Translation of the high-sensitivity CYFRA 21-1 Free Solution Assay from the Research-to-Clinical Lab: A model for investigator-initiated technology transfer

Assays for biomarker quantification performed within clinical laboratories form a foundation of clinical decision making.  When new assays are developed, they can be implemented as a Lab Developed Test (LDT) in a high complexity certified clinical lab through the Clinical Lab Improvement Amendment (CLIA). For new assays using existing platforms, this path is well defined.  For novel technologies, however, the path from a research lab to clinical testing is less clear.

Lung cancer is the leading cause of cancer mortality in the United States. The management of indeterminate pulmonary nodules (IPN) remains a major challenge in lung cancer diagnosis and treatment. Current clinical management of IPNs presents high rates of diagnostic error and risks associated with unnecessary invasive diagnostic procedures – thus determining non-invasive diagnostic strategies for IPNs remains a crucial focus on lung cancer research. Recently, an integrated biomarker model containing high sensitivity (hs)-CYFRA 21-1 level in serum, quantitative radiomic signature, and the Mayo Clinical Model (Mayo) risk score demonstrated improved accuracy for IPN diagnosis compared to current clinical standard of care. A crucial component of this classifier is the hs-CYFRA 21-1 assay, which is enabled by a novel technological platform, the free solution assay (FSA) measured by the compensated interferometric reader (CIR), which provides enhanced analytical sensitivity for biomarkers in human serum when compared to standard quantification methods.

To assess the clinical utility of the integrated biomarker approach, a randomized controlled prospective trial will begin enrolling patients at Vanderbilt University Medical Center (VUMC) in 2022. To facilitate the blood biomarker measurement for this clinical trial, we will be transferring the FSA-CIR assay to the clinical Molecular Diagnostic Laboratory at VUMC for testing and reporting as an LDT. We have developed and will be implementing an assay and instrument translation plan for an LDT based on guidelines from the College of American Pathologist (CAP) guidelines. This process involves three stages: (1) Development: software and instrument optimization for ease of use by clinical staff. (2) Validation: a series of experiments preformed to confirm the reproducibility of the assay and determine the analytical and clinical performance characteristics of the optimized FSA-CIR instrument in the clinical setting. (3) Testing and Reporting: logistics of sample collection, transport and processing and reporting of the results in the scope of the clinical trial. In these three stages, we illustrate the novel process of instrument translation from the lab bench to a clinical decision-making tool without commercial or corporate intervention. This work describes the steps taken for this translation effort and presents a path that can be followed for future Research-to-Clinical laboratory technology translation projects.