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.