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Regenerative Medical Products

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Regulatory Framework

Regenerative medicine, which is expected to overcome intractable and serious diseases, is expected to play an important role in conventional medicine worldwide. The Japanese government must implement comprehensive policies to promote the development of regenerative medicine, inform the public, and increase public acceptance, and ensure that medical professionals and investigators cooperate with the policies. In this background, two regulatory frameworks for regenerative medicine, ‘‘The Act on the Safety of Regenerative Medicine’’ (ASRM) and the ‘‘Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act’’ (PMD Act), came into effect in November 2014. The ASRM sets out legal regulations not only for research, but also for the daily medical practice of cell therapy, which had previously been under the jurisdiction of the Medical Practitioners’ Act and the Medical Care Act.
The PMD Act regulates the commercialization of regenerative medical products. Regenerative medical products in the PMD Act are defined as:

  1. Processed (more than minimal manipulation) live human/animal cells that are intended to be used for either
    • reconstruction, repair, or formation of structures or functions of the human body
    • treatment or prevention of human disease
  2. Gene therapy (excluding the products that are prophylactic vaccines against infectious diseases).

 

Approved Regenerative Medical Prodcuts

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Related Guidelines and Notifications for Regenerative Medical Products

Good tissue practice (GTP)

  • Standards of biological raw materials, MHLW Notification No. 210, 2003. [Japanese] [English]

*Latest partial revision on 2018, MHLW Notification No. 37

  • Standards of biological raw materials, Operational guideline, PFSB/ELD Notification No. 1002-1, PFSB/MDRMPE Notification No. 1002-5, 2014. [Japanese] [English]
  • Standards of biological raw materials, Operational guideline Q&A, PFSB/ELD, FSB/MDRMPE Administrative Notice, 2015. [Japanese] [English]
  • General Principles for the Handling and Use of Cellular- and Tissue-based Products, Annex 1, PFSB Notification No. 1314, 2000. [Japanese] [English]

Guidelines on ensuring quality and safety of cell and tissue-based products 

  • Guidelines on ensuring quality and safety of products derived from processed cell and tissue (Autologous cells), PFSB Notification No. 0208003, 2008. [Japanese] [English]
  • Guidelines on ensuring quality and safety of products derived from processed cell and tissue (Allogeneic cells), PFSB Notification No. 0912006, 2008. [Japanese] [English]
  • Guidelines on ensuring quality and safety of products derived from processed cell and tissue (Autologous somatic stem cells), PFSB Notification No. 0906-2, 2012. [Japanese]​

Hayakawa T., Aoi T., Umezawa A., Ozawa K. et al. (2015) A study on ensuring the quality and safety of pharmaceuticals and medical devices derived from processing of autologous human somatic stem cells. Regen. Ther. 2, 57-69.

  • Guidelines on ensuring quality and safety of products derived from processed cell and tissue (Allogeneic somatic stem cells), PFSB Notification No. 0906-3, 2012. [Japanese]

Hayakawa T., Aoi T., Umezawa A., Ozawa K. et al. (2015) A study on ensuring the quality and safety of pharmaceuticals and medical devices derived from processing of allogeneic human somatic stem cells. Regen. Ther. 2, 70-80.

  • Guidelines on ensuring quality and safety of products derived from processed cell and tissue (Autologous iPS (-like) cells), PFSB Notification No. 0906-4, 2012. [Japanese]

Hayakawa T., Aoi T., Umezawa A., Ozawa K. et al. (2015) A study on ensuring the quality and safety of pharmaceuticals and medical devices derived from processing of autologous human induced pluripotent stem(-like) cells. Regen. Ther. 2, 81-94.

  • Guidelines on ensuring quality and safety of products derived from processed cell and tissue (Allogeneic iPS (-like) cells), PFSB Notification No. 0906-5, 2012. [Japanese]

​Hayakawa T., Aoi T., Umezawa A., Ozawa K. et al. (2015) A study on ensuring the quality and safety of pharmaceuticals and medical devices derived from processing of allogeneic human induced pluripotent stem(-like) cells. Regen. Ther. 2, 95-108.

  • Guidelines on ensuring quality and safety of products derived from processed cell and tissue (Embryonic stem cells), PFSB Notification No. 0906-6, 2012. [Japanese]

​Hayakawa T., Aoi T., Umezawa A., Ozawa K. et al. (2015) A study on ensuring the quality and safety of pharmaceuticals and medical devices derived from processing of allogeneic human embryonic stem cells. Regen. Ther. 2, 109-122.

  • Technical guidance for quality, and nonclinical and clinical studies of regenerative medicines (human cell-processed therapeutic products), PFSB/MDRMPE Administrative Notice, 2016. [Japanese] [English]
  • Considerations in studies to detect undifferentiated pluripotent stem cells and transformed cells, tumorigenicity, and genetic instability of human cell-based products, PSEHB/MDED Notification No .0627-1, 2019. [Japanese] [English]
  • Current perspective on evaluation of tumorigenicity of cellular and tissue-based products derived from induced pluripotent stem cells (iPSCs)* and iPSCs as their starting materials, PMDA Science Board, 2012. [Japanese] [English]

Guidelines on ensuring quality and safety of gene therapy products 

  • Ensuring the quality and safety of gene therapy products, PSEHB/MDED Notification No. 0709-2, 2019. [Japanese] [English]
  • Ensuring the quality and safety of gene therapy products using genome-editing technology, PMDA Science Board, 2020. [Japanese] [English]

 Aspects of gene therapy products using current genome-editing technology in Japan. Yamaguchi Y., Uchida E., Okada T. et al. (2020) Human Gene 31, 1043-1053.

Guidelines on development of cancer immunotherapy

  • Report (2015) Guidance on cancer immunotherapy development in early-phase clinical studies, Cancer Sci. 106, 1761-1771.
  • 1) General principles on late-phase clinical studies, 2) Basic principles in quality, non-clinical and clinical studies of cellular products used for cancer immunotherapy, 3) Guidance on nonclinical study for cancer vaccine/adjuvant, PSEHB/PED Notification No. 0308-1, PSEHB/MDED Notification No. 0308-1, 2019. [Japanese] [English]

Projects for preparing evaluation guidance for next-generation medical devices and cellular- and tissue-based products

  • Guidance on evaluation for the treatment of decompensated cirrhosis using, 1) Autologous born marrow-derived mesenchymal stem cells, 2) Allogeneic born marrow-derived mesenchymal stem cells, 3) Autologous CD34-positive peripheral blood stem cells, PSEHB/MDED Notification No. 0217-1, 2022. [Japanese] [English]
  • Guidance on evaluation for the treatment of subacute spiral cord injury using allogeneic iPS-like cells, PSEHB/MDED Notification No. 0226-1, 2021. [Japanese] [English]
  • Guidance on evaluation of epidermis/skin regeneration using allogeneic epidermis cellular- and tissue-based product, PSEHB/MDED Notification No. 0725-1, 2018. [Japanese] [English]
  • Guidance on evaluation of articular cartilage regeneration using cellular- and tissue-based product, PFSB/MDED Notification No. 0630-1, 2016. [Japanese] [English]
  • Guidance on evaluation of articular cartilage regeneration using human (allogeneic) iPS-like cell-based product, PFSB/MDED Notification No. 0630-1, 2016. [Japanese] [English]
  • Guidance on evaluation of nasal cartilage regeneration, PFSB/MDRMPE Notification No. 0925-1, 2015. [Japanese] [English]
  • Guidance on evaluation of allogeneic iPS-like cells derived retinal pigment epithelial cells, PFSB/MDRMPE Notification No. 0912-2, 2014. [Japanese] [English]
  • Guidance on evaluation of autologous iPS-like cells-derived retinal pigment epithelial cells, PFSB/MDED Notification No. 0529-1, 2013. [Japanese] [English]
  • Guidance on evaluation of periodontal regeneration using cell sheet, PFSB/MDED Notification No. 1207-1, 2011. [Japanese] [English]
  • Guidance on evaluation of articular cartilage regeneration, PFSB/MDED Notification No. 1215-1, 2010. [Japanese] [English]
  • Guidance on evaluation of corneal endothelial cell sheet, PFSB/MDED Notification No. 0528-1, 2010. [Japanese] [English]
  • Guidance on evaluation of severe heart failure using cell sheet, PFSB/MDED Notification No. 0118-1, 2010. [Japanese] [English]

Genetically Modified Organisms (GMO)/ Living Modified Organisms(LMO)

Good gene, cellular and tissue-based products manufacturing practice (GCTP)

  • Ministerial ordinances on GCTP for regenerative medical products, Ministerial Ordinances No. 93, 2014. ​[Japanese] [English]

​*Latest partial revision on 01/08/2021, MHLW Notification No. 15

  • Ministerial ordinances on GCTP for regenerative medical products, Q&A #1, PFSB/CLD Notification No. 0317-1, 2015. ​[Japanese] [English]
  • Ministerial ordinances on GCTP for regenerative medical products, Q&A #2, PFSB/CLD Notification No. 0728-4, 2015. ​[Japanese] [English]
  • Ministerial ordinances on GCTP for regenerative medical products, Q&A #3, PSEHB/ CLD Notification No. 0629-1, 2017. ​[Japanese] [English]
  • Proposal on basic principle to quality assurance of cell therapy (CT) products, PMDA Science Board, 2015. [Japanese] [English]

Good clinical practice (GCP)

  • Ministerial ordinance on GCP for regenerative medical products, Ministerial Ordinance No. 89, 2014. [Japanese] [English]

*​Latest partial revision on 29/01/2021, MHLW Ordinances No. 15.

  • Ministerial ordinance on GCP for regenerative medical products, Guide by Director, PFSB, PFSB Notification No. 0812-16, 2014. [Japanese] [English]

​*Latest partial revision on 21/07/2016, PFSB Notification No. 0721-1

  • Ministerial ordinance on GCP for regenerative medical products, Guide by Director, PFSB/MDED, PFSB/MDED Notification No. 0730-1, 2021. [Japanese] [English]
  • Procedure for document compatibility for marketing authorization application dossier and GCP/GPSP inspection for regenerative medical products, PFSB/MDED Notification No. 0520-8, 2021. [Japanese] [English]
  • Procedure for remote inspection as a part of compliance inspection on drugs and regenerative medical products, PMDA/CPE Notification No. 0525001, 2022. [Japanese] [English]

Real world data (RWD)

  • Basic principles on utilization of registry for applications, PSEHB/PED Notification No. 0323-1, PSEHB/MDED Notification No. 0323-1, 2021. [Japanese] [English]
  • Points to consider for ensuring the reliability in utilization of registry data for applications, PSEHB/PED Notification No. 0323-2, PSEHB/MDED Notification No. 0323-2, 2021. [Japanese] [English]
  • Points to consider for ensuring the reliability of post-marketing database study for regenerative medical products, PSEHB/MDED Notification No. 0323-4, 2020. [Japanese] [English]

​Safety Information

 

Publications

  • Fujiwara Y, Maruyama Y, Honda F. Balancing safety and efficacy with early availability in the regulation of regenerative medicine product. Clin Pharmacol Ther. 2021; 109:1182-1185. https://doi.org/10.1002/cpt.2034
  • Maruyama Y, Kasai M, Fujiwara Y, et al. Current status and future perspective of gene therapy products in Japan. Cell Gene Ther Insights. 2020;7:131-140. https://doi.org/10.18609/cgti.2021.026
  • Maruyama Y, Kasai M, Fujiwara Y, et al. Experiences from Japan: conditional and time-limited approval, an early approval scheme for regenerative medical products. Cell Gene Ther Insights. 2019;5:561-568. https://doi.org/10.18609/cgti.2019.064
  • Maruyama Y, Kasai M, Oyama K, et al. Experiences from Japan: SAKIGAKE designation system for regenerative medical products. Cell Gene Ther Insights. 2018;4:545-554. https://doi.org/10.18609/cgti.2018.045