The applications of biomarkers in early clinical drug development to improve decision-making processes.

Selecting and evaluating biomarkers in drug discovery and early drug development can substantially shorten clinical development time or the time to reach a critical decision point in exploratory drug development. Critical decisions such as candidate selection, early proof of concept/principle, dose ranging, development risks, and patient stratification are based on the appropriate measurements of biomarkers that are biologically and/or clinically validated. The use of biomarkers helps to streamline clinical development by determining whether the drug is reaching and affecting the molecular target in humans, delivering findings that are comparable to preclinical data, and by providing a measurable endpoint that predicts desired or undesired clinical effects and will increase the success rate in the confirmatory stage of clinical development. Appropriateness of biomarkers depends on the stage of development, development strategy, and the nature of the medical indication. Even if a biomarker fails in the validation process there may be still a benefit of having used it. More knowledge about pathophysiology of the disease and the drug has been obtained. Different levels of validation exist at different development phases. Biomarkers are perhaps most useful in the early phase of clinical development when measurement of clinical endpoints may be too time-consuming or cumbersome to provide timely proof of concept or dose-ranging information. Examples of biomarkers are illustrated for the development of new drugs in variant cardiovascular, pulmonary, and CNS diseases.