The Importance of Dose Optimization Prior to Initiation of a Registration Trial

摘要

H&O What is the current process for establishing dosages of new pharmaceutical agents? NR The aim of a clinical development program is to identify the right dose, as too high a dose can result in unacceptable toxicity and too low a dose decreases the chance of obtaining a clinically meaningful response from a therapy. The dosages of new drugs are established based on the optimal rate of administration of a dose that provides the maximum benefit in terms of balancing the efficacy and safe use of a product. Although the current oncology drug products are predominantly targeted therapies, the traditional dose-escalation scheme of a "3 + 3" design to assess the safety of chemotherapies is still being implemented in the development of targeted therapies. In this design, a cohort of 3 subjects (mostly patients with advanced cancer) is tested to establish a safe starting dose. Subsequently, a new cohort of 3 patients receives the next higher dose. The objective of the dose-escalation trial is to assess the dose-limiting toxicity and establish a maximum-tolerated dose of the drug. This approach may not be suitable for targeted therapy. The dose-escalation trials of targeted therapy assess not only the safety of the drug, but also the preliminary activity using sensitive and reliable biomarkers or clinical endpoints in phase 1 safety trials. Based upon the dose-escalation trial, a single dose or a limited number of doses are then tested in a phase 2 trial to establish effectiveness of the drug using surrogate endpoints. Usually, a single dose is then tested in the confirmatory registration trial.