Detailed revisions to the subordinate regulation following the amendment of the Act on the Safety of Regenerative Medicine in Japan

Abstract

The amended Act on the Safety of Regenerative Medicine (RM Act) in Japan expands its scope to include in vivo gene therapy and related technologies, classifying them into Class I, the highest-risk category. Furthermore, the amended RM Act introduces additional requirements, such as proper conflict of interest management and a specific evaluation of the scientific validity of provision plans by Certified Committees for Regenerative Medicine to ensure a fair review. These detailed regulatory amendments will be stipulated in the cabinet order and the ministerial ordinance, which are subordinate to the law. The amendments are set to take effect on May 31, 2025. This article provides a detailed overview of the amendments introduced under the RM Act.

Highlights

• •The amended Act is set to take effect on May 31, 2025, in Japan.
• •In vivo gene therapy and related technologies are classified into Class I risk.
• •Requirements for proper COI management and scientific validity evaluation at CCRMs are introduced.
• •Further discussions will be encouraged for the next two- and five-year review framework.

1. Introduction

The Act on the Safety of Regenerative Medicine (RM Act) was enacted in 2014 to establish a foundation for the safe provision of regenerative medicine (RM) and to promote further research and development in Japan [1]. Unlike in other countries, medicine using technologies involving unapproved cellular products, which refer to those not approved under the Pharmaceuticals and Medical Devices Act (PMD Act), are subject to regulation under the RM Act. Recognizing the continuous innovation in medicine and research, the law included a provision requiring a review of necessary amendments within five years of its enforcement. Subsequently, discussions on amendments began in 2019, leading to the “Summary of the Review of the Act on the Safety on the Safety of Regenerative Medicine, Five Years After Its Enforcement” (“the Summary”) in June 2022 [2,3].

Based on the Summary, the amended law was promulgated on June 14, 2024, and is set to take effect on May 31, 2025. A key amendment is the inclusion of gene therapy that does not involve processed cells (“in vivo gene therapy”) and related technologies under the RM Act [4]. Another major amendment involves the establishment of on-site inspections and disqualification criteria for Certified Committees for Regenerative Medicine (CCRM) to ensure a fair and transparent review process. Furthermore, based on the Summary, the governmental advisory board, the Regenerative Medicine Evaluation Committee (RMEC) of the Health Science Council (HSC), has discussed various aspects of the amended law, including the legal scope of medicine using technologies involving “Nucleic Acids and the Related Compounds (NARCs)”, their risk classification, review processes required for gene therapy, revisions to conflict-of-interest management at CCRMs, and the clinical evaluation methods for assessing the scientific validity of RM provided as private practice [5,6].

Following these discussions and the Summary, detailed regulatory amendments to the cabinet order and the ministerial ordinance supplementing the law have been promulgated. This article provides an overview of these detailed amendments under the RM Act.

2. Detailed provisions of the subordinate regulation of the RM Act before the amendment

Under the RM Act, RM using regenerative medical technologies are classified into three categories based on their associated risks. Particularly high-risk RM, such as those utilizing pluripotent stem cells (e.g., induced pluripotent stem cells and embryonic stem cells), allogeneic cells, or animal cells, are classified as Class I. Each RM Provision Plan must undergo review by a CCRM for Class III RM or a Specific CCRM (SCCRM) for Class I and II RMs. Additionally, for Class I RM, the RM Provision Plan must adhere opinions from the RMEC of the HSC, a governmental advisory board, before clinical implementation (Fig. 1(A)). Furthermore, processed cells must be manufactured at manufacturing facilities that have been permitted, certified, or notified under the RM Act. These legal frameworks collectively regulate unapproved RM by establishing various provisions for medical institutions providing RM, CCRMs, and the manufacturing facilities. (Fig. 1(B)) [7].

Fig. 1.

Regulatory Overview of the Act on the Safety of Regenerative Medicine. (A) Procedures based on the risk classification. (B) The review process for RM Provision Plans. ESC, embryonic stem cell; iPSC, induced pluripotent stem cell; NARCs, Nucleic Acids and the Related Compounds; CCRM, Certified Committee of Regenerative Medicine; MHLW, Ministry of Health, Labour and Welfare; SCCRM, Specific Certified Committee of Regenerative Medicine; RM, Regenerative Medicine.

The detailed regulations governing the implementation of the RM Act are stipulated in subordinate legal frameworks, including the cabinet order and the ministerial ordinance (Fig. 2). The cabinet order primarily defines the scope of the medical technologies subject to the RM Act. Specifically, certain medical technologies utilizing cells, such as transfusion, hematopoietic stem cell transplantation, and assisted reproductive technology, are explicitly exempted from the law's application. Meanwhile, the ministerial ordinance provides specific regulations concerning RM provision, as well as the requirements for CCRMs and the manufacturing facilities. The chapter on the Provision of RM outlines the necessary content of an RM Provision Plan, the procedures for its submission, and the obligation to provide regular reports on its implementation status. The chapter on CCRMs details requirements for organizations establishing committees and committee members, and the standards that must be upheld to ensure an appropriate review process, including requirements for convening review meetings. Additionally, the chapter on the manufacturing facilities specifies requirements for notification, permission and certification applications, facility structures and equipment, and manufacturing management practices.

Fig. 2.

Legal system of the Act on the Safety of Regenerative Medicine. RM, Regenerative medicine; The Minister of HLW, The Minister of Health, Labour and Welfare; CCRM, Certified committee of regenerative medicine; NARCs, Nucleic Acids and the Related Compounds.

Then, we provide an overview of the newly introduced regulations, categorizing them into two main areas: (1) provisions related to in vivo gene therapy and medicine using the related technologies, which has now been included within the legal regulatory scope following the recent amendment, and (2) newly established provisions necessary for the appropriate implementation of other RM practices. The summaries of amendments regarding in vivo gene therapy and related technologies and those regarding other points are shown Table 1, Table 2, respectively.

Table 1.

Amendments regarding in vivo gene therapy and related technologies.

Amendment items	Brief contents	Regulation	Regulation targets
New scope of the RM Act	- The amended RM Act newly targets;a . in vivo gene therapy (gene transfection or modification within the body) . Medicine using the related technologies (such as technologies delivering mRNA or applied genome-editing enzymes into human body)	Cabinet order	Medical institutions
Risk classification of in vivo gene therapy and medicine using related technologies gene therapy and medicine using related technologies	-Medicine using technologies involving NARCs, are classified into Class I, the highest-risk category, of the RM Act.	Ministerial ordinance	Medical institutions
Requirements for SCCRMs reviewing RM provision plans related to in vivo gene therapy and medicine using related technologies gene therapy and medicine using related technologies	- The SCCRMs need to include following members; . Expert(s) with substantial scientific knowledge and insight regarding the effects of gene therapy on humans . Expert(s) with expertise in handling recombinant organisms, particularly those involved in the manufacturing of viral vectors using recombinant DNA technology	Ministerial ordinance	SCCRM
Standards for the manufacturing facilities producing NARCs	-No additional requirements in the structural and equipment standards have been confirmed, compared to the facilities producing processed cells. -The facilities need to undergo on-site inspections by the PMDA to obtain permission or certification from the Minister of HLW.	Ministerial ordinance	The manufacturing facilities
Unapproved vaccines utilizing NARCs for the prevention of infectious diseases	-Unapproved vaccines under the PMD Act can be exempt from the RM Act if they got pharmaceutical approval in specific countries and the HSC acknowledges the appropriateness of the exemption.	Cabinet order	Medical institutions

Abbreviations: RM Act; Act on the Safety of Regenerative Medicine, mRNA; messenger ribonucleic acid, NARCs; Nucleic Acids and the Related Compounds, SCCRM; Specific certified committee of regenerative medicine, DNA; deoxyribonucleic acid, RM; regenerative medicine, PMDA; Pharmaceuticals and Medical Devices Agency, the Minister of HLW; the Minister of Health, Labour and Welfare, PMD Act; Pharmaceutical and Medical Device Act, HSC; Health Science Council.

^aMedicine using extracellular vesicles, oligonucleotide therapeutics (such as micro RNA/silent interfering RNA) and genome-edited-fertilized embryo are out of the scope.

Table 2.

Amendments regarding other points.

Amendment items	Brief contents	Regulation	Targets
Proper management of conflicts of interest in CCRMs	-Committee members with conflicts of interest involving third parties related to the RM provision plan cannot participate in the plan's review at CCRMs. -The details of any services received from such third parties need to be specified in the RM provision plan. -CCRMs must properly retain documents confirming conflicts of interest.	Ministerial ordinance	CCRMs
Evaluation of scientific validity of RMs	-RM provision plans must explicitly include evaluation criteria for scientific validity, including the expected efficacy. -Annual reports to CCRMs must now include treatment outcomes assessed against the scientific validity criteria.	Ministerial ordinance	Medical institutions
Handling of medicine using technologies involving processed cells or NARCs with medical devices	-Medicine using technologies involving processed cells or NARCs with approved medical devices including their indicated use under the PMD Act have been out of scope of the RM Act.	Cabinet order	Medical institutions
Revision of principal investigators' responsibilities in research plans	-Responsibilities regarding research procedures, such as preparation of research protocols and monitoring, have been reassigned from the administrator to the principal investigator.	Ministerial ordinance	Medical institutions
Additional requirements for the use of animal-derived cells	-Provisions for measures to prevent microbial contamination of donor animals during the breeding process and the obligation of confirming its records have been specified.	Ministerial ordinance	Medical institutions The manufacturing facilities

Abbreviations: RM Act; Act on the Safety of Regenerative Medicine, RM; regenerative medicine, CCRM; certified committee of regenerative medicine, NARCs; Nucleic Acids and the Related Compounds, PMD Act; Pharmaceutical and Medical Device Act.

3. In vivo gene therapy and medicine using the related technologies

3.1. New scope of the RM act

A recent legal amendment has extended the scope of medicine covered under the act to in vivo gene therapy and medicine using the related technologies. Specifically, the revised RM Act covers the following medicine using the technologies involving NARCs. This amendment is based on the discussion that in vivo gene therapy has clinical challenges such as safety and ethical issues, genetic impact on next generations, and impact on biodiversity by virus vectors, similar to those associated with ex vivo gene therapy, which is already subject to regulatory oversight.

• •
  In vivo Gene Therapy:

  • ○
    Medicine using technologies involving gene transfection into human cells within the human body (e.g., introducing a defective gene via a viral vector)
  • ○
    Medicine using technologies involving gene modification of human cells within the human body (e.g., gene deletion using enzymes required for the CRISPR-Cas9 system)
• •
  Medicine using the Related Technologies, such as:

  • ○
    Medicine using technologies delivering applied genome-editing enzymes directly into the human body (e.g., epigenome editing using enzymes required for the CRISPR-dCas9 system)
  • ○
    Medicine using technologies delivering messenger ribonucleic acid (mRNA) directly into the human body (e.g., introducing mRNA through lipid nanoparticles to activate immune responses against cancer)

Conversely, the following medicines remain outside the scope of the amended RM Act.

• •Medicine using the ribonucleic acid interference technology, including micro ribonucleic acid or small interfering ribonucleic acid
• •Medicine using extracellular vesicles, such as exosomes
• •Medicine using technologies applying genome-editing techniques to fertilized embryos or germ cells

3.2. Risk classification of in vivo gene therapy and medicine using related technologies

Under the revised RM Act, in vivo gene therapy and medicine using related technologies have been categorized as Class I RM, the highest-risk classification. This designation is based on the discussion that these medicines using such technologies pose risks similar to those associated with ex vivo gene therapy. The primary risks include oncogenicity, transmission of infectious diseases, and immunogenicity.

As a result of this classification, any provision of medicine using technologies involving NARCs, must undergo a review process by the SCCRM and adhere additional opinions from the RMEC of the HSC before implementation. Furthermore, where applicable, medical institutions and the manufacturing facilities must complete the necessary approval procedures from the competent minister under the Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms (the Cartagena Act), in addition to complying the requirements under the RM Act.

3.3. Requirements for SCCRMs reviewing RM provision plans related to in vivo gene therapy and medicine using related technologies

SCCRMs intending to review RM Provision Plans related to gene therapy must now obtain certification from the Minister of Health, Labor, and Welfare (MHLW). In addition to the conventional membership requirements, these committees must include the following members.

• •Expert(s) with substantial scientific knowledge and insight regarding the effects of gene therapy on humans.
• •Expert(s) with expertise in handling recombinant organisms, particularly those involved in the manufacturing of viral vectors using recombinant DNA technology.

Previously, under the RM Act, SCCRMs were required to include a member with expertise in manufacturing processed cells. However, with the recent amendment expanding the RM Act to include gene therapy without the use of processed cells, this requirement has been revised to evaluate quality and safety of the provision plans from the viewpoint of viral vectors and effects of gene therapy on humans. Committees must now include a member with expertise in manufacturing each modality (proposed cells or NARCs) under review.

3.4. Standards for the manufacturing facilities producing NARCs

Following discussions within the RMEC, the structural and equipment standards for the manufacturing facilities producing NARCs, as well as compliance requirements for operators, have been confirmed as appropriate and consistent with those for facilities manufacturing processed cells. Consequently, no additional requirements have been introduced in the ministerial ordinance.

Additionally, facilities manufacturing NARCs must undergo on-site inspections by the Pharmaceuticals and Medical Devices Agency to obtain either permission for domestic facilities or certification for overseas facilities from the MHLW. However, the exception already applies to facilities manufacturing processed cells, allowing them to operate through notification to the MHLW instead of requiring permission in the following cases.

• •Facilities located within a hospital or clinic.
• •Facilities that have already obtained manufacturing permission under the PMD Act.

This exception has now been extended to the manufacturing facilities that produce NARCs.

3.5. Unapproved vaccines utilizing NARCs for the prevention of infectious diseases

A new provision has been established to exempt certain vaccines using NARCs from the RM Act's application under specific conditions. This exemption applies to vaccines that.

• •Lack of pharmaceutical approval under the PMD Act for preventing infectious diseases.
• •Have been approved in designated countries (United States, United Kingdom, Canada, Germany, and France).
• •Are deemed appropriate for exemption by the HSC.

For the purpose of public health control, this exemption primarily applies to vaccines used by overseas travelers and for emergency management purposes. Designated vaccines under this provision may continue to be provided without undergoing RM Act procedures, as was the case before the legal amendment. This includes distribution through physician-led personal importation.

4. Necessary regulations for the Proper Implementation of other RM technologies

4.1. Proper management of conflicts of interest in CCRMs

Under the pre-amendment ministerial ordinance, regulations required the confirmation of conflicts of interest between the medical institution submitting an RM Provision Plan and committee members. However, concerns have recently arisen regarding cases where third parties providing benefits to both the institution and committee members were suspected of having conflicts of interest. To enhance fairness in the review process within CCRMs, the following new regulations have been introduced:

First, committee members with conflicts of interest involving third parties providing services, such as the preparation of the RM Provision Plan under review, are prohibited from participating in that plan's review. Second, a medical institution's administrator must specify the details of any services received from such third parties in the plan, including the identity of the service provider. Third, committees must properly retain documents confirming conflicts of interest among their members and maintain records of any involvement by committee operational support personnel in the review process. Additionally, every summary of the review process must be uniformly published on the “e-Regenerative Medicine,” website (URL: https://saiseiiryo.mhlw.go.jp/), managed by the MHLW.

Before the ministerial ordinance amendment in May 2024, the MHLW had published the “Guidance on the Proper Implementation of Review Processes in Certified Committees for Regenerative Medicine” (the Guidance) (in Japanese) [8]. This guidance aims to enhance the quality and fairness of CCRM review processes by providing clear review perspectives including safety and validity perspectives and conflict of interest management guidelines. CCRMs are required to adhere to this guidance in both their operations and review processes. Following these regulatory revisions, CCRMs must continue to ensure fair and high-quality reviews of RM Provision Plans.

4.2. Evaluation of scientific validity of RMs

Concerns have been raised about cases where the scientific validity of RM provided in private practice lacked sufficient justification, particularly regarding their efficacy and safety. To promote proper evaluation during the review process of RM Provision Plans, the following revisions have been introduced. Specifically, RM provision plans must now explicitly include evaluation criteria for scientific validity, particularly regarding the expected efficacy of the RM being provided, which needs to be reviewed in CCRMs. Additionally, annual reports submitted by medical institutions to CCRMs must include treatment outcomes assessed against the scientific validity criteria specified in the RM provision plan. Furthermore, CCRMs must review these annual reports and assess the appropriateness of continuing the RM Provision Plan, referring to the Guidance on review procedures. MHLW will assess the effects of these amendments and consider additional measures as necessary to ensure the appropriate provision of RM.

4.3. Handling of medicine using technologies involving processed cells or NARCs with medical devices

Medicine using technologies involving RM products approved under the PMD Act provided they adhere to their approved dosage and administration, are already excluded from the RM Act's scope. With the recent cabinet order amendment, this exemption has been extended. Specifically, Medicine using technologies involving processed cells or NARCs in combination with medical devices that have obtained pharmaceutical approval, including their indicated use under the PMD Act, are now also exempted from the RM Act's provision, as their efficacy and safety have been confirmed under the PMD Act.

4.4. Revision of principal investigators’ responsibilities in research provision plans

Under the previous ministerial ordinance, responsibilities related to research procedures, such as preparing research protocols, monitoring, auditing, developing a conflict of interest management plan, and disclosing research plan information, were assigned to the medical institution's administrator. However, with the latest amendment, these responsibilities have been reassigned to the principal investigator conducting the research, aligning the regulation with actual research practices.

4.5. Additional requirements for the use of animal-derived cells

New requirements have been introduced concerning the procurement and management standards for animal-derived cells used in RM. Specifically, medical institution administrators must now confirm that appropriate measures have been taken to prevent microbial contamination of donor animals during the breeding process. Additionally, new manufacturing management standards have been established for the manufacturing facilities using animal-derived cells. These facilities must confirm that measures are in place to prevent microbial contamination during cell collection, create records of this confirmation, and retain these records along with supporting documentation. Since the RM Act covers xenotransplantation [9], any provision plans involving xenotransplantation must also comply with these newly established regulations.

5. Conclusion

The amended cabinet order was promulgated on December 6, 2024, and the amended ministerial ordinance on February 28, 2025. Both are set to take effect on May 31, 2025, in alignment with the enforcement of the amended RM Act in Japan. The amended RM Act also includes the following review provisions: a five-year review framework to evaluate the RM Act, considering innovation in RM, and a two-year review framework to assess the adequacy of legal provisions—including the RM Act—governing highly advanced medicine using technologies involving RM, such as those utilizing cell secretions (extracellular vesicles) or genome-edited fertilized embryos.

Following the enforcement of the amended RM Act, newly regulated medicine using technologies involving NARCs including those provided as private practice, can be mentioned similarly to medicine using technologies involving processed cells [10,11]. Looking ahead, further constructive discussions should be made to ensure the safe and efficient implementation of RM technologies, considering the status of legal enforcement and its practical applications.

Author contributions

SH: conceptualization, methodology, investigation, writing – original, project administration, draft YU: conceptualization, writing – review and editing KM: conceptualization, writing - review and editing EM: conceptualization, writing - review and editing JS: conceptualization, writing - review and editing MH, conceptualization, writing - review and editing, supervision.

All authors confirmed the final version of the manuscript.

Declaration of generative AI and AI-assisted technologies

During the preparation of this work the authors used ChatGPT for proper translation. After using this tool, the authors reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Declaration of competing interest

The following authors are affiliated with the following organizations without compensation.

SH: The Jikei University School of Medicine, National Center for Child Health and Development, YU: Osaka University, KM: Institute of Science Tokyo.