Exploratory Clinical Trials: Implementation Modes & Guidelines, Scope and Regulatory Framework

¹ Novartis, Rueil-Malmaison, France
² Centre de Pharmacologie Clinique, CHU, Clermont-Ferrand, France
³ Afssaps, Unité Essais Cliniques, Saint-Denis, France

Received: 15 October 2008
Accepted: 20 November 2008

Abstract

The working group focused on defining exploratory trials on medicinal products and developing recommendations for their implementation in France (notably concerning non-clinical requirements, the pharmaceutical quality of the investigational medical product and the conditions under which this type of clinical trial may be performed).
To this end, the working group took account of existing guidelines (notably those in the USA and Belgium) and a draft revision of the ICH M3 guideline.
Exploratory trials are clinical trials performed early in Phase I, prior to dose escalation and safety and tolerability trials. These trials are de facto first-in-man studies but lack a therapeutic or diagnostic goal and do not seek to establish the maximum tolerated dose (MTD). The objective is to answer precise questions which condition the continuation or suspension of the drug's development program. Exploratory trials include a small number of patients or healthy subjects and expose them (over a short period of time) to a low dose of an investigational medicinal product.
The draft revision of M3 describes five approaches (two involving microdoses and three with pharmacological doses).
The group's main recommendations can be summarized as follows:
An exploratory trial may be performed when it is (i) justified, (ii) useful for product development and (iii) consistent with prerequisites. The pharmaceutical dossier should take account of the low quantity of product available, the short period of product administration and the low doses used. Good Manufacturing Practices can be adapted accordingly. The non-clinical dossier should also be adapted to suit the development phase and particular features of product use. In this respect, the group has commented on the recommendations in the draft revision of M3. The protocol must be designed to provide answers to a set of specific, pertinent questions concerning this administration phase – particularly on choice of the initial dose, the size of the dose escalation and the rules for subject withdrawal and trial suspension. In general, so-called "vulnerable" populations should not be involved in this type of trial, apart from duly justified exceptions. The group considered that approaches 3 to 5 should only apply to a medicinal product intended for treatment of a severe or rare disease or a condition with significant unmet medical needs. Pre-filing at the Afssaps (the French Agency for Healthcare Product Safety) is recommended, notably for approaches using pharmacological doses.