More stringent conditions for the conduct of Phase I clinical trials in France will apply from 27 August 2006, when Decree No 2006-477 transposes the European Union’s clinical trials directive, 2001/20/CE, into national law.
The French health-products safety agency, Afssaps, has prepared the ground by issuing recommendations on Phase I studies, which account for more than 20% of all drug trials conducted in France. In line with Directive 2001/20/CE, under the new clinical trials regime all studies, including Phase I trials, will be subject to pre-authorisation by Afssaps as well as by the relevant committee for the protection of trial subjects (CPP, ethics committee).
While the recommendations do make vague reference to the disastrous Phase I trial with TeGenero’s monoclonal antibody TGN1412 in the UK, they are not a direct response to that incident. Afssaps launched a pilot study of its new approval procedures for Phase I trials in November 2003. As part of this exercise, it examined existing dossiers for first-in-man studies of new active substances as well as inspecting some trials.
These investigations revealed in particular that the reasons given for the selection of initial doses and modes of administration in Phase I studies were “inadequate, and indeed sometimes non-existent”, Afssaps noted. Consequently, a large part of the agency’s recommendations is devoted to issues around calculating the initial dose, and subsequent dose progression, of a new drug.
The recommendations also point to the lack of international guidance on Phase I protocols. The US Food and Drug Administration published a note on selecting initial doses for healthy volunteers in 2005, but this did not include any recommendations on dose progression or maximum doses, nor did it go into the kind of information sponsors need to provide in Phase I protocols.
On the dosing issue, Afssaps recommends basing the initial dose on a No Observed Adverse Effect Level (NOAEL) in a suitable animal model. In cases where the substance in question may have an aggravated pharmacological effect on the target organ or function (e.g., vasoldilators, anticoagulants, recombinant proteins, monoclonal antibodies, growth factors), the initial dose should be calculated on the basis of a No Observed Effect Level (NOEL), the agency says.
Whether a NOAEL or a NOEL is used, a safety factor of at least 10 should then be applied. Simultaneous dosing of volunteers should be restricted according to the identified risk factors, while sequential dosing should allow an appropriate interval for observation, Afssaps stresses.
The recommendations also address the administrative and ethical requirements for Phase I protocols. For example, they advise sponsors strongly to conduct first-in-man trials at a single location so that volunteers’ responses can be tracked in real time. A checklist of key information to be both supplied and justified in the Phase I protocol includes the decision to use healthy or patient volunteers for the study as well as provisions for monitoring volunteers.
Announcing the availability of the recommendations, Afssaps noted its statutory obligation to turn around approval applications for clinical trials within 60 days. In some cases though, and especially for first-in-man trials, the aim is to complete the evaluation in around 30 days, providing the information filed is sufficiently convincing.
The recommendations on Phase I trials are available (in French) on the Afssaps website at http://agmed.sante.gouv.fr/htm/10/filcoprs/indco.htm.