ABSTRACT
The term “biomarker” refers to any small or large molecule or any measurement that is an indicator of a normal biological process, a disease state, or a pharmacological response to a drug treatment [1,2]. The various types of biomarkers are summarized in Table 10.1. Why is the pharmaceutical industry interested in biomarkers? In an elegant article, Kola and Landis [3] described a few key reasons due to which only one in nine compounds makes it through development and gets approved by regulatory agencies. The two top causes for a compound’s attrition in the clinical phase of drug
TABLE 10.1 Types of Biomarkers
development in 2000 were lack of ef cacy accounting for about 30% of failures and lack of safety accounting for another 30% of failures. This explains why biomarkers have been in the center of interest of pharmaceutical and diagnostic companies over the last ve years. Currently, in the discovery stage, the majority if not all pharmaceutical companies focus on understanding rst the molecular target and the molecular basis of a disease so that biomarkers of disease and ef cacy can be proposed and eventually be used for demonstrating proof-of-concept in the clinical studies. In these early stages of drug development, biomarkers are used to optimize the selection of a lead compound based on its in vitro and in vivo preclinical activity pro les. As the compound is nominated for development, additional preclinical studies are initiated to better understand the safety and ef cacy pro le of a drug candidate. Biomarkers are used to study the correlation between the ef cacy and PK/PD data to optimize clinical drug formulation as well as starting clinical dose and dosing regimen. Safety studies are conducted in preclinical animal species (typically rodent and non-rodent large animals) to characterize target organ toxicities and to de ne the maximum tolerated dose. At this stage opportunities arise to search for novel, more speci c, and sensitive biomarkers of safety. Metabonomics and other “omics” can be used to study whether an observed toxicity is mechanism or non-mechanism based so that compounds with mechanism-based toxicity can be eliminated [3-5]. Once a compound enters the clinical phase of development, one of the biggest challenges is to evaluate and properly validate whether the biomarker ndings from preclinical studies in animals translate into ndings in humans. In the late clinical stage of drug development, biomarkers can improve the statistical power of clinical study designs so that fewer patients are enrolled and enable selection of patients who are more likely to respond to a treatment. Once a drug is marketed, biomarkers are used to diagnose a disease and can allow for a real-time monitoring of treatment safety and ef cacy [2,5-7].
