The Genetically Modified Organism Medicinal Framework in Europe, United States, and Japan: Underlying Scientific Principles and Considerations Toward the Development of Gene Therapy and Genetically Modified Cell-Based Products

In vivo viral gene therapy and somatic cell therapy products (whether autologous, allogeneic, or xenogeneic) that have been subjected to an ex vivo gene transfer procedure will normally be classified as genetically modified organisms (GMOs) in Europe, not just the gene transfer vectors used in their construction. These products are, therefore, expected to fulfill certain environmental requirements with regard to the biosafety aspects of their clinical use (which may be subject to review by government departments responsible for environmental affairs). In the European Union (EU), clinical trials using GMOs generally require three levels of review (in addition to local review processes), which are often performed by separate national agencies. In this study, the principles under which certain EU member states control use of the GMOs in clinical trials under the definitions of either "contained use" or "deliberate release" will be discussed and evaluated from a scientific and a regulatory perspective, with comparisons with non-EU expectations as described by the U.S. Food and Drug Administration and the Japanese living modified organisms (LMOs) regulations. For the latter, an understanding of the criteria under which LMOs exemptions apply, notably with respect to the nature of the viral construct used, the manufacturing process, and demonstration that there is no detectable residual replication-competent virus in the final gene-modified cells, is of paramount importance. Building on the existing European, U.S., and Japanese experience with GMOs/LMOs within the context of experimental gene and cell therapies, a through reflection on, and harmonization of, the current global GMO framework is needed to avoid unnecessary delays in clinical development and to ensure a smooth and a rapid access by patients to innovative life-saving therapies.