Biologicals xxx (2015) 1e3
Contents lists available at ScienceDirect
Biologicals journal homepage: www.elsevier.com/locate/biologicals
Meeting report
Regulatory perspectives of Japan Tetsuya Kusakabe* Ministry of Health, Labour and Welfare, 1-2-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-8916, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 February 2015 Received in revised form 21 April 2015 Accepted 1 May 2015 Available online xxx
In this article, the 2013 regenerative medicine laws and regulations in Japan are addressed. The Regenerative Medicine Promotion Law was promulgated in May 2013 to promote comprehensive measures from research and development to practical use of regenerative medicines. In line with this purpose, two acts have been passed by the National Diet in November 2013. One is the Act on the Safety of Regenerative Medicine, which classifies regenerative medicines based on risk. Additionally this Act stipulates the procedures for offering regenerative medicines, the measures for appropriate provision of the regenerative medicines, and authorization to manufacture designated cellular therapeutic products for therapeutic use. The other is the Act on Pharmaceuticals and Medical Devices, previously named the Pharmaceutical Affairs Act, which establishes regulations tailored to the characteristics of regenerative medicinal products, including an expedited approval system.
Keywords: Regenerative medicine Cell and gene therapy Regenerative Medicine Promotion Law Act on the Safety of Regenerative Medicines Act on Pharmaceuticals and Medical Devices Expedited approval system
1. Introduction
2. Government's policy
Global competition in the development of advanced therapeutic products, including regenerative medicines, is becoming more and more intense. In order to accelerate the practical applications while maintaining the safety of the therapy, new regulations suited for the characteristics of these advanced therapeutic products are needed. Under these circumstances, the Regenerative Medicine Promotion Law [1] was promulgated in May 2013 to comprehensively promote such measures from research and development to practical use of regenerative medicines. The Regenerative Medicine Promotion Law was legislated by House members with the goal of promoting the development and application of regenerative medicines. In line with this purpose, the Act on the Safety of Regenerative Medicine [2] and the Act on Pharmaceuticals and Medical Devices [3], formerly the Pharmaceutical Affairs Act, were passed by the National Diet in November 2013 to create a stable framework of regulations for regenerative medicines and their products.
A priority of the Japanese government is accelerating the introduction of regenerative medicinal products into the market. In this plan, the cabinet offices will work out a strategy to take the initiative, and the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Ministry of Economy, Trade and Industry (METI), and the Ministry of Health, Labour and Welfare (MHLW) will collaborate to promote regenerative medicine policy. The government's priorities include: 1) integrated support from basic to clinical research, 2) development of infrastructure to promote regenerative medicines, and 3) supporting the use of induced pluripotent stem cells (iPS cells) as a drug-discovery tool. The goals for the next seven years are: 1) to apply new drugs developed by iPS cells technology in clinical trials, 2) to increase the number of approved cellular therapeutic products, 3) to expand the target illnesses for clinical trials, and 4) to develop equipment or devices related to regenerative medicines, etc. 3. New acts regulating regenerative medicines
Abbreviations: MHLW, Ministry of Health, Labour and Welfare; PMDA, Pharmaceuticals and Medical Devices Agency. * Tel.: þ81 3 3595 2436. E-mail address: [email protected].
There are two approaches to bringing regenerative medicines to patients. The Act on the Safety of Regenerative Medicine promotes usage of regenerative medicines within hospitals and clinics. The Act on Pharmaceuticals and Medical Devices promotes the development and manufacture of products by industry.
http://dx.doi.org/10.1016/j.biologicals.2015.05.003 1045-1056
Please cite this article in press as: Kusakabe T, Regulatory perspectives of Japan, Biologicals (2015), http://dx.doi.org/10.1016/ j.biologicals.2015.05.003
2
Meeting report / Biologicals xxx (2015) 1e3
Legislation of the Act on the Safety of Regenerative Medicine was needed because the guidelines are not based on the law. Also a growing need for collaboration between medical institutions and industry from the early stage of development existed. This Act will cover the study of medical technologies using processed cells, for which safety and efficacy have not been established. The therapy will be classified into one of three risk categories (Class I, II, and III). This classification is made on the basis of its potential impact on human health using a risk-based approach. High risk therapies such as those with products derived from iPS or embryonic stem (ES) cells are Class I. Medium risk therapies such as those with products derived from somatic stem cells are Class II. Low risk therapies such as those with products derived from somatic cells are Class III. Medical institutions are required to submit provisional plans to MHLW after the evaluation by the certified committee for regenerative medicine. The Act also requires hospitals and clinics to make regular reports to MHLW about the status of implementation (i.e., any adverse health events, etc.). Another important point is the expansion of facilities that can conduct cell processing outside of medical institutions. These facilities are required to obtain a license for quality and efficacy control, and meet standards set by MHLW. Additionally, the Act on Pharmaceuticals and Medical Devices has been recently amended to better consider the safety and risks of such products. One example is the conditional approval system. The Act introduced a new pathway to enable earlier patient access to regenerative medicinal products (Fig. 1). Specifically, this path is for the approval of products that have difficulty proving efficacy within a short timeframe. The demonstration of probable benefit (efficacy with a small patient population) and the safety (detection as well as evaluation of any adverse event) in the early phase of clinical trial will be considered sufficient for conditional approval for up to seven years, during which additional data on efficacy and safety will be collected. During this stage, informed consent is required and better applications for the product will be sought. After this phase, the marketing authorization holder submits an application for the second approval. The Pharmaceuticals and Medical Devices Agency (PMDA) will review the application prior to MHLW's final determination. Should the risks outweigh the benefits: i.e., the applicants fail to gather enough information or new information does not support their application, the authorization will be revoked. Should the benefits continue to outweigh
the potential risks, the second approval will be admitted. Informed consent is still required even after the second approval. 4. Regulatory framework of marketing authorization Marketing authorization of products derived from processed human cells/tissues is regulated by the Act on Pharmaceuticals and Medical Devices and related regulatory documents. There are four regulatory levels in Japan. First level is the Act on Pharmaceuticals and Medical Devices, the basis of regulatory framework. The second level are ministerial announcements such as Japanese Pharmacopoeia, Standards for Biological Ingredients, and Minimum Requirements for Vaccines, Antitoxins and Blood Products. The third level are ministerial ordinances, including Good Clinical Practice (GCP) and Good Post-Marketing Surveillance Practices (GPMSP). The last level are notifications or administrative letters which describes specific measures. The guidelines relating to cellular therapeutic products, including regenerative medicines, are announced or notified by MHLW. There are at least 18 guidelines listed: two guidelines for Good Tissue Practice (GTP) [4,5], twelve guidelines for product evaluation [6e17], and four guidelines for Good Manufacturing Practice (GMP) and Quality Management System (QMS) [18e21]. 5. Definitions of regenerative medicinal product and cell/ tissue processing The Act on Pharmaceuticals and Medical Devices defines “Regenerative Medicinal Products” in Chapter 1 Article 2e9. “Regenerative Medicinal Product” is a product that reconstructs, restores or reproduces the structure or functions of human or animal body (1-A), “Cell Therapy Product” is a product that treats or prevents disease in humans or animals (1-B), and “Gene Therapy Product” is a product intended to be used in the treatment of disease in humans or animals, and is transgened to express in human or animal cells (2). Chapter 1 Article 2e9 The term “Regenerative Medicinal Products” (as “SAISEI-IRYOUTOU-SEIHIN” in Japanese) used in this act refers to the articles (excluding quasi-drugs and cosmetics) specified in the following items which are specified by the cabinet order.
Fig. 1. Comparison of the old and new approval systems. The demonstration of probable benefit and the safety in the early phase of clinical trial will be considered sufficient for conditional approval. Should the benefit-risk assessment conclude a failure, the authorization will be revoked at the re-application process.
Please cite this article in press as: Kusakabe T, Regulatory perspectives of Japan, Biologicals (2015), http://dx.doi.org/10.1016/ j.biologicals.2015.05.003
Meeting report / Biologicals xxx (2015) 1e3
(1) The articles specified in the following items which are intended to be used in the medical treatment in humans or animals, and are cultured and/or processed human or animal cells. A: To reconstruct, restore or reproduce the structure or functions of human or animal body. B: To treat or prevent disease in humans or animals. (2) The articles which are intended to be used in the treatment of disease in humans or animals, and are transgened to express in human or animal cells. “Cell/Tissue Processing” is defined in the guidelines on Ensuring Quality and Safety of Products Derived from Processed Cell/Tissue [6,7]. It should be noted that whether the products are processed or not is judged on a case-by-case basis, and consultation with MHLW/ PMDA is strongly recommended. Cell/Tissue Processing Any processing of a cell or tissue with the aim of treating a disease, restoring or reconstructing tissue, including: -
propagation of a cell or tissue, pharmaceutical or chemical treatment to activate cell or tissue, altering a biological characteristic, combining with a noncellular component, manipulation by genetic engineering.
The isolation of tissue, disintegration of tissue, separation of cells, isolation of specific cells, treatment with antibiotics, washing, sterilization by g-irradiation, freezing, thawing, and such similar procedures are not considered to be processing. 6. Conclusions This article has addressed the new laws and regulations in Japan; the 2013 Regenerative Medicine Promotion Law, the Act on the Safety of Regenerative Medicine, and the Act on Pharmaceuticals and Medical Devices. In order to market the regenerative medicinal products in Japan, MHLW guidelines shall also be followed. These have been designed to better assure patient safety as more treatments become available. Collaboration between academia and industry during the early stages of research and development will also be improved.
3
References [1] [2] [3] [4] [5] [6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] [15] [16] [17]
[18]
[19] [20] [21]
Regenerative Medicine Promotion Law. May 10, 2013. Law No. 13. Act on the Safety of Regenerative Medicines. November 27, 2013. Law No. 85. Act on Pharmaceuticals and Medical Devices. November 27, 2013. Law No. 84. Standard for biological ingredients. May 20, 2003. Ministerial Announcement No. 210. General principles for the handling and use of cellular/tissue-based products. December 26, 2000. MHLW Notification No. 1314. Guideline on ensuring quality and safety of products derived from processed cell/tissue targeting for autologous. February 8, 2008. MHLW Notification No. 0208003. Guideline on ensuring quality and safety of products derived from processed cell/tissue targeting for allogeneic. September 12, 2008. MHLW Notification No. 0912006. Guideline on Ensuring the quality and safety of products derived from processed human stem cells targeting for autologous somatic stem cells. September 7, 2012. MHLW Notification No. 0907e2. Guideline on Ensuring the quality and safety of products derived from processed human stem cells targeting for allogeneic somatic stem cells. September 7, 2012. MHLW Notification No. 0907e3. Guideline on ensuring the quality and safety of products derived from processed human stem cells targeting for autologous iPS-like cells. September 7, 2012. MHLW Notification No. 0907e4. Guideline on ensuring the quality and safety of products derived from processed human stem cells targeting for allogeneic iPS-like cells. September 7, 2012. MHLW Notification No. 0907e5. Guideline on ensuring the quality and safety of products derived from processed human stem cells targeting for embryonic stem cells. September 7, 2012. MHLW Notification No. 0907e6. Points to consider for the evaluation of cell sheet for heart failure and corneal epithelial cell sheet. January 18, 2010. MHLW Notification No. 0118e1. Points to consider for the evaluation of corneal endothelial cell sheet. May 28, 2010. MHLW Notification No. 0528e1. Points to consider for the evaluation of articular cartilage repair. December 15, 2010. MHLW Notification No. 1215e1. Points to consider for the evaluation of cell sheet for periodontal tissue regeneration. December 7, 2011. MHLW Notification No. 1207e1. Points to consider for the evaluation of autologous induced pluripotent stem cells-derived retinal pigment epithelial cells. December 7, 2011. MHLW Notification No. 1207e1. Standard for manufacturing control and quality control for medical devices and in-vitro diagnostic reagents. December 17, 2004. Ministerial Ordinance No.169. Standard for manufacturing control and quality control for drugs and quasidrugs. December 24, 2004. Ministerial Ordinance No.179. Standard for manufacturing control and quality control of investigational products. July 9, 2008. MHLW Notification No. 0709002. Points to consider on manufacturing and quality control of autologous cellular and tissue-based products. March 27, 2008. MHLW Notification No. 0327025.
Please cite this article in press as: Kusakabe T, Regulatory perspectives of Japan, Biologicals (2015), http://dx.doi.org/10.1016/ j.biologicals.2015.05.003
Contents lists available at ScienceDirect
Biologicals journal homepage: www.elsevier.com/locate/biologicals
Meeting report
Regulatory perspectives of Japan Tetsuya Kusakabe* Ministry of Health, Labour and Welfare, 1-2-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-8916, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 February 2015 Received in revised form 21 April 2015 Accepted 1 May 2015 Available online xxx
In this article, the 2013 regenerative medicine laws and regulations in Japan are addressed. The Regenerative Medicine Promotion Law was promulgated in May 2013 to promote comprehensive measures from research and development to practical use of regenerative medicines. In line with this purpose, two acts have been passed by the National Diet in November 2013. One is the Act on the Safety of Regenerative Medicine, which classifies regenerative medicines based on risk. Additionally this Act stipulates the procedures for offering regenerative medicines, the measures for appropriate provision of the regenerative medicines, and authorization to manufacture designated cellular therapeutic products for therapeutic use. The other is the Act on Pharmaceuticals and Medical Devices, previously named the Pharmaceutical Affairs Act, which establishes regulations tailored to the characteristics of regenerative medicinal products, including an expedited approval system.
Keywords: Regenerative medicine Cell and gene therapy Regenerative Medicine Promotion Law Act on the Safety of Regenerative Medicines Act on Pharmaceuticals and Medical Devices Expedited approval system
1. Introduction
2. Government's policy
Global competition in the development of advanced therapeutic products, including regenerative medicines, is becoming more and more intense. In order to accelerate the practical applications while maintaining the safety of the therapy, new regulations suited for the characteristics of these advanced therapeutic products are needed. Under these circumstances, the Regenerative Medicine Promotion Law [1] was promulgated in May 2013 to comprehensively promote such measures from research and development to practical use of regenerative medicines. The Regenerative Medicine Promotion Law was legislated by House members with the goal of promoting the development and application of regenerative medicines. In line with this purpose, the Act on the Safety of Regenerative Medicine [2] and the Act on Pharmaceuticals and Medical Devices [3], formerly the Pharmaceutical Affairs Act, were passed by the National Diet in November 2013 to create a stable framework of regulations for regenerative medicines and their products.
A priority of the Japanese government is accelerating the introduction of regenerative medicinal products into the market. In this plan, the cabinet offices will work out a strategy to take the initiative, and the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Ministry of Economy, Trade and Industry (METI), and the Ministry of Health, Labour and Welfare (MHLW) will collaborate to promote regenerative medicine policy. The government's priorities include: 1) integrated support from basic to clinical research, 2) development of infrastructure to promote regenerative medicines, and 3) supporting the use of induced pluripotent stem cells (iPS cells) as a drug-discovery tool. The goals for the next seven years are: 1) to apply new drugs developed by iPS cells technology in clinical trials, 2) to increase the number of approved cellular therapeutic products, 3) to expand the target illnesses for clinical trials, and 4) to develop equipment or devices related to regenerative medicines, etc. 3. New acts regulating regenerative medicines
Abbreviations: MHLW, Ministry of Health, Labour and Welfare; PMDA, Pharmaceuticals and Medical Devices Agency. * Tel.: þ81 3 3595 2436. E-mail address: [email protected].
There are two approaches to bringing regenerative medicines to patients. The Act on the Safety of Regenerative Medicine promotes usage of regenerative medicines within hospitals and clinics. The Act on Pharmaceuticals and Medical Devices promotes the development and manufacture of products by industry.
http://dx.doi.org/10.1016/j.biologicals.2015.05.003 1045-1056
Please cite this article in press as: Kusakabe T, Regulatory perspectives of Japan, Biologicals (2015), http://dx.doi.org/10.1016/ j.biologicals.2015.05.003
2
Meeting report / Biologicals xxx (2015) 1e3
Legislation of the Act on the Safety of Regenerative Medicine was needed because the guidelines are not based on the law. Also a growing need for collaboration between medical institutions and industry from the early stage of development existed. This Act will cover the study of medical technologies using processed cells, for which safety and efficacy have not been established. The therapy will be classified into one of three risk categories (Class I, II, and III). This classification is made on the basis of its potential impact on human health using a risk-based approach. High risk therapies such as those with products derived from iPS or embryonic stem (ES) cells are Class I. Medium risk therapies such as those with products derived from somatic stem cells are Class II. Low risk therapies such as those with products derived from somatic cells are Class III. Medical institutions are required to submit provisional plans to MHLW after the evaluation by the certified committee for regenerative medicine. The Act also requires hospitals and clinics to make regular reports to MHLW about the status of implementation (i.e., any adverse health events, etc.). Another important point is the expansion of facilities that can conduct cell processing outside of medical institutions. These facilities are required to obtain a license for quality and efficacy control, and meet standards set by MHLW. Additionally, the Act on Pharmaceuticals and Medical Devices has been recently amended to better consider the safety and risks of such products. One example is the conditional approval system. The Act introduced a new pathway to enable earlier patient access to regenerative medicinal products (Fig. 1). Specifically, this path is for the approval of products that have difficulty proving efficacy within a short timeframe. The demonstration of probable benefit (efficacy with a small patient population) and the safety (detection as well as evaluation of any adverse event) in the early phase of clinical trial will be considered sufficient for conditional approval for up to seven years, during which additional data on efficacy and safety will be collected. During this stage, informed consent is required and better applications for the product will be sought. After this phase, the marketing authorization holder submits an application for the second approval. The Pharmaceuticals and Medical Devices Agency (PMDA) will review the application prior to MHLW's final determination. Should the risks outweigh the benefits: i.e., the applicants fail to gather enough information or new information does not support their application, the authorization will be revoked. Should the benefits continue to outweigh
the potential risks, the second approval will be admitted. Informed consent is still required even after the second approval. 4. Regulatory framework of marketing authorization Marketing authorization of products derived from processed human cells/tissues is regulated by the Act on Pharmaceuticals and Medical Devices and related regulatory documents. There are four regulatory levels in Japan. First level is the Act on Pharmaceuticals and Medical Devices, the basis of regulatory framework. The second level are ministerial announcements such as Japanese Pharmacopoeia, Standards for Biological Ingredients, and Minimum Requirements for Vaccines, Antitoxins and Blood Products. The third level are ministerial ordinances, including Good Clinical Practice (GCP) and Good Post-Marketing Surveillance Practices (GPMSP). The last level are notifications or administrative letters which describes specific measures. The guidelines relating to cellular therapeutic products, including regenerative medicines, are announced or notified by MHLW. There are at least 18 guidelines listed: two guidelines for Good Tissue Practice (GTP) [4,5], twelve guidelines for product evaluation [6e17], and four guidelines for Good Manufacturing Practice (GMP) and Quality Management System (QMS) [18e21]. 5. Definitions of regenerative medicinal product and cell/ tissue processing The Act on Pharmaceuticals and Medical Devices defines “Regenerative Medicinal Products” in Chapter 1 Article 2e9. “Regenerative Medicinal Product” is a product that reconstructs, restores or reproduces the structure or functions of human or animal body (1-A), “Cell Therapy Product” is a product that treats or prevents disease in humans or animals (1-B), and “Gene Therapy Product” is a product intended to be used in the treatment of disease in humans or animals, and is transgened to express in human or animal cells (2). Chapter 1 Article 2e9 The term “Regenerative Medicinal Products” (as “SAISEI-IRYOUTOU-SEIHIN” in Japanese) used in this act refers to the articles (excluding quasi-drugs and cosmetics) specified in the following items which are specified by the cabinet order.
Fig. 1. Comparison of the old and new approval systems. The demonstration of probable benefit and the safety in the early phase of clinical trial will be considered sufficient for conditional approval. Should the benefit-risk assessment conclude a failure, the authorization will be revoked at the re-application process.
Please cite this article in press as: Kusakabe T, Regulatory perspectives of Japan, Biologicals (2015), http://dx.doi.org/10.1016/ j.biologicals.2015.05.003
Meeting report / Biologicals xxx (2015) 1e3
(1) The articles specified in the following items which are intended to be used in the medical treatment in humans or animals, and are cultured and/or processed human or animal cells. A: To reconstruct, restore or reproduce the structure or functions of human or animal body. B: To treat or prevent disease in humans or animals. (2) The articles which are intended to be used in the treatment of disease in humans or animals, and are transgened to express in human or animal cells. “Cell/Tissue Processing” is defined in the guidelines on Ensuring Quality and Safety of Products Derived from Processed Cell/Tissue [6,7]. It should be noted that whether the products are processed or not is judged on a case-by-case basis, and consultation with MHLW/ PMDA is strongly recommended. Cell/Tissue Processing Any processing of a cell or tissue with the aim of treating a disease, restoring or reconstructing tissue, including: -
propagation of a cell or tissue, pharmaceutical or chemical treatment to activate cell or tissue, altering a biological characteristic, combining with a noncellular component, manipulation by genetic engineering.
The isolation of tissue, disintegration of tissue, separation of cells, isolation of specific cells, treatment with antibiotics, washing, sterilization by g-irradiation, freezing, thawing, and such similar procedures are not considered to be processing. 6. Conclusions This article has addressed the new laws and regulations in Japan; the 2013 Regenerative Medicine Promotion Law, the Act on the Safety of Regenerative Medicine, and the Act on Pharmaceuticals and Medical Devices. In order to market the regenerative medicinal products in Japan, MHLW guidelines shall also be followed. These have been designed to better assure patient safety as more treatments become available. Collaboration between academia and industry during the early stages of research and development will also be improved.
3
References [1] [2] [3] [4] [5] [6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] [15] [16] [17]
[18]
[19] [20] [21]
Regenerative Medicine Promotion Law. May 10, 2013. Law No. 13. Act on the Safety of Regenerative Medicines. November 27, 2013. Law No. 85. Act on Pharmaceuticals and Medical Devices. November 27, 2013. Law No. 84. Standard for biological ingredients. May 20, 2003. Ministerial Announcement No. 210. General principles for the handling and use of cellular/tissue-based products. December 26, 2000. MHLW Notification No. 1314. Guideline on ensuring quality and safety of products derived from processed cell/tissue targeting for autologous. February 8, 2008. MHLW Notification No. 0208003. Guideline on ensuring quality and safety of products derived from processed cell/tissue targeting for allogeneic. September 12, 2008. MHLW Notification No. 0912006. Guideline on Ensuring the quality and safety of products derived from processed human stem cells targeting for autologous somatic stem cells. September 7, 2012. MHLW Notification No. 0907e2. Guideline on Ensuring the quality and safety of products derived from processed human stem cells targeting for allogeneic somatic stem cells. September 7, 2012. MHLW Notification No. 0907e3. Guideline on ensuring the quality and safety of products derived from processed human stem cells targeting for autologous iPS-like cells. September 7, 2012. MHLW Notification No. 0907e4. Guideline on ensuring the quality and safety of products derived from processed human stem cells targeting for allogeneic iPS-like cells. September 7, 2012. MHLW Notification No. 0907e5. Guideline on ensuring the quality and safety of products derived from processed human stem cells targeting for embryonic stem cells. September 7, 2012. MHLW Notification No. 0907e6. Points to consider for the evaluation of cell sheet for heart failure and corneal epithelial cell sheet. January 18, 2010. MHLW Notification No. 0118e1. Points to consider for the evaluation of corneal endothelial cell sheet. May 28, 2010. MHLW Notification No. 0528e1. Points to consider for the evaluation of articular cartilage repair. December 15, 2010. MHLW Notification No. 1215e1. Points to consider for the evaluation of cell sheet for periodontal tissue regeneration. December 7, 2011. MHLW Notification No. 1207e1. Points to consider for the evaluation of autologous induced pluripotent stem cells-derived retinal pigment epithelial cells. December 7, 2011. MHLW Notification No. 1207e1. Standard for manufacturing control and quality control for medical devices and in-vitro diagnostic reagents. December 17, 2004. Ministerial Ordinance No.169. Standard for manufacturing control and quality control for drugs and quasidrugs. December 24, 2004. Ministerial Ordinance No.179. Standard for manufacturing control and quality control of investigational products. July 9, 2008. MHLW Notification No. 0709002. Points to consider on manufacturing and quality control of autologous cellular and tissue-based products. March 27, 2008. MHLW Notification No. 0327025.
Please cite this article in press as: Kusakabe T, Regulatory perspectives of Japan, Biologicals (2015), http://dx.doi.org/10.1016/ j.biologicals.2015.05.003
