Use of PD biomarkers to drive dose selection and early clinical decision making

Abstract

A major challenge facing the development of new therapies is the high level of compound attrition in late-stage clinical studies. A key factor in reducing these unsustainable levels of attrition is the successful evaluation of the level of drug effect on its target pathway in early development, otherwise known as testing the compound mechanism. Incorporation of PD biomarkers into Phase I/II trials to demonstrate compound binding to its molecular target and the subsequent modulation of downstream pathways enables early testing of compound mechanism and provides a data-driven framework for decisions on compound progression. This review will discuss the identification and validation of such 'fit-for-purpose' PD biomarkers, and case studies illustrating their use and value in dose selection and accelerating the clinical development of small-molecule drugs will be described.

Cancer Research UK Centre for Drug Development: translating 21st-century science into the cancer medicines of tomorrow

“…This situation has been recognised for some time and, in the current era of molecularly targeted agents, there is increasing movement away from traditional clinical development approaches (that served chemotherapy well for decades) toward a more adaptive paradigm [4]. Spurred on by costly late-stage attrition, crucial decision-making points are being pushed back earlier into the clinical development pathway guided by a deeper understanding of tumour biology and pharmacology of the test agents [5,6].…”

In vitro dissolution testing models of ocular implants for posterior segment drug delivery

“…Another challenge is to get serial measurements of drug concentrations in a live eye since putting invasive serial probe sampling in the human eye is not feasible for ethical purposes. This aspect is essential to achieve level A IVIVC regulatory related to drug approval or determine drug dose regimens based on pharmacokinetic parameters [98]. The researcher usually constructs time curves from multiple studies since only single sample can be obtained at paracentesis in eye surgery.…”