Regulatory insights on gene therapies, adeno-associated virus-based gene therapies, cell/tissue-based products, and medical care/practice in cell and gene therapies: Report from the 7th Asia partnership conference - April 25, 2024

Abstract

The 7th Asia Partnership Conference of Regenerative Medicine (APACRM) was held both in person and online on April 25, 2024, to promote the regulatory harmonization of regenerative medicine products across Asia. Recognizing domestic regulatory guidelines and their underlying rationales within each country and region is an important initial step toward achieving harmonious regulation. The 7th APACRM featured open dialogues on the non-clinical evaluations of adeno-associated virus gene therapy products, regulation of gene therapies, considerations for conducting clinical trials, and provision of cell and gene therapies as medical practices without market authorization. These discussions included presentations by industry experts and panel discussions with regulatory agencies. The latest updates on regenerative medicine from each country and region were also introduced. This paper summarizes the proceedings of the 7th APACRM to foster future discussions and disseminate information to the public.

1. Introduction

The Asia Partnership Conference of Regenerative Medicine (APACRM) was established in 2018 to optimize and harmonize regulations for regenerative medicine (RM) across Asian countries and regions. This included aspects such as quality control of the final products and raw material requirements for preclinical evaluation, manufacturing, patient eligibility, and clinical safety. Leading industry associations for RM in Asia have contributed to this forum (Fig. 1). Although RM is usually defined narrowly as cell therapy, tissue engineering products, and human cells or tissue products, it has been expanded to include in vivo or ex vivo gene therapy products. The broader mission of APACRM is to support the development and delivery of high-quality RM products to Asian patients.

Fig. 1.

Participating members of APACRM: Association of Biotechnology Led Enterprises (ABLE, India); China Medicinal Biotech Association (CMBA, China); Biotechnology and Pharmaceutical Industries Promotion Office (BPIPO, Taiwan); Singapore Association of Pharmaceutical Industries (SAPI, Singapore); Regenerative Medicine Acceleration Foundation (RMAF, Korea); The Council for Advanced Regenerative Medicine (CARM, Korea); and the Forum for Innovative Regenerative Medicine (FIRM, Japan).

The 7th APACRM meeting was held in a hybrid format, both online and onsite, on April 25, 2024, with 89 online and 205 virtual participants. In addition to the six county or regional industry associations, the event attracted many regulators from Asian countries and regions, including India, Japan, Korea, Malaysia, the Philippines, Singapore, Taiwan, and Vietnam. Health authority regulators from each country and region joined the discussions as panelists and provided comments and insights.

This paper summarizes the contents of the 7th APACRM, particularly focusing on discussions with regulators, based on the survey results of three working groups (WGs): WG1 for non-clinical assessments of adeno-associated virus (AAV), WG3 for regulation of gene therapy products, and CT-WG for considerations in clinical trials and relevant regulations, and future business opportunities for processed cells in regulatory categories different from that of typical RM products.

2. Program & session summaries

The 7th APACRM comprised five sessions (Supplementary Table 1).

2.1. Session 1: update on regenerative medicine from each industrial association

In the first session, an array of topics on RM from each country and region was shared through sequential presentations.

2.1.1. Japan

Takayuki Nakano, a presenter from FIRM, provided updates on RM product pipelines, pricing systems, future directions, and support for strengthening RM startups.

As of March 2024, Japan had approved 20 regenerative medical products, primarily tissue and cell transplants, with increasing numbers of chimeric antigen receptor (CAR)-T cells and in vivo gene therapies, mostly by foreign companies. Although regenerative medicine is expanding in Japan, no domestically produced product has received international approval.

Comparing Japan's pipeline with that of the US and Europe, the lack of growth in domestically developed drugs is concerning. Of the 56 products launched in these regions by 2023, 35 were not developed in Japan, highlighting the need to address this gap and address the unmet medical needs.

In Japan, National Healthcare Expenditure, which covers prescription medication costs, accounts for approximately 20 % of the total at ¥9 trillion. However, the highest sales of regenerative medical products have only reached ¥3.5 billion, a fraction of this amount. One reason for this discrepancy is the current pricing system, which does not adequately reflect the unique cost structure of regenerative medical products compared to that of traditional pharmaceuticals. Addressing this issue is crucial for properly valuing innovation, and can influence the growth of the pharmaceutical industry. FIRM is actively lobbying the Japanese government for change, and its efforts have led to some of its recommendations being incorporated into Japan's Basic Policy 2023.

In Japan, startups and academia are the key drivers of innovation in regenerative medicine, often creating initial product concepts. Japan excels in basic and early clinical research, which is vital for successful product commercialization. However, a gap exists in provision of support during the early development phase, known as the “Death Valley,” where funding for advancing basic research to the clinical stage is scarce.

Even when research progresses to candidate creation, significant investment is required to establish the appropriate manufacturing processes. Private venture capital funding is limited, likely because of uncertainties. Governmental support exists but is not yet optimally allocated, and thus, support from the pharmaceutical industry is crucial for bridging this gap.

FIRM is actively working with the government to address these challenges by providing matching support and forums for venture establishments. The government is aware of these issues and is working to enhance its support schemes through ongoing collaboration between FIRM and governmental bodies.

2.1.2. China

Eugene J. Wang, chief executive officer of HELP Therapeutics shared an update on RM regulations, standards, and industry developments as a presenter from CMBA.

The Center for Drug Evaluation (CDE) of the NMPA in China released two guidelines in 2023 to expedite the development of gene and cell therapies. The first guideline addresses clinical trials for human stem cells and related cell therapy products [1], while the second focuses on clinical communication for gene and cell therapy products [2]. Additionally, the National Health Commission in China has issued guidelines [3] to refine investigator-initiated trials (IIT) for somatic cell therapies, clarifying that somatic cell products are ineligible if similar products are in or have completed drug clinical trials. These guidelines also outline the regulatory requirements for medical institutions, preclinical research, clinical protocols, and ethical standards.

In the regenerative medicine updates from the last year in China, the CDE has approved several therapies. Fucaso, co-developed by IASO Biotherapeutics and Innovent, is an autologous CAR-T cell therapy that targets B-cell maturation antigens for treating multiple myeloma and autoimmune diseases. Inaticabtagene autoleucel, developed by Juventus, is a CD19 CAR-T cell therapy designed to treat B-cell acute lymphoid leukemia (ALL) and is the first commercialized CAR-T cell therapy in China. Further, an autologous B-cell maturation antigen (BCMA)-targeted CAR-T cell therapy has been developed by CARsgen Co. For adults with relapsed or refractory multiple myeloma after at least three prior therapies.

Additionally, nine clinical trials in phase II or III are ongoing for mesenchymal stem cell-based products for various conditions, including graft versus host disease (GvHD), osteoarthritis, and chronic bronchitis. Further, five trials are ongoing for induced pluripotent stem cell-based therapies, mostly in phase I or II, targeting conditions such as advanced heart failure, post-stroke hemiplegia, osteoarthritis, critical lower-limb ischemia, and acute ischemic stroke.

The regenerative medicine industry in China has undergone significant updates. Wang introduced three notable companies: IASO Bio, a biopharmaceutical company focused on novel cell therapies and biologics for oncology and autoimmune diseases, with capabilities ranging from discovery to commercial production; Juventas Cell Therapy, specializing in R&D and commercialization of immune cell therapies, aiming to be a leader in the clinical transformation of cell therapies, and HELP Therapeutics, a clinical-stage biotech company developing treatments for degenerative diseases. The company's leading pipeline, an iPSC-based cardiac regenerative therapy, has recently announced clearances of IND in both China and the United States. They have shown promising results in treating heart failure using iPS cell-derived cardiomyocytes, including improved heart function and quality of life in patients.

2.1.3. Korea

Bryan Choi, a presenter from CARM and RMAF, provided an update on the progress of the RM industry in Korea.

The Advanced Regenerative-Bio Act, enacted in Korea in 2020, established a dual regulatory framework: one for the Clinical Research of Advanced Regenerative Medicine (ARM) overseen by the Ministry of Health and Welfare (MOHW) and another for the Commercial IND Process of Advanced Biological Products (ABPs) managed by the Ministry of Food and Drug Safety (MFDS). Since 2005, the MFDS has released numerous technical guidelines with a significant update following enactment of the law, particularly concerning gene therapies from 2023.

The MFDS actively provides information services, education, training, and consultations, with the Regulatory Science Center playing a pivotal role. The center also publishes “Advanced Bio-Focus,” a monthly electronic magazine featuring updates on global Cell and Gene Therapies (CGTs).

The RMAF supports the MOHW in ARM-related activities including policymaking and industry promotion (https://www.rmaf.kr/). The MOHW also operates the K-ARM portal, which offers resources and data for ARM-related clinical research (https://www.k-arm.go.kr/main.do).

The Korean Congress approved significant revisions to the Advanced Regenerative-Bio Act in February 2024. These changes removed the disease limitations previously restricted to life-threatening or incurable conditions, and allowed paid treatments for such diseases following safety and efficacy confirmation in the Clinical Research. The MOHW has been developing detailed regulations and processes to address these changes.

Last year, CARVYKTI, a CAR-T therapy, was the only product that received market approval in Korea, marking the first approval since the latest product of CartiLife in 2019. Numerous companies are developing gene therapies, including CAR-T and iPSC-based products, with domestic approvals expected soon.

Regarding CGT product reimbursement, Luxturna initially failed to secure the National Health Insurance coverage, but succeeded in April 2024. The treatment cost is approximately $250,000 per eye, with patients paying up to $7500. The coverage for CARVYKTI is still under review.

As of December 2023, Korea had 1240 Sponsor-Initiated Trials (SITs) and 134 Investigator-Initiated Trials (IITs) for cell therapy clinical trials, with 79 SITs and 9 IITs ongoing. Most of these trials are on stem cells and immune cells, whereas a few trials involve xenogeneic cells. For gene therapy clinical trials, there were 104 SITs with 65 products and 16 IITs with 8 products, and 29 SITs and 4 IITs are currently active. Naked plasmids and adenovirus vectors are prevalent for in vivo gene therapies, whereas retro- and lenti-vectors are used dominantly for ex-vivo therapies.

Since the enactment of the Advanced Regenerative Bio Act, 93 institutions, mainly universities and general hospitals, have been certified for the ARM Clinical Research. As of April 2024, there have been 42 applications for clinical research, with 29 for cell therapies and 6 for gene therapies, categorized by risk as follows: 21 high, 13 medium, and 8 low. High-risk therapies underwent MFDS review after committee approval, with 7 approved, 5 rejected, and 9 under review.

In November 2020, CARM became legally affiliated with the MOHW. Since then, CARM has actively engaged in both domestic and international activities.

2.1.4. India

Pawan Kumar Gupta of ABLE in India provided an update on the regenerative medicine regulations in the country.

There are no definitive regulations for regenerative medicine in India. National guidelines are available for stem cell research, gene therapy, hematopoietic stem cell transplantation (HSCT), and umbilical cord banking developed by Indian Council of Medical Research (ICMR), Department of Biotechnology (DBT), and Indian Food and Drug Administration (FDA).

The New Drug and Clinical Trial Rules 2019 issued by the Indian FDA classify substantially manipulated or genetically engineered products as new drugs, which necessitates regulatory approval. Products with minimal manipulation may not require such approval. These rules ensure that regenerative therapies meet safety and efficacy standards before clinical use.

The regulatory processes for stem cell and gene therapy products in India includes obtaining Ethics Committee approval, submitting applications to the Indian FDA, and potentially, additional approvals for gene therapies. The approval process involves specific forms and reviews by expert committees, with a typical timeline of about 3–4 months for clinical trial approval.

Manufacturers must secure Good Manufacturing Practice (GMP) facility approval and undergo inspections before manufacturing test batches. After preclinical studies, the same application process is followed, leading to marketing authorization. Importers follow a similar process, but with a longer approval timeline. Clinical trials are required for new drugs, with Phase I trials needed for Indian discoveries and at least Phase III trials for international drugs to ensure efficacy and safety in the Indian population.

Special provisions allow accelerated approval for serious or rare diseases, conditional approval based on phase IV study results, and waivers from local clinical trials for drugs approved in certain countries. These regulations ensure that the drugs meet Indian standards prior to marketing and use.

India has introduced new rules under the CDSCO to expedite the use of treatments for areas with unmet medical needs. A document released by the ICMR titled “Evidence based status of stem cell therapy for human diseases” provides recommendations on whether stem cells can be used for ten different diseases. The ICMR only recommends the use of stem cells in approved indications of HSCT and other indications if approved by regulatory agencies. The National Medical Council, which enforces high ethical standards in all aspects of medical services, advises against stem cell therapy for autism spectrum disorder (ASD), labeling it professional misconduct unless it is part of a controlled trial.

Approved therapies in India include cultured osteoblasts for hip-bone necrosis, chondrocytes for knee cartilage defects, dendritic cell immunotherapy for ovarian and lung cancers, and mesenchymal stromal cells for chronic limb-threatening ischemia and osteoarthritis of knee. The first CAR-T cell therapy, NexCAR19, has been approved for B-cell leukemia and lymphoma, along with anti-CD19 CAR-T cells for non-Hodgkin's lymphoma.

Ongoing clinical trials include CAR-T cells for multiple myeloma, gene therapies for hemophilia and thalassemia, and mesenchymal stem cells (MSCs) for diabetic foot ulcers and Crohn's disease-related perianal fistulas.

2.1.5. Taiwan

Chia-Ning Shen, a research fellow/Professor at the Genomics Research Center, Academia Sinica on behalf of the BPIPO, presented the status of cell therapy and RM in Taiwan.

He emphasized strategic advantages in Taiwan, including its geographic location, robust healthcare system, comprehensive health database, innovative R&D environment, manufacturing expertise, and strong regulatory support for cell and gene therapies. He also highlighted the growth and achievements of regenerative medicine in Taiwan, citing the number of trials, coverage of CAR-T treatment by the national health insurance, and ongoing autologous cell therapy projects.

The CellTech Innovation Venture Studio was established to promote innovation in cell and gene therapy, facilitating the translation of new cell therapeutic techniques from basic research to commercialization.

Taiwan's expertise in ICT and automated manufacturing positions it favorably for establishing high-standard equipment, digital monitoring, and logistics systems for the regenerative medicine industry. These include advanced cell-processing units that integrate these technologies. In addition, its skilled workforce ensures high-quality control in manufacturing, making it an ideal location for the growth of regenerative medicine.

The Taiwanese government is actively preparing for advancements in regenerative medicine by revising the biotechnology and new drug industry laws. Two draft acts are in the legislative process for enhancing regulation. A dual-track regulatory system has been established in which low-risk cell therapies are governed by medical practice regulations. These therapies adhere to the Good Tissue Practice (GTP) and GMP standards and are registered under specific medical exemption laws, with potential to be classified as pharmaceuticals or biologics. The Autologous Cell Therapy Regulation has been passed to allow the use of low-risk cell therapies for urgent medical needs.

Over 300 autologous cell therapy projects are currently underway in Taiwan. Additionally, more than 120 clinical trials in regenerative medicine are in progress, including 33 gene therapy trials for rare diseases and cancer and 87 cell therapy trials for cancer, neurological diseases, and cardiovascular diseases. Some have progressed to phases two or three, showing initial safety and benefits.

Taiwan is fostering an ecosystem to support the development of regenerative medicine that encompasses basic research, regulatory and policy frameworks, market and business development services, preclinical and clinical trial management, quality control, CDMO services, and automated platforms for product development.

Taiwan has established the Industry Cloud Alliance for Regenerative Medicine (iCARM) to gather essential resources for the regenerative medicine sector. iCARM consists of the top regenerative medicine institutes and tech companies in Taiwan and provides a cloud system that allows research teams and startups to conveniently access the resources necessary for their technological and product development.

2.1.6. Singapore

Srinivasan Kellathur from SAPI presented an overview of the ecosystem for Cell, Tissue, and Gene Therapy Products (CTGTPs) in Singapore.

The Health Sciences Authority (HSA) in Singapore implemented regulations for CTGTPs in March 2021 under the Health Products Act. These regulations cover the entire product life cycle, including clinical trials, product registration, dealer licensing, post market vigilance and surveillance, and adverse event reporting.

CTGTPs are risk-stratified into two classes: Class 1 and Class 2. Class 1 CTGTPs are low-risk and satisfy all the following criteria: minimally manipulated, intended for homologous use, not combined, or used in conjunction with therapeutic products or medical devices. Examples of Class 1 CTGTPs include bone grafts and amniotic membranes. Class 2 CTGTPs are higher-risk products that do not fulfill the criteria for Class 1 CTGTPs. Examples of Class 2 CTGTPs are genetically modified cell-s and culture-expanded cells.

Class 1 CTGTP dealers are required to submit a notification for activities related to manufacture, import, and supply, while Class 2 CTGTPs require the respective dealer licenses and adherence to GMP or GDP standards.

For product marketing, Class 1 products should be notified and receive acceptance of notification from HSA prior to supply. Class 2 products must undergo registration, organized in either an International Council for Harmonization Common Technical Document (ICH CTD) or ASEAN CTD (ACTD) format supported by CMC, clinical and non-clinical study reports, and an appropriate risk management plan and post-approval commitments.

Both Class 1 and 2 CTGTPs must comply with advertising restrictions, serious adverse events, product defects, recall reporting, and traceability system maintenance. Class 2 CTGTPs also require environmental risk assessment if they contain genetically modified organisms.

As of April 2024, Singapore has approved five Class 2 CTGTPs: Kymriah®, Luxturna®, Yescarta®, Zolgensma®, and SpheChon®.

On January 2, 2024, the HSA launched a new IT system called the Singapore Health Product Access and Regulatory E-system (SHARE). This is a one-stop digital portal for CTGTP Dealer's Notice and Class I CTGTP Notification and its expansion to Class 2 CTGTPs and other health products in future has been planned.

A self-help tool was also developed by HSA to aid stakeholders in classifying their product as CTGTPs and its classification as a Class 1 or Class 2 CTGTP.

The ACCESS Consortium, comprising like-minded regulatory agencies from Australia, Singapore, Canada, Switzerland, and the UK, has established a new working group called ACCESS Advanced Therapy Medicinal Product (ATMP) working group in November 2023, which aims to foster scientific discussions and explore opportunities for work-sharing and regulatory reliance.

Singapore has also established a national manufacturing facility with GMP clean rooms and laboratories, called Singapore's Advanced Cell Therapy and Research Institute (ACTRIS) located at the Singapore National Cancer Center, which supports the development and manufacture of cellular-based therapeutics, and aims to serve as a regional Center of Excellence.

2.2. Session 2: WG1 for non-clinical assessments for AAV

2.2.1. Introduction

WG1 aimed to explore the differences in the nonclinical data packages required for gene therapy using AAV vectors among various Asian countries/regions. It also seeks to promote the development of regulatory science.

There are two main types (ex vivo and in vivo) of gene therapy. WG1 focused on in vivo gene therapy. In vivo methods involve the insertion of a therapeutic gene into a gene transfer vector, which is then directly administered into the body for gene delivery. Some examples of these therapies are Zolgensma^Ⓡ and Luxturna^Ⓡ, which are already in use. The mechanism of action is illustrated in Fig. 2.

Fig. 2.

AAV delivery process (Mechanism of Action: MoA) [[5], [6], [7], [8]].

2.2.2. Background

A virtual AAV product was set up to evaluate the nonclinical package of AAV vectors (Table 1). This product is intended to treat amyotrophic lateral sclerosis (ALS), a neurological disease caused by the loss of ADAR2, one of the genes implicated in ALS. The scope was set for children and adults. Loss of ADAR2 is thought to increase calcium permeability, induce TDP-53 protein expression, and eventually cause myonecrosis and muscle atrophy [4].

Table 1.

Virtual AAV (adeno-associated virus).

Product Profile
Indication	ALS (neurological disease) (children-adults)
MoA	1. Infects a specific cells, 2. Expresses a specific protein continuously and efficiently, 3. Exists as an episome outside the chromosome.
AAV type (vector)	AAV 9
Target gene	ADAR2 (adenosine deaminase acting on RNA2)
Promoter	Hybrid CMV enhancer and CB promoter
Development phase	First in human
Clinical administration route	Intravenous (i.v.)
Dose	1 × 1014 vector genomes/kg (weight)
Clinical administration frequency	One time treatment

AAV9 was selected because of its high transduction efficiency in the nervous system. A hybrid CMV enhancer/CB promoter was selected as the promoter, and its first in-human application was assumed during development. The clinical route of administration was intravenous, with a dose of 1 × 10¹⁴ vector genomes and a single-dose frequency.

We asked industry associations in Asian countries/regions about the non-clinical studies required for virtual AAV products. It is then reviewed by the Health Authority (HA) of each country. The non-clinical package of the virtual AAV product was divided into pharmacology, absorption, distribution, metabolism, excretion (ADME), and toxicology studies. In the questionnaire, the respondents indicated whether each non-clinical study was mandatory, optional, or unnecessary for starting a clinical study or approval application. Additionally, comments on the detailed non-clinical study design were collected in a free-text format.

First, we gathered opinions from core member companies at FIRM. FIRM is composed of Japanese industry organizations, and commonly collects opinions from companies. Opinions were also collected from companies in other Asian countries/regions, with responses obtained from China and India as shown in Table 2. Their responses were based on the guidelines listed in Table 3. Although we sought opinions from Korea, Taiwan, and Singapore, no responses were received, as appropriate non-clinical representatives were not available.

Table 2.

WG1 participants/name (Affiliation).

Country/Region	Committee	Membership
Japan	FIRM	Yusuke Kagawa (Novartis Pharma K.K.), Aki Kito (Chugai Pharmaceutical Co., Ltd.), Yoshihide Iwaki (FUJIFILM Corporation), Shun-ichi Konno (CellGenTech., Inc.), Yoshie Tsurumaki (Novartis Pharma K.K.), Shunsuke Tominaga (Novartis Pharma K.K.)
China	CMBA	Biao Dong (Sichuan Real&Best Biotech co. Ltd.), Longxiang Sheng (Guangzhou Packgene Biotechnology Co., Ltd.), Minmin Xu (Guangzhou Packgene Biotechnology Co., Ltd.), Shuai Liu (BOE Regenerative Medicine Technology Co., Ltd), Fengjuan Yang (Astellas (China) investment Co., Ltd.)
India	ABLE	Dr Pawan Kumar Gupta, Dr Uday Kumar K
Korea Taiwan Singapore	SCRM/CARM BPIPO SAPI	Not available

Table 3.

Guidelines applicable for AAV.

Country/region	Guideline/Guidance
China	Guidelines on non-clinical research and evaluation techniques for gene therapy products (trial) (2021.11) ICH S12: Non-clinical biodistribution considerations for gene therapy products (2023.03)
India	New drug and clinical trials rules (2019) issued by the Ministry of Health and Family Welfare National guidelines for gene therapy product development and clinical trials issued by the ICMR, CDSCO, & DBT
Japan	Guidelines on ensuring the quality and safety of drugs for gene therapy products (PSEHB/MDED Notification No.0709-2 July 9, 2019) ICH S12: Guideline on the non-clinical biodistribution considerations for gene therapy products ICH considerations of general principles to address virus and vector Shedding (June 2009) ICH considerations general principles to address the risk of Inadvertent Germline integration of gene therapy vectors (October 25, 2006)

This briefing was sent to country/regional HAs in Asia for review. The results of the questionnaire included comments from the HAs. In addition, the results were mostly in agreement with the responses of industry organizations. Finally, the responses were compared with questionnaire results from other Asian countries/regions, and the differences were discussed and examined based on the guidelines.

2.2.3. Responses from Japan, China, and India

2.2.3.1. Comparison of the pharmacology package

As shown in Table 4, the pharmacology package was comparable among Asian countries/regions. Pharmacology studies on “Item 4: Duration of effect in vivo” and “Item 5: Dose-response” were optional in Japan and India, but mandatory in China. The reason for this difference is that the Chinese NMPA (National Medical Products Administration) guidelines require studies to support the mechanism of action, dose-response characteristics, and pharmacodynamic activity prior to clinical trials of gene therapy products.

Table 4.

Questions on the pharmacology package and answers from industry members.

Q: Are the following items mandatory for the non-clinical study package for Investigational New Drug (IND) submission? (M, mandatory: O, optional)
Item		Japan	China	India
1	To conduct non-clinical pharmacology studies	M	M	M
2	To show in vitro function, supporting MoA	M	M	M
3	To evaluate efficacy using disease model animal (in vivo)	M	M	M
4	To show onset time and duration of effect (in vivo)	O	M	O
5	To show dose-response curve (in vivo)	O	M	O
6	To define minimal effective dose	M	M	M
7	To define optimal dose (in vivo)	O	O	O
8	To show transduction efficiency of AAV vector	M	M	M
9	To show target protein expression	M	M	M
10	To conduct gene expression analysis	O	O	O
11	Additional items needed for NDA submission (Yes or No)	No	No	No

Note: Items 4 and 5 show the different responses between Japan, China, and India in bold.

2.2.4. Free text questions and answers for pharmacology

The responses to the nine pharmacology-related questions are shown in Supplementary Table 2. Eight of the questions, except for Item 6, were answered similarly across the three Asian countries/regions (responses from Japan are shown as examples).

In response to Item 6 regarding the rationale for setting an effective dose, Japan and India indicated that evaluating the progress of the disease, such as the prolongation of survival and maintenance of motor function in model animals, is mandatory, whereas China emphasized on evaluating the protein expression and enzyme activity of the transgene. These differences highlight the varying approaches adopted by the three countries/regions.

2.2.5. Comparison of ADME study packages

As shown in Table 5, a comparison of ADME study packages across the three Asian countries and regions revealed similar results.

Table 5.

Questions on the ADME study package and answers from industry members.

Q: Are the following items mandatory for ADME study packages for NDA submission? (M, mandatory: O, optional)
Item		Japan	China	India
1	Methods of analysis validation (biodistribution)	M	M	M
2	Methods of analysis validation (anti-AAV antibody)	M	M	M
3	Absorption	O	O	O
4	Biodistribution	M	M	M
5	Metabolism	O	O	O
6	Excretion (shedding study)	M	M	M
7	Other Pharmacokinetic studies	O	O	O

2.2.6. Free text questions and answers for ADME

As shown in Supplementary Table 3, answers to the four ADME-related questions were investigated. The results indicated that the responses to three of the questions, except for Item 4, were similar among Asian countries/regions (answers from Japan are shown as examples).

For Item 4, regarding the need to detect antibodies against the proteins produced, Japan and India responded that the detection of anti-vector antibodies is mandatory, while detecting antibodies to the produced protein is optional. However, China indicated that detection of antibodies against both the vector and produced protein is mandatory based on experience. Thus, detection of anti-vector antibodies is mandatory in all three countries/regions, but the responses differed regarding the detection of antibodies to the produced protein.

The Chinese National Medical Products Administration (NMPA) requires detection of the immunogenicity of overexpressed proteins from the recombinant AAV (rAAV) transgene in its guideline.

2.2.7. Comparison of the toxicology package

As shown in Table 6, a comparison of the toxicology packages among Asian countries/regions revealed almost similar results.

Table 6.

Questions on the toxicology package and answers from industry members.

Q: Are the following items mandatory for toxicological study packages for NDA submission? (M, mandatory: O, optional: N, Not necessary)
Item		Japan	China	India
1	Safety pharmacology (CV, CNS, respiratory)	M	M	M
2	Single dose toxicity studies	M	M	M
3	Repeated dose toxicity studies	O	O	O
4	Genotoxicity studies	O	O	M
5	Carcinogenicity studies	N	N	O
6	Reproduction toxicity studies	O	O	O
7	Juvenile animal toxicity	O	O	O
8	Immunogenicity (anti-AAV antibody titration)	M	M	M
9	Local tolerance studies	M	M	M
10	Other toxicity studies (Abuse liability, Photosafety testing, etc.)	N	N	N

Note: Items 4 and 5 show the different responses in bold between Japan, China, and India.

Regarding the genotoxicity study specified in Item 4, Japan and China responded that conducting the study was optional because the AAV genome is extrachromosomal; therefore, it does not show genotoxicity. However, India indicated that a genotoxicity study is mandatory.

Regarding the necessity of carcinogenicity studies specified in Item 5, Japan and China responded that no carcinogenicity studies are required because the representative AAV vector does not contain the Rep/Cap gene, making it a non-replicating virus. AAV products exist extrachromosomally as episomes. Therefore, the risk of integration into the host chromosome is considered to be low. As AAV products are usually non-proliferative, the possibility of carcinogenic risk is low. However, India, responded that carcinogenicity studies are optional.

The Indian guideline, New Drugs and Clinical Trials Rules 2019, mandates genotoxicity assessment.

2.2.8. Free text questions and answers for toxicology

As shown in Supplementary Table 4, responses to nine toxicity-related questions were surveyed. With the exception of Item 8, which evaluates gene integration, and Item 9, which evaluates toxicity caused by overexpression of the target protein, the responses were similar across the three Asian countries/regions (examples of responses for Japan are provided).

2.2.9. Differences among Asian countries/regions

Regarding the responses to Item 8 regarding the need for gene integration testing, no gene integration test is required in Japan, while it is mandatory in China and India. In Japan, several approved AAV products have shown no integration of the vector into the chromosomes, thus eliminating the requirement for toxicity studies. In contrast, the Chinese NMPA guidelines (Study May Proceed Letters) require gene integration studies to be conducted during or before clinical trials.

For Item 9, regarding the need for a safety assessment of target protein overexpression, Japan does not require a safety evaluation, while India has no specific guidelines. In contrast, respondents from China indicated that safety evaluation of the overexpressed target proteins is necessary. The Chinese NMPA guidelines require the inclusion of immunogenicity assessments for overexpressed target proteins in GLP toxicology studies. However, the safety assessment of target protein overexpression is not described in the current PMDA guidelines. Regarding the immunogenicity evaluation of AAV vectors and produced proteins, all three countries/regions responded that such evaluations will be performed commonly.

2.3. Session 2 summary/next steps

In conclusion, the responses to the non-clinical package and related questionnaires across Asian countries/regions were largely similar but differed in the following four items. These differences were based on local guidelines and there were no large gaps overall.

• •Showing a rationale for setting the effective dose for pharmacology
• •Detect antibodies to the produced proteins for ADME
• •Conducting a gene integration study for toxicology
• •Assessing the safety of overexpressed target proteins for toxicology

In future, we aim to further elaborate and discuss the similarities and differences in non-clinical testing for AAV with additional members/responses from Asian countries/regions for a more effective and efficient construction of non-clinical data packages in Asian countries/regions.

2.4. Session 3: CT-WG for clinical trial considerations

Previously, we have discussed ideas regarding the “quality” and “non-clinical” aspects of cell/tissue-based products in Asian countries/regions at APACRM. This was the first working group activity regarding clinical issues. While the importance of discussions around clinical trials has been highlighted, facilitating a general discussion proved that challenges in the design of clinical trials largely depend on the products themselves and the target indications. The Clinical Trial WG (CT-WG) has identified the typical issues expected when designing clinical trials for cell/tissue-based products (Table 7). We then prepared questionnaires for each of the key issues identified and asked for responses on how to address them in other Asian countries/regions. Subsequently, we gathered and compared the answers and the relevant guidelines offered by the Asian countries and regions. Shigeaki Hayashi from Japan Tissue Engineering presented the survey results and discussion to the audience at the 7th APACRM.

Table 7.

Issues about the “Clinical” aspect of cell/tissue-based products.

1. Issues with targeting rare diseases

1.1 Difficulties in conducting randomized controlled trials (RCTs)

2. Issues associated with product implantation (ex. Cell sheet implantation)

2.1 Difficulties in blinding treatment groups or setting a sham group

3. Issues caused by the use of living cells

3.1 The therapeutic effect is not necessarily dose-dependent because implanted cells can proliferate in the body and is exerted by cell engraftment.

3.2 In case of allogeneic cells, continuous use of immunosuppressants may affect efficacy and safety evaluations.

2.4.1. Survey results

We selected four clinical issues that had a full set of responses from Asian countries to our questions and reported on some of them at the conference. The responses from Japan were based on a case of an autologous cultured corneal epithelium approved for treating limbal stem cell deficiency (LSCD).

• 1)Issues with targeting rare diseases: Difficulties in conducting RCTs

2.4.2. Question

• •Designing clinical trials for cell/tissue-based products to treat rare diseases requires consideration of unique challenges.
• •These include the limited number of target patients and the absence of existing treatments in Japan.
• •Please provide any ideas or examples of what can be done when conducting RCTs in each country is difficult.

India Industry: Most clinical trials for Gene Therapy Products (GTPs) are single-arm trials; therefore, obtaining the historical clinical data and natural history of the disease is necessary before considering a clinical design.

Japan Industry: The difficulty of blinding the treatment groups and setting a control group between the sponsor of the LSCD therapy and the PMDA was discussed, resulting in a single-group open trial as the solution. An independent third-party efficacy evaluation committee was established to ensure objectivity. Referring to the global LSCD guidelines [9] available, the most promising efficacy evaluation indicators and trial designs were devised. Because of the available global guidelines, the post-application review process proceeded smoothly, as demonstrated by the example.

• 2)Issues associated with product implantation: Difficulties in blinding treatment groups or setting up a sham group

2.4.3. Question

• •For cell/tissue-based products that require implantation, such as cell sheets, clinical trials need to be designed considering that blinding is challenging owing to the nature of the implantation procedure.
• •Please provide ideas or examples of solutions for cases where blinding is difficult for this reason in each country.

India Industry: There are no regulatory guidelines or restrictions that only blinded trials can be initiated. In case of cell therapy products such as cell sheets, which require transplantation, the treatment procedures and administration methods are unique, making blinding difficult. The effectiveness of the endpoint evaluation can be achieved by assigning an independent blinded evaluator to assess the efficacy.

China Industry: Some clinical trials cannot be blinded because of the specificity of the drugs and administration methods. Unblinded clinical trials may influence the effectiveness evaluation by the principal investigator. If the main effectiveness evaluation of a clinical trial is only a subjective indicator, a third-party blinded evaluation is recommended.

South Korea Industry: Maintaining the blinding can be difficult but can be achieved by assigning a separate unblinded person responsible for preparing the investigational product.

Japan Industry: Owing to the disease characteristics and ethical issues, setting up blinded trials is difficult in these cases, and there is no experience in adopting them. Blinding was determined to be impossible owing to the surgical techniques involved in the use of the trial device and the product specifications of the cell sheet. Consequently, a single-group trial was conducted after consulting with the PMDA, which led to regulatory approval.

• 3)Issues caused by the use of living cells: The possibility of conducting clinical trials to confirm dose-response

2.4.4. Question

• •Cell/tissue-based products have unique characteristics such as the proliferation of cells in the body and their efficacy through the engraftment of living cells.
• •Consequently, their therapeutic efficacy may not always be dose dependent.
• •Please provide any ideas or examples of how each country responds to the characteristics of cell-/tissue-based products.

India Industry: For dose selection, establishing an appropriate dose range is essential for the trial design of all clinical developments involving GTPs. Otherwise, the dose can be assessed in earlier clinical trials performed for the same indication elsewhere or extrapolated from preclinical studies.

China Industry: Not limited to Regenerative Medical Products (RMPs), products like chemical drugs and antibody medicines do not always exhibit dose-dependency. In preclinical safety and efficacy evaluation tests, the relationship between dosage and safety/efficacy can be assessed.

South Korea Industry: Unlike other drugs, confirming a clear dose-dependent response to cell therapy is difficult. Various domestic and international guidelines recommend referring to dosages used in previous clinical trials when determining the clinical dosage.

Japan Industry: In the case of cell sheets, the PMDA argued that the appropriateness of optimal usage and dosage was based on the exploratory clinical research outcomes of the investigators, in addition to a single use and size, and this was accepted.

• 4)Issues caused by the use of living cells: Handling of immunosuppressants in clinical trials during the development of allogeneic products

2.4.5. Question

• •For products derived from allogeneic cells, continued use of immunosuppressants may affect efficacy and safety evaluations.
• •Clinical trials of allogeneic products require study plans that consider the use of immunosuppressants, and detailed information on their use needs to be collected.
• •In CAR-T preparations, lymphocyte-depleting chemotherapy with immunosuppressants is required for pre-treatment.
• •When creating a clinical trial protocol, information on any treatment that can affect the efficacy and safety of the investigational products must be collected.
• •Please provide any ideas or examples of how each country responds to the characteristics of cell-/tissue-based products.

India Industry: In domestic guidelines, immunosuppression is considered an important element to be addressed in the clinical trial design. Immune responses can significantly reduce the effectiveness of GTPs and potentially cause Serious Adverse Events (SAEs). Furthermore, careful consideration is needed to reduce immune responses, because certain routes of administration (RoAs) may have higher immunogenicity than others. This is particularly important for therapies that activate the immune system as several immune-related SAEs have been highlighted.

China Industry: Domestic guidelines recommend that trial sponsors include details on the use of pre-medication and pre-treatment in the clinical trial implementation plan to mitigate potential risks. In the manufacture and administration of immune cell therapy products, if procedures such as blood cell apheresis, lymphocyte clearance pre-treatment, and human leukocyte antigen (HLA) transplantation are required, the safety standards and evaluation procedures for subjects before apheresis, pre-treatment, and re-infusion should be clearly stated in the clinical trial implementation plan to reduce the risk to trial participants.

South Korea Industry: For immunosuppressants, owing to serious side effects, safety data are collected and reflected in the clinical trial protocol. Measures to ensure the safety of the participants are outlined in the protocol. The side effects of lymphocyte removal are clearly defined because they affect the safety of the drug. CAR-T cell therapy mostly involves a single dose along with lymphocyte removal. For multiple-dose cell therapies, lymphocyte removal cannot be performed before each dose. Thus, the difference between the effects of lymphocyte removal and those of cell therapy is considered.

2.4.6. Session 3 summary

This study examined the challenges in the clinical development of cell/tissue-based products and current measures applied in various Asian countries. Some countries, including India, China, and Japan, have established technical guidelines for the development and clinical trials of cell- and tissue-based products. Regenerative medicine products for tissue transplantation have limited availability across Asia except in Japan and Korea, which have many approved products. This study suggests that insights from Japan and other Asian countries can accelerate the development of such products in Asia.

This study identified three main challenges: difficulties in RCTs, selection of dosage, and use of immunosuppressants. The difficulties in conducting RCTs is addressed using a case-by-case approach to ensure robust data from single-group clinical trials. However, a more systematic approach is beneficial for improving the predictability of study feasibility, especially when a clinical trial is conducted on a global scale. Dosage selection is another challenge because cell/tissue-based regenerative medicine products do not always show a dose- or usage-dependent response in terms of safety and efficacy. Determining the “optimal” dosage/application of cell/tissue-based products requires different approaches from those for conventional drugs, potentially based on their characteristics such as physical properties, cell types, and cell quality. The use of immunosuppressants in cell-/tissue-based regenerative medicine products presents a challenge because of the lack of consensus and difficulty in investigating the safety and efficacy of therapeutic products, thereby setting a regimen for clinical trials.

The study further aimed to identify the specific steps that each country has implemented to address these clinical challenges, thereby improving the reliability of clinical trials and the predictability of regulatory approval. We hope that the challenges identified in this CT-WG will help accelerate further discussions across industries and countries to facilitate clinical trials for cell/tissue-based products across Asia.

2.5. Session 4: WG3: points to consider for regulations on MAA/BLA for gene therapies in six Asian countries/regions

2.5.1. Introduction

Masaaki Miyano of Chugai Pharmaceuticals introduced the session by providing an overview of the objectives, history, and activities of the APACRM Working Group 3 (WG3). WG3 focused on researching the regulations and regulatory processes for AAV gene therapy and CAR-T therapies across six Asian countries/regions in the Marketing Authorization Applications (MAA)/Biologics License Applications (BLA) phase, aiming to harmonize and converge regulatory standards to facilitate faster delivery of advanced therapies to patients in the region. In the previous year, WG3 handled the regulations on the IND phase for gene therapies^10,11.

Over the past year, the WG 3 has collected extensive information on the regulatory systems, clinical and non-clinical requirements, CMC/GMP topics, and the status of regulatory alliances in six Asian countries/region. Several key topics were selected from the information collected and discussed by the panel. The selected topics included clinical data requirements, reliance situations, out-of-specification (OOS) product management, and in-country release testing.

2.6. Panel discussion 1: regulatory review systems

Hirokuni Mizoguchi and Ruriko Shinozaki from Astellas moderated this panel discussion, focusing on two topics: regulatory review systems for BLA/MAA in AAV gene therapy and CAR-T products in Asian countries/regions.

• 1.Requirement of clinical data obtained from patients in their own countries (usage of clinical data obtained in other countries)

2.6.1. Background

Gene therapies have been developed primarily by small biotechnology companies. In many cases, clinical development until the Phase 3 study is conducted in the US/EU and the participation of Asian countries/regions may not be necessarily involved. Target indications for gene therapy are rare diseases in many cases and commonly involve gene mutations. Indications for gene therapies developed in the US or EU may have fewer Asian patients, because of which patient enrollment for clinical trials is not practically feasible. Requirements of clinical trial data obtained from patients in their own countries/region for BLA/MAA in six Asian countries/region are various as shown in Table 8. Therefore, we posed the following three questions to the regulators and industry participants.

Table 8.

Requirements of clinical trial data obtained from patients in their own countries/region for BLA/MAA in six Asian countries/region.

Requirements of clinical data obtained from patients in their own countries/region for BLA/MAA (usage of clinical data obtained in other countries)
Mandatory	Case-by-case	Not mandatory
•China •India •Japan	•South Korea •Taiwan	•Singapore

2.6.2. Question 1: for the requirement of own country/region's clinical data of for BLA/MAA, could you explain the advantages and issues?

• •PMDA, Japan Regulator: The PMDA requires local clinical data from Japanese patients to assess the efficacy and safety in local medical practice, although this can be burdensome for applicants.
• •CMBA, China Industry: Similar to Japan, China mandates local clinical data to ensure the safety and efficacy of its population, which can be time-consuming and costly to obtain product approval.
• •SAPI, Singapore Industry: Singapore has a small population of 6 million, and it may be challenging to accrue sufficient number of subjects for clinical trials, especially for rare diseases. Singapore does not mandate local clinical data, instead, it relies on multi-regional clinical trials (MRCT) to gather relevant data from diverse populations.
• •Taiwan CDE, Taiwan Regulator: Taiwanese clinical data for BLA and MAA are welcomed as these data provide the efficacy and safety information for patients in Taiwan. In addition, clinical professionals can know more about the products, including their administration, post-treatment observation, and adverse reaction management, before approval.
• •MFDS, South Korea Regulator: The South Korean regulator emphasized ethnic differences in safety and efficacy indicating the requirement for local data unless substantial similarity to other ethnic groups regarding intrinsic and extrinsic factors is demonstrated.
• •CDSCO, India Regulator: India requires local clinical data for new drugs, but allows phase IV studies for orphan conditions or drugs with unmet medical needs if the product is already approved in other countries/regions.

2.6.3. Question 2: If you do not have own country/region's clinical data, but you have other Asia country/region's clinical data (or Asian ethnic data), what do you think about its use for BLA/MAA review?

• •PMDA, Japan Regulator: PMDA generally requires additional local clinical data.
• •CMBA, China Industry: China accepts other Asian data as supportive evidence if they comply with GCP and demonstrate the safety and efficacy. All data must be proven safe and efficacious for the Chinese population.
• •SAPI, Singapore Industry: HSA accepts Asian data to support the BLA, provided it meets the ICH GCP standards.
• •Taiwan CDE, Taiwan Regulator: Taiwan applies ICH E5 principles, considering both intrinsic and extrinsic factors, to evaluate other Asian data.
• •MFDS, South Korea Regulator: If the safety and efficacy data of drugs obtained from other ethnic groups are similar to those of Koreans, Korean clinical data may be exempted.
• •CDSCO, India Regulator: India aligns with the ICH guidelines and we require a demonstration of similarity to the Indian population in the Asian population from the clinical dataset.

2.6.4. Question 3: When you do not have own country/region's clinical data, what do you think about the requirements of post-marketing studies in your country/region?

• •PMDA, Japan Regulator: PMDA generally requests local clinical data at the time of application for approval. In addition, the PMDA will request all-case surveillance as post-marketing surveillance if local clinical data are limited.
• •CMBA, China Industry: This has never occurred before, but the medical needs and products need to be carefully evaluated.
• •SAPI, Singapore Industry: Singapore participates in global post-marketing studies and registries without mandating local studies by the HSA.
• •Taiwan CDE, Taiwan Regulator: Taiwan necessitates post-marketing studies or long-term follow-ups based on product risk, especially if local data are absent.
• •MFDS, South Korea Regulator: South Korea mandates long-term safety surveys but not necessarily clinical trials.
• •CDSCO, India Regulator: India requires phase IV studies for products approved under accelerated pathways with a focus on long-term safety monitoring.
• 2.Alliance and Reference Countries/Region

2.6.5. Background

Several programs allow concurrent collaborative review of NDA/BLA submissions by multiple health agencies (ORBIS, ACCESS, etc.; Singapore is included in both programs). In Asia, Taiwan (only for NCE or new biologics evaluated as no ethnical sensitivity, referring to the US, EU, and JP) and Singapore (referring to the US, Canada, EU, UK, and Australia) have systems for referring to the review/approval status in other countries for an abridged review (Table 9). In gene therapy, the FDA is working on a pilot program for a concurrent collaborative review of new gene therapies, including other ICH health agencies (EU, JP, Canada, and Switzerland), named the Collaboration on Gene Therapies Global Pilot (CoGenT). Concurrent collaborative reviews can be considered effective from the sponsor's perspective, especially for rare diseases with few patients undergoing gene therapy in Asian countries. Therefore, during the panel discussion, we posed questions to regulators from various Asian countries/regions in order to understand their perspectives.

Table 9.

Alliance/reference countries/region in BLA/MAA in six Asian countries/region.

Item	China	India	Japan	Korea	Singapore	Taiwan
Alliance/reference countries/region in BLA/MAA review	No	No	No	No	For abridged – US FDA, Health Canada, EMA, UK MHRA and Australia TGA	Clinical trial: Review report of regulatory agency in ICH regions (US, EU, and JP)

To Taiwan and Singapore: What are your thoughts about the benefits and challenges (such as, review result conflict, alignment with local regulation etc.) of referring to the review/approval status in other countries, from the perspective of health agencies?

• •Taiwan CDE, Taiwan Regulator: Taiwan highlighted challenges, such as review result conflicts arising from different benefit-risk assessments and clinical practices across countries.
• •HSA, Singapore Regulator: The HSA emphasized the need for in-depth benefit-risk analysis despite reliance on the assessments from other agencies, considering local epidemiological factors and expert opinions. The HSA addressed conflicts by consulting with local clinical experts and advisory committees to ensure optimal regulatory decisions.

To Japan: Could you share any information regarding the status of the CoGenT program led by the FDA regarding the concurrent collaborative review to gene therapy?

PMDA, Japan Regulator: We do not have any information to share at present because it is under consideration.

What are your thoughts if CoGenT would be expanded to your country, given the pros and challenges?

Taiwan CDE, Taiwan Regulator: We are interested and would like to join CoGenT as this facilitate the review and patient accessibility of novel, effective and safe treatment. (Please note that this represented CDE opinion and does not represent the view of TFDA or MOHW.)

HSA, Singapore Regulator: We have participated in and benefited from Project Orbis. From our experience with Project Orbis, we could quickly gain the capacity for evaluating novel cancer therapies, though networking with international counterparts. We envision that these benefits will also apply to CoGenT.

CMBA, China Industry: We would like to see CoGenT or Orbis come to China because it will help our program move faster and eventually benefit patients who are ready for many unmet medical needs.

CDSCO, India Regulator: At this point in time, we do not have an alignment of Indian regulations with foreign regulations as a process.

2.7. Panel discussion 2: CMC/GMP topics

• 1.Proceedings of the Regulatory Panel on the Use and Regulation of Out-of-Specification (OOS) Autologous Cell-Derived Products

2.7.1. Introduction

This panel discussion focused on the regulation of out-of-specification (OOS) autologous cell-derived products, primarily CAR-T products, in various countries. These products are often critical for patients with serious and potentially fatal diseases and present unique regulatory challenges. The discussion explored the regulatory frameworks in the United States, Europe, Singapore, Taiwan, China, Japan, South Korea, and India, highlighting the different approaches to handling OOS products and their implications for patient treatment and product safety.

2.7.2. Regulatory frameworks for OOS products

Masaki Fujii from Mitsui-soko began the discussion by comparing the regulatory approaches to OOS products in the US and Europe. In the US, OOS products are used as part of the Expanded Access of Investigational Drugs, which primarily targets patients with severe diseases. In Europe, OOS products can be administered under the Exceptional Administration of Commercial Lots, subject to a physician's request and risk assessment. In this session, we asked each Asian country/region about its situation and position on OOS products.

HSA, Singapore Regulator: The HSA explained that Singapore allows the use of OOS autologous CTGTPs under the Health Products (Exemptions) Order 2016. This Order recognizes the difficulty in ensuring that autologous products derived from patients' own cells always meet specifications, owing to the varying health conditions of patients. This exemption applies to a small subset of autologous products that undergo more than minimal manipulation, excluding those that affect sterility or pose serious medical risks.

Taiwan CDE, Taiwan Regulator: The Taiwan regulator described OOS products under compassionate use in Taiwan, which is determined on a case-by-case basis based on clinical judgment. For example, if CAR-T cells show a slightly reduced viability, their use may still be acceptable after an Institutional Review Board (IRB) review.

CMBA, China Industry: China prohibits the use of OOS products owing to noncompliance with the Drug Administration Law. Such products cannot be legally administered even if requested by patients or physicians.

PMDA Japan Regulator: Regarding its prohibition on the selling OOS products in Japan, PMDA highlighted that Japan's main concern with OOS products is their uncertain quality, efficacy, and safety, which makes their distribution difficult.

MFDS, South Korea Regulator: South Korea allows the exceptional release and administration of autologous OOS cell-derived products if they meet specific quality criteria for sterility, endotoxin, purity, etc., as no other therapeutic options are available.

CDSCO, India Regulator: The CDSCO explained that Indian regulations prohibit the manufacture, import, and distribution of substandard-quality products. However, the decision to use such products depends on a risk-benefit assessment by the treating physician.

• 2.Discussion on In-country Release Testing (Re-Testing)

Masaaki Miyano of Chugai Pharmaceutical introduced the topic of in-country release testing (re-test), emphasizing the time-consuming nature of re-tests for gene and cell therapy products, which can delay the treatment of patients with severe diseases. Further, the limitations of manufacturing quantities of gene and cell therapy products should be considered. This discussion revealed varying practices.

HSA, Singapore Regulator: Singapore does not require retests; instead, it relies on Certificate of Analysis (CoA) provided by manufacturers. This approach is practical because of the high costs and limited quantities of these products as well as the need for timely administration.

Taiwan CDE, Taiwan Regulator: We usually do not request in-country re-testing in Taiwan. However, the central competent authority reserves the right to request it if necessary.

PMDA, Japan regulator: The PMDA mentioned that Japan mandates re-tests as part of its Good Manufacturing Practice (GMP) requirements. However, discussions with industry groups regarding potential exclusions for certain products are ongoing because of their limited quantities. The PMDA also emphasized that it depends on the product specification and situation, and that at least appearance tests are required, and other tests may be omitted.

CMBA, China Industry: China requires retesting to meet the local quality control standards and to ensure safety, particularly for gene and cell therapy products. In addition, retesting is required for the safety assessment of emerging products to avoid the impact of ethnic differences. There is no immediate plan for eliminating this requirement, at least in the near future.

MFDS, South Korea Regulator: Retesting is required according to the importer's matters to be observed in South Korea, except for orphan drugs, with no current plans to change this regulation.

CDSCO, India Regulator: India requires the testing of imported products at a national release laboratory. Although specific rules for cell and gene therapy products are yet to be established, there may be considerations for testing waivers in the future.

2.7.3. Session4 conclusion

The panel concluded with a consensus that while retesting remains a standard requirement in most countries, further discussion, including scientific discussions and regulatory adjustments, is important. The balance between ensuring product safety and efficacy and the practical challenges of retesting highly individualized therapies continues to be a focal point for future regulatory considerations. This discussion underscores the importance of international cooperation and regulatory convergence to facilitate the timely and safe delivery of advanced therapeutic products to patients in need.

2.8. Session 5: regulations and future business opportunities for processed cells in regulatory categories different from RM products

2.8.1. Introduction

This session focused an industry survey and perspectives, aiming to compile and discuss case studies of Cell and Gene Therapy Technology provided to patients as medical care or practice without marketing authorization. The session was chaired by Mr. Kunihiko Suzuki from FIRM.

2.8.2. Background

The theme of this session was selected because of the evolving regulatory landscape of cell and gene therapies across various countries. Japan introduced the Act on the Safety of Regenerative Medicine (ASRM) approximately 10 years ago, influencing similar regulations in Taiwan and ongoing regulatory considerations in Korea and other countries. Participants included members from different countries such as the United States, where many clinics operate under minimal regulations for MSC-based therapies, highlighting the global diversity in regulatory approaches.

2.8.3. Contents

• •Compilation of Case Studies: Focused on the provision of cell and gene therapies as medical care without marketing authorization.
• •Japanese Regulatory Framework: ASRM in Japan categorizes therapies based on risk levels and encompasses both medical practices and clinical research. Statistics on facilities providing cell-processing work and different classes of therapies under the ASRM were presented.
• •
  Taiwanese Regulatory Framework:

  • ○
    Introduction of the Regulation in Taiwan: Taiwan introduced a new regulation in 2018, modeled after that of the ASRM in Japan, to oversee the safety and quality of regenerative medicine practices.
  • ○
    Regulatory Scope: Taiwanese regulations cover the use of autologous and allogeneic cells, with stringent requirements for safety assessments and clinical trials.
  • ○
    Implementation and Impact: Since the introduction of regulations, the number of approved clinical trials and medical institutions compliant with the new standards has increased notably.
  • ○
    Challenges and Future Directions: Taiwan faces challenges in harmonizing regulations with other countries and ensuring a consistent quality of therapies. Future efforts should focus on international collaboration and the continuous improvement of regulatory frameworks.
• •International Context: Comparisons were made with practices in the United States and other countries, emphasizing the need for better understanding and regulation of medical care activities involving cell and gene therapies.
• •
  Manufacturing Considerations:

  • ○
    Quality Control: The session emphasized the importance of stringent quality control measures in the manufacturing process of cell and gene therapies to ensure product consistency and safety.
  • ○
    Scalability: Challenges associated with scaling-up manufacturing processes while maintaining quality standards were discussed, with a focus on ensuring that larger-scale production does not compromise the quality of the therapies.
  • ○
    Regulatory Compliance: Manufacturing facilities must comply with Good Manufacturing Practices (GMP) and other regulatory standards to ensure the safety and efficacy of cell and gene therapy products.

2.8.4. Regulatory opinions

• •Japanese Statistics: The session included a discussion on the number of medical practices and clinical research plans submitted and approved by the ASRM. Notably, Japanese regulatory authorities have categorized therapies based on their risk levels, with Class I indicating the highest risk, Class II indicating a middle risk, and Class III indicating a low risk.
• •Risk Categories: Detailed explanations were provided for the classification and regulatory oversight of the different classes of therapies. The authorities focus on ensuring that the highest-risk therapies (Class I) receive the most stringent monitoring from the Scientific Technology Committee organized by the MHLW.
• •Global Perspectives: The need for international harmonization in regulating cell and gene therapies was highlighted. The differences in regulatory approaches across countries were discussed, emphasizing on the benefits of having a more uniform global regulatory framework.
• •Further Challenges for ASRM: Quality of Certified (Special) Committees will take responsibility for providing GO/NO GO for applicant medical institutions, which intend to provide CGT/RM under ASRM for the Patients. Further, the Clinical Outcome Database should be established using appropriate Patient Registry Systems such as the NRMD at JSRM, to provide scientific evidence on the targeted CGT/RM under ASRM. Moreover, the coverage of ASRM should be expanded to other new modalities on medical technologies, such as EVs, which could exist in the neighboring space of the CGT/RM.

2.8.5. Safety and scientific validity

The Japanese regulatory authorities primarily target safety under the ASRM, leaving efficacy assessments to the discretion of medical doctors. The need for improving the reporting and scientific validity of therapies was discussed. Some participants raised concerns about the qualifications of the medical professionals and the quality of the cell-processing facilities. Suggestions were made to enhance the training and certification processes for medical professionals involved in regenerative medicine. Additionally, improving the scientific rigor of therapies through better data collection and more robust clinical studies was emphasized.

2.8.6. Next steps (as discussed in the above Further Challenges of ASRM)

• •Improvement of ASRM: Japanese regulatory authorities recognize the need for continuous improvements in the ASRM to better address the safety, scientific validity, and quality issues. They plan to implement more stringent monitoring and enhance the scientific assessment processes.
• •Data Collection: The need for better data collection on clinical outcomes and safety has been emphasized to support the efficacy of therapies. This includes establishing more comprehensive databases and encouraging the sharing of clinical data between practitioners and researchers.
• •Future Discussions: Authorities are considering expanding the scope of ASRM to include in-vivo gene therapies. Discussions on improving the quality and monitoring of certified committees and cell-processing facilities to ensure higher standards of practice are ongoing.

2.8.7. Session 5 summary

This session, based on industry observations and perspectives, highlighted the current state of regulatory frameworks for cell and gene therapies, focusing on the ASRM in Japan and the recent regulatory advancements in Taiwan. Manufacturing considerations, such as quality control, scalability, and regulatory compliance, were also discussed to ensure the safe and effective production of cell and gene therapies. The need for continuous improvement, better data collection, and international harmonization were key takeaways. Future steps involve addressing the quality and safety of therapies and expanding regulatory scopes to ensure patient benefit.

3. Conclusions

This report covers the discussions held by regulatory agencies and industries from the participating Asian countries and regions at the 7th APACRM meeting. WG1 compared the necessary items in non-clinical studies for IND/NDA applications to AAV gene therapy products using a virtual case and found that most of the required items were similar across countries. The CT-WG initially gathered opinions on clinical trial-specific considerations for cell-/tissue-based products and will continue to address these issues. In WG3, interesting and important topics for companies considering the international expansion of gene therapy were discussed; WG3 will explore more details in future APACRM meetings. Overall, further efforts are needed to advance the development and commercialization of cell and gene therapies in Asian countries.

Declaration of competing interest

This paper is to review the outcome of the 7th APACRM meeting held on April 25, 2024, and the meeting was funded by FIRM (Forum for Innovative Regenerative Medicine).

Yoshie Tsurumaki, Yusuke Kagawa, Shigeaki Hayashi, Hirokuni Mizoguchi, Masaaki Miyano, Masaki Fujii, Ruriko Shinozaki, Kunihiko Suzuki and Masayuki Nomura are members at FIRM. Since FIRM is an industry association group, no members receive compensation from FIRM.

Yoshie Tsurumaki and Yusuke Kagawa are employees of Novartis Pharma K.K.

Shigeaki Hayashi is an employee of Japan Tissue Engineering Co. Ltd.

Hirokuni Mizoguchi and Ruriko Shinozaki are employees of Astellas Pharma Inc.

Masaki Fujii is an employee of Mitsui-Soko Holdings Co., Ltd.

Srinivasan N Kellathur is an employee of Roche Singapore Technical Operations.

Alex J. Zhang is an employee of HELP Therapeutics Co., Ltd.

Kunihiko Suzuki is an employee of MEDINET Co., Ltd.

Masayuki Nomura is an employee of Asahi Kasei Corporation.

Appendix A. Supplementary data

The following is the Supplementary data to this article.