Attitudes Towards Standardization of Mesenchymal Stromal Cells-A Qualitative Exploration of Expert Views.

Pharmacopoeial standards ensure quality control of established medicines. It is widely believed that translation of cell therapy medicines will be facilitated by defining and adopting relevant standards. Mesenchymal stromal cells (MSCs) are used extensively for multiple indications in regenerative medicine. They are highly heterogeneous in terms of their biological characteristics and their mechanisms of action, making standardization a challenging undertaking. Furthermore, the use of MSCs in therapy appears to attract diverse views, ranging from concern and caution to enthusiastic positivity. We conducted semi-structured interviews with 20 expert stakeholders from academia, industry, regulatory agencies, non-governmental organizations and clinicians to explore their views, experiences, recommendations, and concerns regarding standardization of MSCs. Qualitative thematic analysis of transcribed records led to development of a consensus framework, which identified 5 key themes to facilitate exploration of the interviews' content. On the basis of our findings, we conclude that (1) there is undoubtedly an appetite for standardization, particularly in development of assays that enable comparison or benchmarking across manufacturers, processes, and cell sources; (2) stakeholder groups are not homogeneous in their concerns and attitudes; (3) careful consideration must be given to the points along the development timeline at which different standardization approaches could be beneficial; and (4) the roles of standards could be promoted further for specific aspects of advanced therapy medicinal product (ATMP) development and regulation such as qualification of decentralized manufacturing sites. A unified cross-stakeholder approach will help to advance MSC therapeutics and other cell therapy medicines.

Characterisation of mesenchymal stromal cells in clinical trial reports: analysis of published descriptors.

BACKGROUND: Mesenchymal stem or stromal cells are the most widely used cell therapy to date. They are heterogeneous, with variations in growth potential, differentiation capacity and protein expression profile depending on tissue source and production process. Nomenclature and defining characteristics have been debated for almost 20 years, yet the generic term 'MSC' is used to cover a wide range of cellular phenotypes. Against a documented lack of definition of cellular populations used in clinical trials, our study evaluated the extent of characterisation of the cellular population or study drug. METHODS: A literature search of clinical trials involving mesenchymal stem/stromal cells was refined to 84 papers upon application of pre-defined inclusion/exclusion criteria. Data were extracted covering background trial information including location, phase, indication, tissue source and details of clinical cell population characterisation (expression of surface markers, viability, differentiation assays and potency/functionality assays). Descriptive statistics were applied, and tests of association between groups were explored using Fisher's exact test for count data with simulated p value. RESULTS: Twenty-eight studies (33.3%) include no characterisation data. Forty-five (53.6%) reported average values per marker for all cell lots used in the trial, and 11 (13.1%) studies included individual values per cell lot. Viability was reported in 57% of studies. Differentiation was discussed: osteogenesis (29% of papers), adipogenesis (27%), and chondrogenesis (20%) and other functional assays arose in 7 papers (8%). The extent of characterisation was not related to the clinical phase of development. Assessment of functionality was very limited and did not always relate to the likely mechanism of action. CONCLUSIONS: The extent of characterisation was poor and variable. Our findings concur with those in other fields including bone marrow aspirate and platelet-rich plasma therapy. We discuss the potential implications of these findings for the use of mesenchymal stem or stromal cells in regenerative medicine, and the importance of characterisation for transparency and comparability of literature.