How Often Do Safety Signals Occur by Chance in First‐in‐Human Trials?

: Clinicians working on first-in-human clinical studies need to be able to judge whether safety signals observed on an investigational drug were more likely to have occurred by chance or to have been caused by the drug. We retrospectively reviewed 84 Novartis studies including 1,234 healthy volunteers receiving placebo to determine the expected incidence of changes in commonly measured laboratory parameters and vital signs, in the absence of any active agent. We calculated the frequency of random incidence of safety signals, focusing on the liver, cardiovascular system, kidney, and pancreas. Using the liver enzyme alanine aminotransferase (ALT) as an example, we illustrate how a predictive model can be used to determine the probability of a given subject to experience an elevation of ALT above the upper limit of the normal range under placebo, conditional on the characteristics of this subject and the study.