Interpretation of chemistry, hematology and coagulation laboratory results in early-phase clinical pharmacology trials: a retrospective analysis based on the placebo arm of randomized-controlled trials

Abstract

Early-phase clinical trials focus heavily on demonstrating safety and tolerability of drug candidates. Clinical laboratory test results outside of reference intervals (RIs) are often interpreted as possible indicators of harm. However, values outside RIs do not necessarily constitute drug-induced adverse effects. This retrospective analysis aims to position results outside RIs as common phenomena during clinical pharmacology trials. For this, a retrospective analysis was performed on 37 commonly used blood-based hematology, chemistry and coagulation markers of 11.535 screened participants and patients at screening, and 888 placebo-randomized healthy participants from 88 trials performed at the Centre for Human Drug Research between 2005 to 2025. On average, participants with RI excursions during trial participation already show more extreme values at screening and baseline. Also, after having been medically screened, values outside RIs are still commonly observed in placebo-randomized participants. Results appear centered around the mean of individual participants. The frequency and extent of RI excursions is measurand-specific but generally within 0.7-1.3 times the RI. More significant excursions over 0.5-2.0 times the RI are observed, including for liver transferases, but comprise only 1.5% of all excursions. Diurnal variation impacts some hematological measurands resulting in RI excursion especially around through times. To conclude, an individual predisposition exists towards more extreme values challenging the applicability of RIs in a longitudinal setting. Results during trial conduct can best be interpreted compared to individual baselines. RI excursions remain common in placebo-randomized participants and are therefore poorly indicative of drug-induced adverse events when not considered in their full clinical context.