Blazing the pharmacologic audit trail: Pharmacodynamic biomarkers in early drug development

Abstract

Abstract Pharmacodynamic (PD) biomarkers of drug action are common components of early clinical trials in oncology. However, how to optimally apply biomarker endpoints to rationale decision making is less clear cut. As a consequence, many biomarker programs represent expensive scientific investments in drug development infrastructure yielding little or no practical advantage at the end of the day. The Pharmacologic Audit Trail (PhAT), first proposed by Workman and colleagues, represents a well designed strategic paradigm for the rationale incorporation of PD and mechanism of action biomarkers into early drug development. The PhAT is comprised of a series of key questions addressed sequentially in early clinical trials to assess the pharmacological behavior of an experimental agent. It includes evaluation of target expression, pharmacokinetics, pharmacodynamics, target engagement, pathway modulation, biological effects and, ultimately, clinical activity in early clinical trials. This approach promotes rigorous scientific evaluation and rational decision making in early oncology drug development, culminating in the demonstration of proof of concept. However, success application of this process requires a substantial investment in target evaluation and in vivo preclinical studies. A detailed discussion of the PhAT and its application to the early drug development in oncology therapeutics will be described.