Introduction
Advanced Therapy Medicinal Products (ATMPs) are an umbrella term that
includes gene therapy, cell-based, tissue engineered products and
combined ATMPs (cATMPs) [1,2].
In regulatory terms, gene therapy medicinal products (GTMPs) are
medicines with an active substance that contain or consist of a
recombinant nucleic acid. That nucleic acid is present with the
intention of regulating, repairing, replacing, adding, or deleting a
genetic sequence in the patient, and whose therapeutic, diagnostic, or
prophylactic effect relates either directly or indirectly through a
protein it expresses. For regulatory purposes vaccines against
infectious diseases are not included as ATMPs [3].
When medicines developers apply for a marketing authorisation for a
human medicinal product, they are required to submit an environmental
risk assessment (ERA). The genetically modified organism, or GMO,
contained in GTMPs is the focus of the ERA of these medicines.
The ERA for GMOs is based on quality, preclinical and clinical data. The
process consists of (1) hazard identification, (2) hazard
characterization, (3) assessment of likelihood, and (4) risk estimation.
These data together with the likelihood of the adverse event occurring
and the consequences of such an event, constitute the ERA
[4]. In addition to the risk to the environment
per se, the ERA also considers the potential harmful effects on third
parties exposed to the GMO-containing ATMP, such as medical personnel
handling the product [4].
GTMPs, and all ATMPs, fall under the mandatory scope of the centralized
procedure, which means that a single central application to the European
Medicines Agency (EMA) will achieve marketing authorisation for the
whole of the EU. During the assessment that leads to a marketing
authorisation, the ERA is reviewed by two committees; the Committee for
Advanced Therapies (CAT) and the Committee for Human Medicinal Products
(CHMP). In addition, and in accordance with the legislation, the ERA is
also subject to consultation by the competent authority appointed to be
responsible for GMO dossiers at national level. The fact that different
countries in the EU have different requirements, and sometimes involve
additional bodies creates additional complexity for developers.
Developers of GTMPs are also required to submit a GMO-specific ERA prior
to conduct of clinical trials. This is dependent on the country in which
the trial is to be performed and the level of containment considered
necessary for the product in the conduct of the trial. Under EU
legislation, clinical trials with human products containing or
consisting of GMOs can be performed under contained use (CU)
[5] or deliberate release (DR)
[6] legislation (see glossary 1).
Complications arise because these directives, implemented into the
national legislations, are not uniformly applied or interpreted by
member states (see Table 1 for details country by country). It is
generally only for DR procedures that a formal ERA and a detailed
technical/scientific description of the GMO are required. There are
significant differences between member states in the documentation and
procedures required for authorisation of GMO aspects of clinical trials
for medicines containing GMO and a public consultation is also required
in some countries. The current approach is not ideal for the conduct of
multinational clinical trials and has been considered by many an
impediment to the effective translation of research findings into
clinical applications [7,8,9].
This commentary reviews recent initiatives taken by the European
Commission towards a common procedure for the ERA review for clinical
trials applications for GMO-containing medicinal products, in particular
for cell-based therapies and some viral vector based GTMPs where most
experience is available, and outlines steps taken by the EMA to
streamline the assessment procedures for GMO-containing products for
marketing authorisation applications. Although chiefly focused on GTMPs,
these approaches will also be relevant for some products other than
GTMPs such as GMO-containing vaccines.