Workshop Report and Follow-Up—AAPS Workshop on Current Topics in GLP Bioanalysis: Assay Reproducibility for Incurred Samples—Implications of Crystal City Recommendations

Abstract

Abstract. The Conference Report of the 3rd AAPS/FDA Bioanalytical Workshop (Crystal City III) endorsed the concept that assay methods supporting bioanalytical data in submissions must demonstrate assay reproducibility by using incurred samples. The present Workshop was convened to provide a forum for discussion and consensus building about incurred sample assay reproducibility for both nonclinical and clinical studies. Information about current regulatory perspectives on incurred sample reanalysis (ISR) was presented, implications of ISR for both large and small molecules were discussed, and the steering committee put forth recommendations for performing ISR. These recommendations from the Workshop, along with the subsequent evolution of approaches leading to a robust ISR program, may be used by scientists performing bioanalytical assays for regulated studies to provide additional confirmation of assay reproducibility for incurred samples.

Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann–Pick disease type C in a retrospective study

“…Variability was calculated as defined in [23], using the equation. Variability 5100*(Repeat-original)/mean.…”

Assessment of Incurred Sample Reanalysis for Macromolecules to Evaluate Bioanalytical Method Robustness: Effects from Imprecision

“…Thus, the bioanalytical methods used in their assessment play a significant role in the evaluation of PK/TK parameters and require more stringent criteria to demonstrate the validity of their usefulness relative to those used for diagnostic or research purposes. Incurred sample reanalysis (ISR) is the most recent regulatory recommendation to ensure the reproducibility of bioanalytical methods used in the types of studies mentioned above (1,2). At the AAPS workshop held at Crystal City, VA, in 2008 (1), the FDA presented case studies in which there were discrepancies in results between the original and reanalyzed concentrations in multi-analyte assays (chromatographic assays) for smallmolecule drugs.…”

“…The current recommendation is that ISRs should be conducted for all bioequivalence or comparability studies, for both drug/drug interaction studies as well as preclinical and clinical studies in which PK assessment is the primary endpoint (1,2). At least 5% to 10% of the samples must be reanalyzed to show method reproducibility.…”

Assay Formats: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

“…However, it described the acceptance criteria and assay operations for small molecules run on a LC-MS platform and did not address appropriate acceptance criteria for large molecule immunoassay measurements. Therefore, bioanalysts relied on a mixed interpretation of workshop reports that originated within the American Association of Pharmaceutical Scientists (AAPS) community as well as the original guidance document for both pre-study and within-study validation (2)(3)(4)(5)(6). In 2011, the EMA guideline was published where a section was dedicated to large molecule measurement using ligand binding assays (7).…”