Inventory of shedding data and analysis: possibilities for standardization

During gene therapy, the gene therapy product can be disseminated into the environment through excreta of the treated subject or patient. This phenomenon is called shedding. For the regulatory approval procedure, the applicant is obliged to perform an environmental risk assessment with respect to the risk of shedding and eventual effects of shedding for third persons and the environment. If it cannot be excluded that shedding may occur and that effects of shedding are harmless, shedding analysis will be obligatory. The lack of standardised shedding assays and of a broad inventory of shedding data from historical clinical trials for the support of evidence-based risk assessment hinders the advisory role of the Commission on Genetic Modification (COGEM). Therefore, the COGEM has initiated the project as described in this report.

The way shedding analysis is performed in clinical gene therapy studies using retroviral, adenoviral, adeno-associated viral and ALVAC vectors, has been studied. For this purpose a literature study has been undertaken and academic and commercial experts have been contacted, as well as experts from regulatory authorities, in The Netherlands and abroad. All Dutch gene therapy trials have been included in this project. In addition, an extensive inventory of published shedding data has been made. Based on the outcome of this report, it can be concluded that there is currently a lack of uniformity with respect to shedding analysis performed in academic and commercial clinical gene therapy studies. It is advised to implement the standardisation of shedding assays through recommendations on the methods to be used as well as general requirements for technical aspects and the level of quality for these methods. A uniform guidance is presented that can be used by the investigator for the design of a strategy for shedding analysis. The shedding data from clinical gene therapy trials collected in this report can offer support for this purpose. The proposed guidance is composed of the following steps:
1. Defining the need of performing shedding analysis
2. Defining the type of excreta and the period in which shedding analysis needs to be performed
3. Defining the method to be used for shedding analysis
4. Development and validation of the shedding assay(s)

Such a guidance is to be considered as a continuous process that can be adapted to future developments in gene therapy.