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”.