Biomarkers and proof of concept.

Starting with an overview over the early human phase of drug development, the Pearson index, a normalized measure for the financial net present value of a drug development project, is introduced and it is shown how the value of obtaining critical information early can be quantified. Biomarkers used in this phase can be a means to obtain such information. Biomarkers can be classified as mechanistic, empirical or model based. Proof of concept trials are used to obtain the information. These trials can be proof of mechanism if they use a biomarker to investigate their mode of action, proof of viability if they investigate tolerability of putatively therapeutic doses or proof of efficacy if they use a clinical endpoint in a selected, homogenous population. If these trials are to decide on further development of a candidate drug, traditional statistical methods are not adequate. In the framework of decision analysis. Bayesian statistics offer an alternative. The basic techniques of this concept are introduced. The role of clinical electrophysiology is discussed in this framework.