Healthy volunteers and early phases of clinical experimentation

Abstract

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.

Drug Experimentation in Healthy Volunteers

“…Furthermore, might women under treatment with oestrogen derivatives be eligible for early phases of drug experimentation? These simple examples support the notion that we can use different definitions of healthy subjects and that a critical judgment is required (Pasqualetti et al, 2010).…”

“…For many years, there has been an ongoing ethical-scientific debate on how to take decisions about fair payment of research subjects, viewed as an attempt of compensating them for their "lost wages" and "discomfort" due to their participation in clinical trials. As in the U.S. and other European countries, in Italy a detailed guideline or a specific law about research volunteer reimbursement is still lacking (Pasqualetti et al, 2010). Dickert et al (2002) reported that only 37.5% of clinical research organizations included in their analyses (academic research centers, pharmaceutical companies, contract research organizations, and independent institutional review boards) had written guidelines about the payment of healthy subjects.…”

“…Overall, most organizations require that the estimated payment must be delivered to subjects as prorated (i.e., fractional payment based on the amount of time or procedures actually accomplished) rather than as a contingent payment at the completion of the study (Iltis, 2009). Several authors support the opportunity of a reimbursement to healthy volunteers and propose different hypotheses to resolve this issue (Pasqualetti et al, 2010). Among the proposed ways, those indicated by Iltis (2009) andResnick (2008) appear to be quite interesting.…”

“…Accordingly, a new procedure, designated as "phase 0", has been introduced into the very early stage of clinical drug development in order to gain insight into the clinical suitability of novel compounds before starting conventional phase I trials (EMEA, 2004;Pasqualetti et al, 2010). Additional clinical studies, which are conducted in healthy volunteers, include bioequivalence pharmacokinetic tests.…”

Phase zero trials: a novel approach in drug development process

“…Role of phase 0 studies in drug development [13][14][15] In the segment of cancer studies, the concept of phase 0 is a novel approach for determination of drugs potential. Although phase 0 is being accepted as a versatile technique till date, also a lot many documentary evidences (literature) are required.…”