Incurred Sample Reanalysis: Time to Change the Sample Size Calculation?

Abstract

Reliable results of pharmacokinetic and toxicokinetic studies are vital for correct decision making during drug discovery and development. Thus, ensuring high quality of bioanalytical methods is of critical importance. Incurred sample reanalysis (ISR)—one of the tools used to validate a method—is included in the bioanalytical regulatory recommendations. The methodology of this test is well established, but the estimation of the sample size is still commented on and contested. We have applied the hypergeometric distribution to evaluate ISR test passing rates in different clinical study sizes. We have tested both fixed rates of the clinical samples—as currently recommended by FDA and EMA—and a fixed number of ISRs. Our study revealed that the passing rate using the current sample size calculation is related to the clinical study size . However, the passing rate is much less dependent on the clinical study size when a fixed number of ISRs is used. Thus, we suggest using a fixed number of ISRs, e.g., 30 samples, for all studies. We found the hypergeometric distribution to be an adequate model for the assessment of similarities in original and repeated data. This model may be further used to optimize the sample size needed for the ISR test as well as to bridge data from different methods. This paper provides a basis to re-consider current ISR recommendations and implement a more statistically rationalized and risk-controlled approach.

Osteoarthritis endotype discovery via clustering of biochemical marker data

“…Incurrent sample remeasurement for the adjustment of technical batch effects could not be performed, as no samples were left and available from the FNIH/OAI cohort for this purpose. Therefore precise data alignment on the absolute mean concentrations and variance between the two cohorts was not possible to conduct 30 31. As a result, the only possible type of external validation consisted in replicating the clustering pipeline for the two cohorts restricted to the common set of 11 biomarkers and evaluating the consistency of the identified clusters across cohorts.…”

European Bioanalysis Forum Feedback on Draft ICH M10 Guideline on Bioanalytical Method Validation During the Step 2b Public Consultation Period

“…These data could be used to refine the ISR requirements for the ICH M10 guideline, not only for which studies, but after data mining, likely also for the number of samples required. From this and supported by many other papers providing scientific evidence that reanalysis of large sets of samples does not add scientific value [31][32][33], we commented to consider a cap, that is, a maximum sample number to be analyzed as part of ISR: reanalyze 10% of the study samples, with a minimum of 20 and a maximum of 100 samples.…”

Novel methodology to perform incurred sample reanalysis on dried blood spot cards: Experimental data using darolutamide and filgotinib

“…Incurred sample reanalysis (ISR) is not only gaining importance but also has become a mandatory requirement in bioanalytical method validation as this parameter provides a basis for early detection and/or identification with respect to the discrepancies between original and repeat analysis (Rocci, Devanarayan, Haughey, & Jardieu, 2007; Rudzki, Biecek, & Kaza, 2017, 2019; Srinivas, 2011). The rigorous conduct of the ISR in early drug development process keeps a check on method reproducibility issues and supports the validity of the pharmacokinetic data gathered in both preclinical and clinical studies.…”