Advanced applications, biomarker studies

FIGURE 6.1 Conceptual diagram of fit for purpose biomarkers method validation. The method validation processes include four activity circles prevalidation (preanalytical consid eration and method development), exploratory method validation, in study method validation and advanced method validation. The processes are continuous and iterative, dictated by the purpose of the biomarker application. The solid arrows depict the normal flow of biomarker development (prevalidation), method validation (exploratory or advanced), and application (in study method validation). The process could include moving the chosen biomarkers from exploratory mechanistic pilot studies to advanced validation and confirmatory studies, or from exploratory validation to advanced validation after changes in critical business decision. The broken arrows represent scenarios where validation data do not satisfy study requirements, necessitating assay refinement or modification. 

At a minimum, documentation of the characterization and stability of a standard, such as a certificate of analysis (Co A) and/or a certificate of stability (CoS), is typically available from the suppliers. The certificate should be obtained and recorded. The quantity of reference standard is typically limited in commercial kits designed for research use, and it is not uncommon that the reference material values may differ substantially between lots and manufacturers [16]. Novel biomarkers rarely have established gold standards against which their potency and abundance can be calibrated. A comparison of available sources can be useful, and when validating an assay for advanced applications it is desirable to plan ahead to obtain and reserve a sufficient supply of the same reference material. The example in Fig. 6.5 compares three reference standard curves, each prepared from a concentrated stock solution from a commercial supplier, an in-house reference standard, and a commercial kit, respectively. The instrument responses (optical density, OD) were highest with the standard from the commercial stock, the lowest with the kit, while the in-house reference standard response was intermediate. In this case, either the same commercial stock or the in-house reference standard can be used throughout the clinical study. 

Determination of the appropriate level of documentation for an exploratory or advanced biomarker application is made by the organization or laboratory responsible for the biomarker study. In general, an analytical procedure and a validation memo containing the summary data should be adequate for exploratory application. For an advanced validation, the record keeping and reporting may be similar to that of the methods for PK support. The basic idea is that the data should be traceable and subjected to QC and QA review. The final method should be documented in an analytical procedure and the results presented in a validation report. 

Rapid determination of biomarkers of product origin and contamination has illustrated the capability of modem data analysis techniques in combination with advanced NMR systems. Characterisation of biological systems has also been performed in support of genetic improvement and for the detection and characterisation of the effects of genetic modification. These application-focussed studies have led to the development of the... 

Recent advancements in genomics and proteomics have generated considerable interest in the discovery and validation of biomarkers in mechanism-based drug development [69-71], These advances have been welcomed to reduce the cost, increase success rates, and accelerate timelines in the drug discovery and development process. Herein, a brief overview of the application of biological markers in early discovery, development, toxicological assessments, and efficacy studies in humans is presented. 

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