Bioanalytical method requirements and statistical considerations in incurred sample reanalysis for macromolecules
Abstract
Background: Incurred sample reanalysis (ISR) is the most recent in-study validation parameter that regulatory agencies have mandated to ensure reproducibility of bioanalytical methods supporting pharmacokinetic/toxicokinetic and clinical studies. The present analysis describes five representative case studies for macromolecule therapeutics. Method: Single ISR acceptance criteria (within 30% of the averaged or original concentration) and a modified Bland–Altman (BA) approach were used to assess accuracy and precision of ISR results. General concordance between the two criteria was examined using simulation studies. Results: All five methods met the ISR criteria. The results indicated that thorough method development and prestudy validation were prerequisites for a successful ISR. The overall agreement between the original and reanalyzed results as determined by BA was within 20%. Simulation studies indicated that concordance between the ISR criteria and BA was observed in 95% of the cases. Dilution factors had no significant impact on the ISR, even for Cmax samples where 1:100 or higher dilutions were used. Conclusion: The current ISR acceptance criteria for macromolecules was scientifically and statistically meaningful for methods with a total error of 25% or less.
Papers of special note have been highlighted as: ▪ of interest
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