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

Selecting, evaluating and applying biomarkers in drug discovery and exploratory drug development do substantially shorten the time to reach a critical decision point. Biomarkers are most useful in the early phase of clinical development when measurement of clinical endpoints or true surrogates may be too time-consuming or cumbersome to provide timely proof of principle or dose-ranging information. The use of biomarkers in early drug development 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. Critical decisions such as candidate selection, early proof of mechanism or proof of concept, dose ranging and patient stratification as well as the assessment of development risks regarding safety, toxicity and drug interactions can be based on measurement of appropriate biomarkers that are biologically and/or clinically validated. Preclinical and phase I development plans can be focused to support an early s.d. or m.d. biomarker study in healthy volunteers or mildly diseased patients, thus saving both resources and time. Dose estimates and patient stratification may reduce the size and duration of clinical studies in later phases of development, and safety and toxicity biomarkers may help to stop or continue a programme early on. Even if a biomarker fails in the validation process there may still be a benefit of having used it as more knowledge about pathophysiology of the disease and the drug may be obtained. Thus, appropriateness of biomarkers depends on the stage of development, development strategy and the medical indication. Examples of biomarkers in exploratory clinical development are given for the development of new drugs in various indications.