Healthy volunteers and early phases of clinical experimentation

The main goal of early phase trials is to gain knowledge about the clinical suitability of novel compounds, without pursuing specific therapeutic purposes. Healthy volunteers usually represent the ideal model for conducting phase I clinical trials, in order to investigate pharmacokinetics and pharmacodynamics as well as to document safety and tolerability without interference by concomitant pathological conditions. The increasing cost of novel drug development, in conjunction with ethical considerations, has fostered a new procedure for first-in-man trials, designated as "phase 0," which is conducted very early on a limited number of healthy volunteers who are exposed to low drug levels. The present review discusses issues concerning the enrollment of healthy volunteers in the early phase of drug development from different points of view, with some focus on the Italian experience. From the ethical standpoint, much discussion revolves around payments to healthy volunteers. Most authors agree that an adequate remuneration must be provided to healthy subjects, while avoiding coercion and excessive psychological pressure. Pending the lack of international and national guidelines, our center for clinical drug experimentation has implemented an operative procedure to estimate payments for healthy volunteers based on specific items, including restriction, time spent, discomfort, and risk. Other unresolved issues about the recruitment of healthy volunteers are represented by the lack of international consensus on the definition of healthy status and the need for guidelines about advertisement on clinical trials addressed to potential participants.