Biomarker Discovery Development And Translation

Biomarker discovery can be performed using animal models, but it is now commonly carried out in humans from the very beginning stages of biomarker development. Biomarkers analyzed in preclinical animal studies are eventually transferred to the human, clinical settings. In a controlled laboratory environment the conditions are relatively constant, and "subjects" (i.e., the animals) are homogeneous and free of complicating co-morbidities. In these laboratory settings there are generally more options regarding the assays available, and the possibility of frequent and repeated testing in individual animals or groups of similar or identical animals allows for changes in the measured matrix of analytes to be detected with high precision and sensitivity. Ideally, a candidate biomarker discovered in this fashion would then be transferred into the clinical environment and evaluated further on human samples. The drawback of this approach is that many of the biomarkers discovered in animal models cannot be translated for use in humans. Animal models often do not accurately reflect human biology [4]. Further, the biomarker candidate may not achieve acceptable performance standards in heterogeneous patients with age, gender, and racial differences. This is why it has been suggested that pilot studies of biomarkers be conducted in humans first, in early phase II clinical trials that incorporate the variability in various ambient influences, and then that the marker be validated in preclinical studies, and in a later stage, clinical trials in parallel. This approach expedites the biomarker development process and minimizes the attrition rate of biomarker candidates since they are developed from the beginning under human clinical conditions.

In patients, biomarker candidate discovery is performed preliminarily in an internal primary cohort and is confirmed subsequently in an external secondary cohort. These two discovery phases are typically performed in observational or retrospective cohorts, and less and less often in preclinical studies. Some companies are avoiding animal models for discovery all together to avoid spending time and money on animal-based biomarkers that can often lead to a dead end.

It is not always practical to pursue validation of biomarker candidates identified in the discovery process. It is important to establish parameters for rational, statistically sound, and evidence-based selection and rejection of candidate biomarkers [5-7] . The decision to continue development of a bio-marker candidate is largely based on its potential to contribute cost- effectively to disease management [8] . Biomarkers used in the early phases of clinical development may be useful in providing more timely proof of concept or dose-range information than a real clinical endpoint [9]. Biomarker development should also be driven by clinical need [8]. A clinically useful biomarker must favorably affect clinical outcomes such as decreasing toxicity or increasing survival [10].

Once cost - benefit ratios are evident and more than one institution has consistently confirmed a biomarker's ability to perform at the requisite levels of sensitivity and specificity, a biomarker is ready for prospective testing in clinical trials [ 8] . The U.S. Food and Drug Administration (FDA) pharma-cogenomic submission guidelines recommend that transferring genomic bio-marker sets from microarrays to other platforms (such as quantitative real-time polymerase chain reaction) be attempted only once it has been demonstrated that the differential expression of such genes is sensitive, specific, and reproducible. Analytical quality assurance is performed continually throughout biomarker and drug development for most biomarkers; however, if a bio-marker is to be used as an endpoint in a phase III efficacy study, it should be validated beforehand [11]. Assay and analytical specificity and sensitivity should be established and validated prior to clinical phases such that clinical qualification can be carried out using proven, analytically robust methods [12]. However, as biomarker and drug development are intertwined processes, they may often occur concurrently throughout the different stages of clinical trials.

Project Management Made Easy

Project Management Made Easy

What you need to know about… Project Management Made Easy! Project management consists of more than just a large building project and can encompass small projects as well. No matter what the size of your project, you need to have some sort of project management. How you manage your project has everything to do with its outcome.

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