Safety, Efficacy, and Regulation of Mesenchymal Stromal/Stem Cells
The scientific progress during the last decades has led to the development of cell therapy and tissue-engineered products that are moving rapidly into clinical application. Cranio-maxillofacial applications have paved the way for cell therapy and especially for tissue-engineered products. Cell-based medicinal products (CBMP) differ from conventional drug products, as they are often more complex and variable and less comprehensively characterizable. In addition, they often have complex mechanisms of action that remain incompletely understood. The overall risk/benefit to the proposed indication in certain patient population is evaluated with respect to the available data on quality, safety, and efficacy on a case-by-case basis. In this chapter, safety and efficacy of CBMP, especially mesenchymal stromal/stem cells (MSC)-based products, are discussed. The demonstration of quality, safety, efficacy, and comparability between production batches may be demanding for CBMP. Thus, a well-established and controlled manufacturing process is needed in order to produce a qualified product to guarantee reproducible data from nonclinical and clinical studies. In this chapter, we will also provide an overview of the regulation of CBMP in the European Union (EU) and the United States of America (US).
KeywordsMesenchymal stromal/stem cells MSC Cell-based medicinal products Advanced medicinal products Safety Efficacy Cell therapy Clinical trials Regulation
Permission to reproduce extracts from British Standards is granted by BSI Standards Limited (BSI). No other use of this material is permitted. British Standards can be obtained in PDF or hard copy format from the BSI online shop: www.bsigroup.com/Shop.
- 8.Khojasteh A, Kheiri L, Behnia H, Tehranchi A, Nazeman P, Nadjmi N, et al. Lateral ramus cortical bone plate in alveolar cleft osteoplasty with concomitant use of buccal fat pad derived cells and autogenous bone: phase I clinical trial. Biomed Res Int. 2017;2017:6560234.PubMedPubMedCentralCrossRefGoogle Scholar
- 30.Blazquez-Prunera A, Diez JM, Gajardo R, Grancha S. Human mesenchymal stem cells maintain their phenotype, multipotentiality, and genetic stability when cultured using a defined xeno-free human plasma fraction. Stem Cell Res Ther. 2017;8(1):103. https://doi.org/10.1186/s13287-017-0552-z.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Chase LG, Yang S, Zachar V, Yang Z, Lakshmipathy U, Bradford J, et al. Development and characterization of a clinically compliant xeno-free culture medium in good manufacturing practice for human multipotent mesenchymal stem cells. Stem Cells Transl Med. 2012;1(10):750–8.PubMedPubMedCentralCrossRefGoogle Scholar
- 32.Haack-Sorensen M, Juhl M, Follin B, Harary Sondergaard R, Kirchhoff M, Kastrup J, et al. Development of large-scale manufacturing of adipose-derived stromal cells for clinical applications using bioreactors and human platelet lysate. Scand J Clin Lab Invest. 2018;78(4):293–300.PubMedCrossRefGoogle Scholar
- 36.Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, et al. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007;67(19):9142–9.PubMedCrossRefGoogle Scholar
- 44.European Medicines Agency (EMA). Guideline on the risk-based approach according to annex I, part IV of directive 2001/83/EC applied to advanced therapy medicinal products (EMA/CAT/CPWP/686637/2011). Available at European Medicines Agency (EMA). Guideline on the risk-based approach according to annex I, part IV of directive 2001/83/EC applied to advanced therapy medicinal products (EMA/CAT/CPWP/686637/2011). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500139748.pdf. Accessed 7 Jan 2019.
- 45.Brennan MA, Renaud A, Guilloton F, Mebarki M, Trichet V, Sensebe L, et al. Inferior in vivo osteogenesis and superior angiogeneis of human adipose tissue: a comparison with bone marrow-derived stromal stem cells cultured in xeno-free conditions. Stem Cells Transl Med. 2017;6(12):2160–72.PubMedPubMedCentralCrossRefGoogle Scholar
- 50.Correction for Takao and Miyakawa, Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2015;112(10):E1163-7.Google Scholar
- 58.Prins HJ, Schulten EA, Ten Bruggenkate CM, Klein-Nulend J, Helder MN. Bone regeneration using the freshly isolated autologous stromal vascular fraction of adipose tissue in combination with calcium phosphate ceramics. Stem Cells Transl Med. 2016;5(10):1362–74.PubMedPubMedCentralCrossRefGoogle Scholar
- 59.Rickert D, Vissink A, Slot WJ, Sauerbier S, Meijer HJ, Raghoebar GM. Maxillary sinus floor elevation surgery with BioOss(R) mixed with a bone marrow concentrate or autogenous bone: test of principle on implant survival and clinical performance. Int J Oral Maxillofac Surg. 2014;43(2):243–7.PubMedCrossRefGoogle Scholar
- 60.Heberer S, Wustlich A, Lage H, Nelson JJ, Nelson K. Osteogenic potential of mesenchymal cells embedded in the provisional matrix after a 6-week healing period in augmented and non-augmented extraction sockets: an immunohistochemical prospective pilot study in humans. Clin Oral Implants Res. 2012;23(1):19–27.PubMedCrossRefGoogle Scholar
- 62.Rickert D, Sauerbier S, Nagursky H, Menne D, Vissink A, Raghoebar GM. Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: a prospective randomized clinical trial. Clin Oral Implants Res. 2011;22(3):251–8.PubMedCrossRefGoogle Scholar
- 64.Galipeau J, Krampera M, Barrett J, Dazzi F, Deans RJ, DeBruijn J, et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy. 2016;18(2):151–9.PubMedCrossRefGoogle Scholar
- 66.Boran T, Menezes-Ferreira M, Reischl I, Celis P, Ferry N, Gansbacher B, et al. Clinical development and commercialization of advanced therapy medicinal products in the European Union: how are the product pipeline and regulatory framework evolving? Hum Gene Ther Clin Dev. 2017;28(3):126–35.PubMedCrossRefGoogle Scholar