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.