External validity in translational biomedicine: understanding the conditions enabling the cause to have an effect

A spectre is haunting biomedical research: It appears that a substantial fraction of published research results cannot be reproduced, while spectacularly successful novel treatments developed in experimental models of disease too often fail in clinical trials. A reproducibility crisis has been proclaimed, and bench‐to‐bedside translation appears to be lost in a “valley of death”. Both predicaments, non‐reproducibility and translational roadblocks, are connected: Why should we expect to successfully “trans‐late” results to humans, if already “cis‐lation”—that is, the generalization from one experimental setting to an identical or fairly similar one—often fails?