Incurred sample reanalysis

Type of studies. Incurred sample reanalysis is applicable to bioequivalence, phase I-IV human trials and GLP preclinical studies, or any study with a unique population. For GLP preclinical studies, the ISR evaluation only needs to be performed once per method, per species. 

The topic of incurred sample reanalysis (ISR) was introduced at the Crystal City III Conference in May 2006 to help understand the poor reproducibility of results found by FDA in some cases when samples from studies were reanalyzed. The recommendation from the workshop report [10] on this topic is that an adequate evaluation of incurred sample reproducibility should be conducted for each species used for GLP toxicology experiments and in selected clinical studies. It is also recognized that the degree of reproducibility could be different in human samples in comparison to the animal samples. Selection of the studies to be evaluated for ISR was left up to the sponsor. 

If a lack of accuracy is not due to assay performance (i.e., analyte instability or interconversion) then the reason for the lack of accuracy should be investigated and its impact on the study assessed. The extent and nature of these experiments is dependent on the specific sample being addressed and should provide sufficient confidence that the concentration being reported is accurate. The results of incurred sample reanalysis studies may be documented in the final bioanalytical or clinical report for the study, and/or as an addendum to the method validation report . 

As per the current health regulatory requirements and pharmaceutical industry practice, incurred sample reanalysis (ISR) should be conducted in separate runs at different days for toxicokinetic studies (once per species), all pivotal bioequivalence trials, first clinical trial, first patient trial, and first trial in patients with impaired hepatic and/or renal function [30,32],... 

Method reproducibility — Individual incurred samples from four subjects (approximately 5% of all samples) were re-assayed individually to evaluate reproducibility. The four samples set for reanalysis and evenly spaced throughout the study were designated 101, 123, 145, and 166. The values generated from the reassays were used only to assess reproducibility and were not used in pharmacokinetic calculations. Table 2.2 summarizes the method reproducibility results. The analytical method used in study M06-830 was accurate, precise, and reproducible. 

In addition to analytical and nonanalytical repeats, some samples in certain studies need to be reassayed to demonstrate incurred sample reproducibility (ISR). This type of testing is a critical step for demonstrating the reproducibility of the bioanalytical method with samples from dosed subjects (as distinct from precision demonstrated with QCs, i.e., blank matrix spiked with drug). Written procedures in this regard should include a description of how the samples are selected for reanalysis, the comparison and reporting of the original and repeat results, and the acceptance criteria for variability between results. 

A second approach to determining freezer storage stability involves the reanalysis of incurred residues found in actual samples that are stored over time. Using this approach, soil from an actual field sample containing residues is periodically analyzed... 

Paper published in September, 2007 by Rocci et al. entitled Confirmatory Reanalysis of Incurred Bioanalytical Samples [24],... 

Rocci ML, Devanarayan V, Haughey DB et al (2007) Confirmatory reanalysis of incurred bioanalytical samples. AAPS J 9(3) E336-E343... 

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