The introduction of new Molecularly Targeted Agents (MTA) has changed the landscape in Early Drug Development (EDD) over the last two decades, leading to an improvement in clinical trial design. Previous Phase 1 (Ph1) studies with cytotoxics focused on safety objectives, only recruiting heavily pre-treated cancer patients, have been left behind. In this review, we will illustrate the slow although unstoppable change that has increasingly been observed in those populations candidate to participate in EDD trials with the advent of MTA. As more evidence regarding oncogene addiction becomes available, molecular-biomarker driven selection has been implemented among Molecularly-Selected Population (MSP) studies. New Window-Of-Opportunity (WOO) and Phase 0 (Ph0) studies have been developed in order to assess whether a MTA produces the hypothetical proposed biological effect. The rising need of getting early pharmacokinetics and pharmacodynamics data has led to the conduction of Healthy Volunteer (HV) studies, in part favoured for the particular and different toxicity profile of these MTA. However, several challenges will need to be addressed in order to boost the implementation of these new clinical trial designs in the forthcoming years. Among the problems to overcome, we would highlight a better coordination effort between centers for ensuring adequate patient accrual among small patient populations and a deepening into the ethics implied in enrolling patients in studies with no therapeutic intent. However, these tribulations will be certainly compensated by the possibility of opening a new horizon of treatment for diseases with dismal prognosis.
Keywords: healthy volunteer; molecularly targeted agents; patient populations; phase 0; window-of-opportunity.