The phrase can be loosely translated as “god from the machine,” which refers to how the deus ex machina was performed in the ancient theater. However, when investigators employ secondary endpoints to explain mechanistic inconsistencies in early-phase translational studies, they run the risk of engaging in the scientific equivalent of an ancient literary device known as “deus ex machina.”ĭeus ex machina is a Latin phrase that describes an ancient plot device used by Greek and Roman tragedy playwrights to help resolve seemingly hopeless plot situations.
Not infrequently, when the chosen primary endpoints of the early-phase studies fail to yield the anticipated statistical results, secondary endpoints are used as a window to understand alternative mechanisms of action. Because phase Ib and II clinical trials lack formal guidelines for defining what a successful clinical outcome looks like, or how it should be measured, there is a frequent temptation to cast a wide net and measure a myriad of secondary endpoints.
In contrast to the later phases of clinical development, which are focused on safety and efficacy, understanding the therapeutic mechanism of action is far more important during the early stages of drug and device development, because the mechanism of action guides the appropriate choice of clinical endpoints that provide “proof of principle.” Given that these early-phase studies are underpowered to study “hard” clinical endpoints, such as cardiovascular death or hospitalization, they often employ a variety of “softer” surrogate endpoints, such as changes in biomarkers or changes in left ventricular function, which may or may not translate into clinically meaningful endpoints in subsequent phase III trials. Insofar as translational clinical studies are smaller, they are inherently fragile by their very nature. Translational research serves as the critical bridge between target identification and early-phase clinical studies that provide critical go/no-go decisions for larger and more expensive phase III clinical trials.
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