Biomarker Discovery, Technical Qualification and Validation

Using LBA, LC-MS and HRAMS Assay Formats

Biomarker validation is a valuable tool in drug development support.  Whether through discovery, analytical validation or clinical validation, these tests can be used for diagnosis, monitoring, prediction, response measurement, prognosis, safety or risk assessment. As the routine application of biomarkers in the drug discovery process has grown, it has become more important to ensure assay results address the relevant question under investigation. To that end, the industry has implemented biomarker working groups and qualification programs to ensure these needs are met.

There are several validation strategies that can be used to assess biomarkers: bioanalytical validation (BAV), clinical trial assay (CTA), laboratory-developed test (LDT), in-vitro diagnostic (IVD), companion diagnostic‐investigational use only (IUO) and research use only (RUO). A fit-for-purpose approach allows you to select the best assay to use, depending on the intended use.  This context of use (COU) approach includes two components, utilizing the BEST (Biomarkers, EndpointS, and other Tools) approach and considering the biomarker’s intended use in drug development. In fact, the U.S. Food and Drug Administration (FDA) has implemented a BEST approach, including a formalized strategy to nominate potential biomarkers for specific COUs.

Given the different types of assays, it’s important to remember that specific analytical challenges exist for biomarkers depending on the type of analyte, the proposed platform, the regulatory requirements, and availability of reagents at a minimum.  Both LC-MS/MS and Ligand Binding Assays (LBAs) can be used to assess biomarkers ranging in size from <50 Da to >100 KDa.  However, there are notable strengths and weaknesses to each of these methods in relation to their sensitivity, precision, accuracy, throughput and sensitivity to matrix interference.  To minimize risk to a drug development program, researchers should seek the advice of bioanalytical experts with demonstrated understanding of the technical and regulatory aspects underlying the application of biomarkers to product development.

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