Clinical Trial Applications
In most circumstances, ERAs are required only for clinical trials
conducted under the deliberate release legislative framework. In Table
1, the legislative framework under which clinical trials with GMOs may
be conducted in the different member states are listed together with the
sequence of authorisations required [8].
Some countries only allow the conduct of GMO clinical trials under one
procedure or the other, however, other countries will consider either
procedure based on a case-by-case evaluation. The content and format
requirements of the DR procedure are broadly harmonised across EU
countries through the standardised use of the
summary notification information
format for notifications concerning the deliberate release into the
environment of genetically modified organisms for purposes other than
for placing on the market, and ERA templates
[7,10]. Contained use dossiers
do not require an ERA but focus on a description of the GMO facilities,
the GMO handling, waste management and protection of workers with the
format differing from country to country [7].
The sequence of steps required in the review of the GMO dossier and the
clinical trial application and the identity of national competent
authorities and advisory bodies for both the contained use and
deliberate release procedure varies according to each country. For
trials conducted under the deliberate release approach a public
consultation is generally required and the summary notification
information dossier becomes publicly available on the EU GMO register.
However, some clinical trials conducted under contained use may also
require a public consultation if the member state considers it
appropriate [7]. These differences in
interpretation of environmental and biosafety aspects for GMO regulatory
procedures across different countries have led to divergent opinions in
classifications regarding the clinical use of the GMO medicine and adds
to the complexity of conducting multinational clinical trials with GMOs
[11].
The new Clinical Trial Regulation [12] will not
address many of the issues associated with GMO-containing clinical
trials. Currently, some member States require authorisation under the
GMO framework before the Clinical trial application can be submitted
(see Table 1). When the regulation becomes applicable, the authorisation
under the GMO framework can no longer be a pre-requisite for a valid
clinical trial authorisation application but it will still be required
before the clinical trial can start [13].
To overcome these hurdles, the national competent authorities and the
European Commission have recently updated and published good practice
documents and common application forms concerning the conduct of
clinical trials with human medicinal products consisting of or
containing GMOs [14, 15,16, 17, 18].
These documents aim to facilitate the conduct of clinical trials by
achieving a degree of harmonisation and clarifying the requirements for
clinical trial applications based on the existing legislation. They have
also introduced, for certain categories of investigational medicinal
products, a “specific ERA” on the basis that they are highly unlikely
to pose a risk to the environment or to public health.
The common application form for viral vectors contained in
investigational medicinal products for human use are applicable to
medicinal products for human use that contain or consist of viral
vectors [14]. Section 2 of the common application
form concerns the information relating to the investigational medicinal
product (parental virus, genetic modification and clinical vector) while
the ERA (to be completed for submissions under deliberate release, or
for all submissions for clinical trials to be performed in Italy) is in
Section 5. A GMO-specific ERA is required (Annex II of Directive
2001/18/EC) for all applications under the deliberate release framework,
however, two categories of products, for which specific common
application forms apply [15,16]
qualify for “specific ERAs”.