Incurred sample reanalysis at GSK: what have we learned?

Outcomes of incurred sample reanalysis (ISR) studies have been reviewed from a decade of internally supported bioanalysis. From over 1000 bioanalytical pharmacokinetic end points, 26 bioanalytical studies have failed against predefined ISR acceptance criteria, ultimately resulting in the rejection of three partial and two full datasets (instability or preanalytic contamination). The remaining investigations highlighted methodological root causes including unexpected within-study assay variability, inappropriate assay range and sample homogeneity. However, the data variability remained acceptable for the purposes of decision-making and asset progression. Overall, ISR adds value in early development to characterize the reliability of a nascent assay and then also at the latter stages where pharmacokinetic data are pivotal to submission. However, for the intermediate development studies there is a question whether ISR adds much additional value in understanding assay performance or whether the industry is just too conservative to follow the guidance. This is where the future debate must be.