Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis

BACKGROUND: It is unclear whether participation in a randomized controlled trial (RCT), irrespective of assigned treatment, is harmful or beneficial to participants. We compared outcomes for patients with the same diagnoses who did ("insiders") and did not ("outsiders") enter RCTs, without regard to the specific therapies received for their respective diagnoses. METHODS: By searching the MEDLINE (1966-2010), Embase (1980-2010), CENTRAL (1960-2010) and PsycINFO (1880-2010) databases, we identified 147 studies that reported the health outcomes of "insiders" and a group of parallel or consecutive "outsiders" within the same time period. We prepared a narrative review and, as appropriate, meta-analyses of patients' outcomes. RESULTS: We found no clinically or statistically significant differences in outcomes between "insiders" and "outsiders" in the 23 studies in which the experimental intervention was ineffective (standard mean difference in continuous outcomes -0.03, 95% confidence interval [CI] -0.1 to 0.04) or in the 7 studies in which the experimental intervention was effective and was received by both "insiders" and "outsiders" (mean difference 0.04, 95% CI -0.04 to 0.13). However, in 9 studies in which an effective intervention was received only by "insiders," the "outsiders" experienced significantly worse health outcomes (mean difference -0.36, 95% CI -0.61 to -0.12). INTERPRETATION: We found no evidence to support clinically important overall harm or benefit arising from participation in RCTs. This conclusion refutes earlier claims that trial participants are at increased risk of harm.