Discussion
GTMPs are a rapidly growing therapeutic modality with the potential for curative treatment of many genetic diseases unresponsive to conventional therapies [9]. In addition to genetic defects, several other conditions that that currently have limited, or no effective therapeutic options can be cured with gene therapy. However, due to their complexity, GTMPs developers have faced major regulatory challenges during assessment of clinical trial applications and marketing authorisation applications [1,2] and these include aspects related to environmental risk assessment. While it is acknowledged that there may be genuine environmental risks from genetically modified viruses and that these must be rigorously assessed, there are categories of products consisting of or containing genetically modified viruses which have been shown to have negligible environmental risk under their conditions of use.
The introduction of common application forms and good practice documents have been an important step in the simplification of the clinical trial application procedures for medicines consisting of or containing GMOs. Although the differences in the legislative frameworks and authorisation procedures between member states remain, the common application forms harmonise the common information needed in the applications and provide information on the additional country-specific requirements.
All marketing authorisation applications for GTMPs need to include a GMO-specific ERA in the submission. This is the case even if all clinical trials have been performed under the CU legislative framework for which an ERA is not required or if the trials were conducted outside of the EU, where different GMO requirements exist. An important advance for GMTPs is the introduction of specific ERAs for certain classes of products (AAVs and human cells with retroviruses/lentiviruses). The latter includes chimeric antigen receptor T-cells (CAR-T) which are one of the most promising subclasses of GTMPs in the field of cellular cancer immunotherapy and for which the first two products, Kymriah® and Yescarta®, obtained regulatory approval in the EU in 2018. The introduction of the common application forms simplifies the regulatory pathway for subsequent similar products in development with regards to GMO-related issues for both clinical trial applications and marketing authorisation applications. Applicants eligible for specific ERAs for clinical trial applications should also submit specific ERAs at marketing authorisation applications.
The two EMA guidelines on the ERA for GTMPs and GMOs should be consulted together with the recently updated EMA pre-authorisation procedural advice for medicinal product containing or consisting of GMOs which refers to the appropriate common application forms and good practice documents. The recent revision of the SOP on the Consultation of environmental competent authorities on genetically modified organisms with respect to environmental risk assessment for medicinal products for human use will streamline the assessment procedure and bring clarity to both developers and regulators. In addition, the Agency will monitor and continue to streamline this process as experience grows and feedback is received.
Finally, although the focus of this article has been the ERA of GTMPs, the same principles are also applicable to the development of vaccine candidates which involve genetic modification and are therefore subject to GMO legislation. In light of current disease outbreaks (e.g. COVID-19 pandemic, Ebola) the European Commission, together with the Member States and the European Medicines Agency, will make the greatest use of existing flexibilities in the EU’s regulatory framework to accelerate the authorisation and availability of successful vaccines against COVID-19. Among other initiatives, the EC has put forward a proposal to provide temporary derogations from certain provisions of the GMO legislation to speed up clinical trials of COVID-19 vaccines containing genetically modified organisms [22]. The proposed Regulation will permit clinical trials with GMO medicinal products against COVID-19 to start in the absence of an ERA and explicit consent under GMO legislation, but introduces limitations to minimise environmental exposure. The massive international efforts to develop a vaccine for COVID-19, will provide candidates to be tested over the second half of 2020, leading to a practical trial of how these simplifications of GMO processes in the EU will work in practice.