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.