CNS trauma biomarkers and surrogate endpoints pipeline from bench to bedside: A translational perspective

A biomarker is a qualitative and quantitative biological substance or characteristic that defines a certain pathological condition and may give indications on disease severity and the type of therapy that should be administered to the patient. Traumatic brain injury (TBI) is an ever-growing public health concern, where the annual number of TBI patients reaches a staggering number of around 1.7 million cases in the United States alone. It is important that we continue the pursuit for the ideal TBI biomarker in order to decrease the number of fatalities secondary to TBI, and its direct and indirect costs. However, the path towards reaching a surrogate endpoint biomarker is not easy but rather long and needs time and effort. In this chapter, we discuss the process of assessment and validation through which a biomarker passes through in order to be finally established as a TBI biomarker and approved by the FDA. We also provide a brief history on TBI biomarkers, discuss the different types and sources of biomarkers and give a summary of TBI biomarkers currently in use and their potential clinical application. The term “biomarker” refers to objective and quantifiable characteristics of biological processes that can define a normal or a pathogenic state. Biomarkers can be identified as a broad subcategory of medical signs, which, by accurate measures and reproducibility, can provide an objective suggestion of the medical state examined from outside the patient. With evolving technology, we are able to better detect, identify, and quantify biomarkers and validate them in the clinical setting. The use of the term biomarker dates back to as early as 1980 (Atkinson et al., 2001). Many precise definitions of biomarkers are found in the literature, and their contexts overlap. In 1998, the National Institutes of Health Biomarkers Definitions Working Group defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” (Strimbu and Tavel, 2010). The National Academy of Sciences defines a biomarker as an indicator that signals events in biological samples or systems (Committee on Biological Markers of the National Research Council, 1987). In addition, the International Program on Chemical Safety, led by the World Health Organization (WHO) and in coordination with the United Nations and the International Labor Organization, has defined a biomarker as “any substance, structure, or process that can be measured in the body, or its products and influences or predicts the incidence of outcome or disease” (WHO, 2001). In its report on the validity of biomarkers in the environmental risk assessment, the WHO went even more broadly with its definition, stating that “a biomarker includes almost any measurement reflecting an interaction between a biological system and a potential hazard, which may be chemical, physical, or biological. The measured response may be functional, physiological and biochemical at the cellular level, or a molecular interaction” (WHO, 1993). All these terms, definitions, and characteristics were proposed to describe a biomarker, indicating that it may have the greatest value in early efficacy and safety evaluations, such as in vitro studies in tissue samples, in vivo studies in animal models, and early-phase clinical trials, to establish “proof of concept” (Atkinson et al., 2001). Yet, biomarkers may have many other important applications in detecting diseases and monitoring the health status of a patient. As Atkinson et al. stated, these applications include the use of such biomarkers as a diagnostic tool to identify patients with a possible disease or abnormal condition, such as hyperglycemia for the diagnosis of diabetes mellitus (Atkinson et al., 2001). Moreover, biomarkers can be used as a method to predict the stage of the disease and its severity such as measuring the concentration of prostate-specific antigen (PSA) in the blood to detect the level of tumor growth and metastasis, even though different clinical trials are currently having conflicting results about the efficacy of this biomarker (Acimovic et al., 2013; Haines and Gabor Miklos, 2013; Izumi et al., 2014; Pataky et al., 2014). Also, they can be used as an indicator of disease prognosis or a predictor of clinical response to an intervention whereby, for example, biomarkers can be measured to detect tumor shrinkage or regression in certain cancers (Everson et al., 2014; Okegawa et al., 2014) or determine the risk of heart disease (Eapen et al., 2014; Ligthart et al., 2014)