Analytical validation of novel cardiac biomarkers used in clinical trials

Blood-based biomarkers such as cardiac troponin and B-natriuretic peptides are widely used in clinical practice for the diagnosis, rule out, and risk stratification for patients with acute coronary syndromes and heart failure. Because neither these nor any other laboratory test meets all clinical needs, there are many novel biomarkers that are proposed and evaluated each year for possible implementation into clinical practice. Results of clinical trials are used as a means to validate their effectiveness and to obtain regulatory approval.

Novel biomarkers are discovered through a targeted approach using knowledge of the pathophysiology disease process and an untargeted approach where proteins from tissues or blood of disease patients are compared against healthy subjects or those with benign conditions. Once a candidate biomarker has been identified, it is important to understand where the protein is located and how it is released into blood. In designing trials, the requirements for Food and Drug Administration clearance and approval should be taken into consideration. There are preanalytical studies that should be considered including the preservative used to collect samples and in vivo and in vitro analyte stability. If the analyte is not stable, a surrogate marker could be used such as stable "pro" molecules (precursor proteins) may be preferred. Assay imprecision and bias, biological variation and criteria for the establishment of a reference range are important analytical attributes. The need for harmonization and commutability and correlation of results to other markers and clinical outcomes are important postanalytical attributes of novel biomarkers.

Inadequate adherence to these variables when conducting clinical trials reduces the quality and value of the information contained in literature reports of novel serum/plasma-based biomarkers.