Synthesis studies (SS): systematic review and meta-analysis are the basis for developing Health Economic Evaluations (HEE). SS allow us to obtain parameters for estimating probabilities and effectiveness from the combination of the results of primary studies, and, as they include in their methodology the selection, evaluation, systematization and synthesis processes, they are considered the first level of hierarchy in scientific evidence. Nevertheless, they can be prone to bias and methodological failures that can affect the validity of their results. This article initially presents the relevance of the randomization in the hierarchic classification of research designs, then it reviews the main factors affecting the validity of the SS, emphasising the publication bias, the heterogeneity and the inclusion of primary studies with main objective differing from the one of the SS. Moreover, it presents individual studies like a valid alternative for the development of a SS. The conclusion is that one of the key aspects in a SS is the correct evaluation of the study types and the objective evaluation of their quality, being these primary or secondary.