Over the past few years, several new achievements have been made from stem cell studies, many of which have moved up from preclinical stages to early, or from early to middle or late, stages thanks to relatively safe profile and preliminary evidence of effectiveness. Moreover, some stem cell-based products have been approved for marketing by different national regulatory authorities. However, many critical issues associated mainly with incomplete understanding of stem cell biology and the relevant risk factors, and lack of effective regulations still exist and need to be urgently addressed, especially in countries where establishment of appropriate regulatory system just commenced. More relevantly, the stem cell regulatory sciences need to be established or improved to more effectively evaluate quality, safety and efficacy of stem cell products, and for building up the appropriate regulatory framework. In this review, we summarize some new achievements in stem cell studies, especially the preclinical and clinical studies, the existing regulations, and the associated challenges, and we then propose some considerations for improving stem cell regulatory sciences with a goal of promoting the steadfast growth of the well-regulated stem cell therapies abreast of evolvement of stem cell sciences and technologies.
Guangzhou General Hospital of Guangzhou Military Command
NCT01446640
Liver cirrhosis
Allogenic UC-MSCs
III
General Hospital of Chinese Armed Police Forces
NCT01491165
Allogeneic UC-MSCs
II
Alliancells Bioscience Corporation Limited
NCT01573923
Autologous BM-MSCs
II
Wenzhou Medical University
NCT01560845
Allogeneic UC-MSCs
II
Chinese Academy of Sciences
NCT01233102
Autologous BM-MSCs
II
Sun Yat-sen University
NCT00993941
Tab.3
Fig.1
1
ISSCR Guidelines for Clinical Translation of Stem Cells. 2008
2
MP De Miguel, S Fuentes-Julián, A Blázquez-Martínez, CY Pascual, MA Aller, J Arias, F Arnalich-Montiel. Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med 2012; 12(5): 574−591 https://doi.org/10.2174/156652412800619950
pmid: 22515979
3
FDA. Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs). 2008
4
Chinese Ministry of Health and Family Planning & China Food and Drug Control Document. Interim Regulatory Guidance: guidelines for quality control and preclinical studies of the stem cell medicinal products. 2013
5
L Elmgren, X Li, C Wilson, R Ball, J Wang, K Cichutek, M Pfleiderer, A Kato, M Cavaleri, J Southern, T Jivapaisarnpong, P Minor, E Griffiths, Y Sohn, D Wood. A global regulatory science agenda for vaccines. Vaccine 2013; 31(Suppl 2): B163−B175 https://doi.org/10.1016/j.vaccine.2012.10.117
pmid: 23598478
6
clinicaltrials.gov website
7
M Olausson. Bioengineered vascular graft with autologous stem cells: first use in the clinic. Regen Med 2012; 7(6 Suppl): 12−15 https://doi.org/10.2217/rme.12.99
pmid: 23210807
TA Blenkinsop, B Corneo, S Temple, JH Stern. Ophthalmologic stem cell transplantation therapies. Regen Med 2012; 7(6 Suppl): 32−39 https://doi.org/10.2217/rme.12.77
pmid: 23210809
10
VK Prasad, KG Lucas, GI Kleiner, JA Talano, D Jacobsohn, G Broadwater, R Monroy, J Kurtzberg. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal™) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant 2011; 17(4): 534−541
pmid: 20457269
11
A Bersenev. Regenerative Medicine and Cell Therapy Industry in 2012. RegenMed Digest. 2012.
ARM Annual Report. Cellular Reprogramming and Disease Modeling. 2013. 24−26
15
A Bersenev. Regenerative Medicine and Cell Therapy Industry in 2011. RegenMed Digest. 2011
16
A Bersenev. Alliance for Regenerative Medicine’s 2012 Report. RegenMed Digest. 2012.
17
DS McMahon, H Thorsteinsdóttir, PA Singer, AS Daar. Cultivating regenerative medicine innovation in China. Regen Med 2010; 5(1): 35−44 https://doi.org/10.2217/rme.09.78
pmid: 20055687
18
Ministry of Heath Reports. Surveys of Stem Cell Clinical Studies and Uses in China. 2012
19
Chinese Ministry of Health and Family Planning & China Food and Drug Control Document. Interim Regulatory Guidance: general requirements for conducting clinical studies of the stem cell-based medicinal products. 2013
20
Chinese Ministry of Health and Family Planning & China Food and Drug Control Document. Interim Regulatory Guidance: qualification for institutions conducting studies of the stem cell-based medicinal products. 2013
21
M Dominici, K Le Blanc, I Mueller, I Slaper-Cortenbach, F Marini, D Krause, R Deans, A Keating, Dj Prockop, E Horwitz. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315−317
pmid: 16923606
EMA. Guideline on Human Cell-Based Medicinal Products. 2007
24
EMA. Reflection Paper on Stem Cell-Based Medicinal Pproducts. 2011
25
FDA. Guidance for Human Somatic Cell Therapy and Gene Therapy. 1998
26
Chinese Pharmacopoeia Commission. Chinese Pharmacopoeia. 2010 Version. Part III. Beijing: China Medical Science Press. 2010
27
Guidelines for Clinical Studies and Quality Control of Human Somatic Cells (in Chinese). 2003
28
WHO. Recommendations for the Evaluation of Animal Cell Cultures as Substrates for the Manufacture of Biological Medicinal Products and for the Characterization of Cell Banks. 2010
29
FDA. Guidance for Industry−Current Good Tissue Practice (CGTP) and Additional Requirements for Manufactures of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)
30
K Tarte, J Gaillard, JJ Lataillade, L Fouillard, M Becker, H Mossafa, A Tchirkov, H Rouard, C Henry, M Splingard, J Dulong, D Monnier, P Gourmelon, NC Gorin, L Sensebé; Société Française de Greffe de Moelle et Thérapie Cellulaire. Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. Blood 2010; 115(8): 1549−1553 https://doi.org/10.1182/blood-2009-05-219907
pmid: 20032501
31
G Lepperdinger, R Brunauer, A Jamnig, G Laschober, M Kassem. Controversial issue: is it safe to employ mesenchymal stem cells in cell-based therapies? Exp Gerontol 2008; 43(11): 1018−1023 https://doi.org/10.1016/j.exger.2008.07.004
pmid: 18694815
E Närvä, R Autio, N Rahkonen, L Kong, N Harrison, D Kitsberg, L Borghese, J Itskovitz-Eldor, O Rasool, P Dvorak, O Hovatta, T Otonkoski, T Tuuri, W Cui, O Brüstle, D Baker, E Maltby, HD Moore, N Benvenisty, PW Andrews, O Yli-Harja, R Lahesmaa. High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nat Biotechnol 2010; 28(4): 371−377 https://doi.org/10.1038/nbt.1615
pmid: 20351689
EA Rayment, DJ Williams. Concise review: mind the gap: challenges in characterizing and quantifying cell- and tissue-based therapies for clinical translation. Stem Cells 2010; 28(5): 996−1004
pmid: 20333747
36
FDA. Guidance−Potency Tests for Cellular and Gene Therapy. 2011
37
M Werner, T Mayleben, G Van Bokkelen. Autologous cell therapies: the importance of regulatory oversight. Regen Med 2012; 7(6 Suppl): 100−103 https://doi.org/10.2217/rme.12.90
pmid: 23210820
38
M Breitbach, T Bostani, W Roell, Y Xia, O Dewald, JM Nygren, JW Fries, K Tiemann, H Bohlen, J Hescheler, A Welz, W Bloch, SE Jacobsen, BK Fleischmann. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 2007; 110(4): 1362−1369 https://doi.org/10.1182/blood-2006-12-063412
pmid: 17483296
39
G Moll, I Rasmusson-Duprez, L von Bahr, AM Connolly-Andersen, G Elgue, L Funke, OA Hamad, H Lönnies, PU Magnusson, J Sanchez, Y Teramura, K Nilsson-Ekdahl, O Ringdén, O Korsgren, B Nilsson, K Le Blanc. Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells 2012; 30(7): 1565−1574 https://doi.org/10.1002/stem.1111
pmid: 22522999
40
US 21CFR211—Current Good Manufacturing Practice for Finished Pharmaceuticals
41
US 21CFR312—Investigational New Drug Application
42
US 21CFR610—General Biological Products Standards
43
US 21CFR1271—Human Cells, Tissues, and Cellular and Tissue-Based Products
44
US FDA. Draft Guidance—Preclinical Assessment of Investigational Cellular and Gene Therapy Products. 2012
45
US FDA. Draft Guidance—Design of Early-Phase Clinical Trials. 2013
46
B George. Regulations and guidelines governing stem cell based products: clinical considerations. Perspect Clin Res 2011; 2(3): 94−99 https://doi.org/10.4103/2229-3485.83228
pmid: 21897884
47
US Pharmacopeia<1046>Cellular and Tissue-Based Products
48
US Pharmacopeia<1043>Ancillary Materials for Cell, Gene and Tissue-engineered Products
49
MA HamburgIncreasing the Prestige of Regulatory Sciences. FDA Commissioner,s speech. 2011
M Krampera, J Galipeau, Y Shi, K Tarte, L Sensebe; MSC Committee of the International Society for Cellular Therapy (ISCT). Immunological characterization of multipotent mesenchymal stromal cells—The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy 2013; 15(9): 1054−1061 https://doi.org/10.1016/j.jcyt.2013.02.010
pmid: 23602578