By Mark E. Arnold
Precision is used in the current world of biomarkers in at least two ways: the precision of the assay for the biomarker, and in relation to the ability of the biomarker to be used within precision medicine, targeting the patients that will benefit from the drug. In the real world, one cannot have a precision medicine biomarker without understanding the precision of the biomarker assay. Assay precision must be evaluated as within-run (repeatability), between-run (intermediate), and between labs (reproducibility).
In both worlds of drug pharmacokinetic (PK) and biomarkers assay validations, these are well understood activities and central to robust and reliable assays. Precision’s complement—accuracy—is well understood in the PK world but is less well understood for biomarker assay validations, where two challenges may compound each other to confound the generation of accuracy information: absence of a true blank matrix and equivalence of the reference standard material to the biomarker in circulation.
In the case of protein biomarkers, posttranslational modification may alter the biomarker resulting in differences from the selected reference standard, while the reference standard may have its own set of differences from the biomarker in circulation (e.g., isoforms). A variety of approaches are used to address the absence of a matrix without the biomarker. Thus, the presence of the biomarker in any matrix sample has resulted in a number of approaches for creating a matrix for standards and quality controls, including stripped matrix and surrogate matrices (from another species, proteins [albumin, alpha-1-acid glycoprotein, etc.] in buffer, and pure buffer approaches). While recognized that these are different from the study samples, opinions differ on what must be done during method development and validation to characterize their impact on the assay.
The upcoming AAPS workshop Crystal City VI: Bioanalytical Methods Validation on Biomarkers on September 28−29 in Baltimore, is where these issues as they relate to ligand binding assays and liquid-chromatography mass spectrometry assays will be debated.