Quantitative Clinical Pharmacology: New Horizons in Integrating Exposure/Response in Clinical Development

Rajesh Krishna

Merck

A careful assessment of overall productivity in drug development has revealed impediments in innovation for new molecular entities, mediated in large part by late clinical stage drug development attrition (i.e., failures due to efficacy and/or safety in pivotal trials). This observation has been independently corroborated by academia, industry, and regulatory agencies, and has translated into a significant decline in the quality as well as the number of new molecular entities, assessed by the submission and approval of new drug applications worldwide. These findings have led to research and discussion in determining approaches to reduce late stage attrition and thus, improve the probability of success for new molecular entities. The current presentation will specifically highlight the benefits and challenges to implementing model based drug development. These approaches involve the proactive use of early biomarkers of target engagement and exposure/response modeling and simulations coupled with application of novel clinical trial designs to maximize elucidation of pharmacodynamic response, thus selecting the winners. This presentation will focus on case examples from various disease segments, where modeling and simulations have positively impacted clinical development, with regard to dose selection, disease progression modeling, design of clinical trials, and compound progression decisions.