Table 2.

An indicative and interconnected list of some considerations to be addressed during the iterative clinical trial development process

1. Transplant cells and method: what disease stage should be targeted; what cell type(s) will produce the best outcome; what stem cell source is most appropriate for producing the cell of interest (i.e., tissue-specific or pluripotent); what cell formulation will produce the best outcome (single cell type, 3D tissue, +/- scaffold); where should the stem cell-derived cells be transplanted; how many cells or what sized tissue is needed; how should the transplant be delivered (directly to site or will cell homing be required); Good Manufacturing Practice manufacturing considerations; cost and timeframe for cell harvest, expansion, storage, transport and transplant preparation (do these fit the disease/injury repair timeframe); how to monitor/track the transplanted cells

2. Autologous vs. allogenic cells: are cells obtained directly from the patient (autologous) more appropriate than those from a donor (allogeneic); do appropriate methods exist for either stem cell source to generate sufficient purified cells for transplantation; cost and timeframe for cell harvest, expansion and transplant preparation (do these fit the timeframe for disease/injury response); likely complications of immune-rejection and/or immunosuppressive regimes; will autologous sources provide non-diseased cell types.

3. Avoidance of tumorigenicity: do the target transplant cells have intrinsic tumor forming potential; how to ensure residual unwanted cells with tumor forming potential are absent from the transplant (e.g., residual pluripotent stem cells); could the transplant environment induce aberrant proliferation of the transplanted cells; how will potential tumorigenicity be managed

4. Navigating the regulatory environment: where will the clinical trial be conducted; what regulations are involved; are patent licenses required; homologous vs. non-homologous cell applications (i.e., will the grafted cells perform exactly the same function as their endogenous normal counterparts or not); degree of manipulation of the cells ex vivo; relevance and risk associated with ‘fast-tracking’ approval of new treatments; ‘compassionate’ use and medical innovation

5. Ethical oversight: how will patients be recruited and at what stage of the disease; how will patients be informed about the cell type to be used, the expected scientific/mechanistic basis of the treatment and associated animal or human evidence for this; what consent will be required; what cells will be transplanted and how; how will treatment efficacy/side-effects be monitored and measured; what human research ethics committee is appropriate/required; what arrangements are in place to contend with adverse outcome and ongoing care; how will the patient’s condition be monitored; how will data be collected and shared

6. Infrastructure and leadership: cell therapy training and clinical expertise of those conducting the clinical research; need for specialist centres and equipment including Good Manufacturing Practice expertise and facilities; medical insurance to provide support in the advent of adverse outcomes; key leadership for integration of procedures; support personnel required for recruitment, patient counseling and clinical support; funding sources and cost-modeling of ultimate therapy; business case; milestones and go/no-go points