![]() ![]() ![]() The assay readout was the quantity of enzyme product, PAR (Polyadenosyl ribose polymer) in patient tissues, previously shown to decrease in tumors and PBMCs after veliparib treatment ( 2). The initial project was to develop and validate an assay that could be objectively demonstrated to accurately report target engagement by veliparib. The development of clinical biomarkers of pharmacodynamic activity at the level of target engagement was initiated at NCI as part of the Division of Cancer Treatment and Diagnosis with the specific intent of providing an accurate, early indication of target engagement by experimental therapeutics in first in man clinical trials, focusing on tumor biopsy specimens as the preferred testing material ( 1). One measure of success of this approach has been that a number of the assays developed at Frederick National Laboratory have ultimately reached the stage of commercialization, enabling wide accessibility of the PD biomarker assays by the research community. Additionally, dispersing assays throughout the NCI’s clinical trials network has required the development of calibrator and control materials as well as formal training courses for smooth implementation. ![]() In our experience, this patient specimen-centered approach has required assay method modifications, some unexpected, but which were critical to successful implementation in clinical trials. Assay transfer across laboratories and testing on actual human clinical specimens are vital for understanding assay performance and robustness. The well-recognized elements of analytical assay validation and demonstration of fitness-for-purpose of the biomarker, specimen collection, handling and assay methods are only a part of the required activities. There is a “life-cycle” of pharmacodynamic (PD) biomarker assays that guides the development and clinical implementation in our laboratories. ![]()
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