Mega-trials vs. meta-analysis: precision vs. heterogeneity?

In recent years, several authors have suggested there is a need for more very large or "mega-trials" (defined in this manuscript as a trial powered to address subgroup differences/interactions/secondary analyses) to answer important clinical questions. Because mega-trials are expensive and funding for clinical research is limited, increasing the number of mega-trials limits funding for other research. The advantages of this approach compared with funding more focused RCTs needs to be debated. Because there is no method to determine gold standard for which method gives the correct answer, we provide theoretical arguments that demonstrate that the two approaches are similar with respect to sample size requirements and the mega-trial approach provides a small advantage with respect to minimizing confounding by chance. However, the inherent heterogeneity in a series of smaller trials may represent a significant advantage over a single mega-trial.