Fig. 3.

Regulatory issues for cell-free therapies. To enable regulatory approval for testing paracrine factor-based therapy, several regulatory issues have to be fulfilled. First, cell-free therapies have to be discriminated from cell-based medicinal products (ATMP). ATMPs deal with living cells, whereas paracrine factor-based therapies, such as APOSEC™, contain only factors produced by living cells. In cell therapies, the mode of action is thought to be mediated by the cells or their paracrine factors, whereas in cell-free therapies multiple paracrine factors are thought to exert the biological activity. The starting material in both therapies are cells of human origin, either autologous or allogeneic. An important difference between these two types of therapies is that viral clearance is not possible in ATMPs, but viral clearance steps can be applied in cell-free therapies such as APOSEC™. In the right side of the figure, the different regulatory steps that have to be performed during the development of a cell-free therapy are depicted, starting from pre-clinical studies and leading to Phase I/Phase II studies