CLINICAL LABORATORY ASSAYS

Well-designed and validated pharmacodynamic (PD) assays allow quick and accurate screening for a PD response in specimens from preclinical models and first-in-human studies. These assays inform drug development decisions by providing evidence of drug action on the intended molecular target. The PD program focuses on developing preclinical and clinical assays for biomarkers in a variety of tissues, including tumor biopsies, blood samples, and hair follicles. The development of PD assays during preclinical stages is supported by the Pharmacodynamics Assay Development & Implementation Section (PADIS) and during clinical stages by the National Clinical Target Validation Laboratory (NCTVL).

The role of PADIS is to develop and validate assays in clinically relevant animal models that mimic human disease and treatment. With humanized treatment and assessment conditions in animal models, the analytical performance of PD assays can be evaluated to establish assay fitness-for-purpose before use in clinical trials. As the lead compound progresses toward IND filing, validated PD assays with associated standard operating procedures (SOPs) for specimen handling, processing, and storage are then transferred to NCTVL to measure drug effects in clinical specimens. Finally, validated assays can be transferred for use in the scientific community. SOPs and information for currently available assays can be found on the DCTD Biomarkers Web site.

Early in the NExT Stage Gate process, the goal is to use rapid PD evaluations in animal models of human cancer to confirm that an optimized lead compound acts as intended on its molecular target. PADIS is responsible for converting discovery assays from the NExT Chemical Biology Consortium Specialized Application and Comprehensive Screening Centers into "fit-for-purpose" PD assays; this should be accomplished with minimal assay adaptation to rapidly provide data concerning drug modulation of the intended molecular target. Data from such early PD studies inform go/no-go decisions on agent development.