Efficacy-effectiveness gap as an obstacle to translating clinical trials to clinical practice

Randomised controlled trials (RCTs) provide the gold standard investigation for medical interventions, allowing for accurate, unbiased measurement of treatment effect, and providing a high degree of internal validity. Eligibility criteria in RCTs allow for the inclusion of a homogenous study population, which increases accuracy of the measurement of treatment effect by reducing inter-patient variability. Unfortunately, the application of eligibility criteria in RCTs results in suboptimal representation of patients treated in the real world setting [ ]. The efficacy-effectiveness gap describes the differences in outcomes between patients treated in RCTs and those treated in the real world [ , , ]. This consequence is best observed in analyses demonstrating that when compared to patients treated on a clinical trial in the same institution at the same time, those treated off-study have poorer survival and greater toxicity [ ]. This observation appears most marked among patients with advanced age or greater comorbidities, a group known to be underrepresented in clinical trials [ , ]. Such patients have been shown to derive significantly less benefit and suffer greater toxicity than trial participants [ ]. It remains unclear whether the efficacy-effectiveness gap results from the eligibility criteria of RCTs being too restrictive or whether clinicians apply new treatments in scenarios beyond the evidence-base.