- Center subgroup analysis was reported in 10% of trials, with one showing a significant interaction.
Conclusions:
- A minority of recent multicenter RCTs effectively account for center effects in their design and analysis.
- The infrequent use of center stratification/minimization and statistical adjustment for center effects may limit the generalizability of findings.
- Subgroup analyses by center are seldom conducted, hindering deeper understanding of site-specific variations.
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