Specific ERA
The most important elements to consider for the ERA of GTMPs are the type of viral vector and whether the viral vector is constituted into genetically modified cells. The key to environmental risk normally focuses on the potential for the presence or generation of an infective viral agent [11].
Investigational medicinal product’IMPs for human use that contain or consist of Adeno-associated (AAV) vectors . Developers are eligible for specific ERAs if the applicant demonstrates:
i) absence of formation of replication competent virus;
ii) that the transgene is not harmful.
AAVs have not been associated with any pathogenic disease in humans or animals and are unable to replicate unless the cell is co-infected with a helper virus. Therefore, the only mechanism by which there could be mobilisation is that the same cell was infected simultaneously with the clinical vector, a wild-type AAV virus and a helper virus (triple infection). The likelihood of simultaneous triple infection can be considered very low. In addition, most of the genome of the wild-type virus is removed in vectors used in clinical practice, except for the inverted terminal repeats. The recombined particles would have the rep and cap genes encoding for proteins required for replication and capsid formation but they would still be replication-defective (as the wild-type virus). In view of these factors and provided that the control measures described by the applicant are implemented, the overall risks for human health and the environment can be considered negligible [15,17].
Human cells genetically modified by means of retro/lentiviral vectors. Human cells cannot proliferate in the environment as they can only survive inside the human body or under in vitro culture conditions. It follows that, when the IMP consist of human cells genetically modified by means of retro/lentiviral vectors, the risks to the environment and public health are mainly linked to the potential for the viral elements to remobilize, with or without recombination with other elements, to release infective virus into the environment [16,18].
Developers of IMPs consisting of human cells genetically modified by means of retro/lentiviral vectors are eligible for the specific ERA described in the Annex of the Good Practice document on the assessment of GMO-related aspects in the context of clinical trials with human cells genetically modified by means of retro/lentiviral vectors if the applicant demonstrates;
i) the absence of formation of replication competent virus;
ii) the absence of residual infectious viral vector particles in the transduced cells.
Under these circumstances, no risks to the environment or animal health can be identified. Provided that the control measures described by the applicant are implemented, the overall risks for third parties exposed to the GMO-containing medicinal product are also considered negligible.
The good practice document specifies that retroviral vectors means murine gamma-retroviral vectors and that lentiviral vectors are those derived from human cells transduced with lentiviral vectors derived from HIV virus. In case of lentiviral vectors derived from other viruses, developers should perform a risk assessment and contact the relevant competent authority.