Quantification of variation in biological input materials and its effect on clinical outcome and manufacture

Regenerative medicines (RMs) will revolutionise healthcare by improving patient quality of life and reducing costs due to their substantial long term health benefit. One particular RM is stem cell therapy, which contains a self-renewing progenitor cell with the capability to differentiate into any cell type of the body. This has exciting possibilities for treatment of chronic disease and injury. Haematopoietic stem cells (HPCs) are one type, derived from the bone marrow, and released into the peripheral blood. These are used in the treatment of blood based cancers and immunological disorders where they can re-establish haemalogical function or allow higher doses of chemo/radiotherapy than the bone marrow would usually tolerate. HPCs are derived from human blood or bone marrow; a raw material that is inherently variable due to geography, ethnicity, lifestyle and quality of life of the donor. This biological variation can affect the safety and efficacy of any cell derived product, and therefore the cell therapy industry will need to design a process around this variation, or control it. A greater understanding of biological variation and its causes will allow a greater understanding of HPCs' mode of action, of the relationship between mode-of-action and dose/response, and in design of RM clinical trials. Blood and bone marrow derived HPC therapies were used as a case example to study the effects of variation. The literature was systematically searched, using the PRISMA guidelines, for data related to donor characteristics to establish a database on baseline biological variation. Bearing in mind a number of noted assumptions, variation in the collected and transplanted material can be as high as 3.5 orders of magnitude of the mean, with a suggestion that the processing step adds up to 2 orders of magnitude of this variation. Additionally a number of observations about the available data were made.