An Overview of Cell and Gene Therapy Development in China

Abstract

China, the first country worldwide to approve a gene therapy in 2003, almost lost the advantage for a head start in cell and gene therapy (CGT) development due to a lack of clear and strict regulatory frameworks. The rapid advancements of CGTs' development worldwide as well as their therapeutic potential have triggered the government to conduct a spate of regulatory reforms to promote normative development of CGTs in China. Encouraged by policy support, the remarkable progress for CGTs in China has been observed over the past few years, thereby catapulting China back into the forefront of CGTs worldwide. This article aims to provide an overview of regulatory reforms, the current development landscape of CGTs, as well as key contributors and challenges for CGT development in China.

Introduction

Cell and gene therapies (CGTs) are designed ideally to halt a disease in its tracks or reverse its progress, which transform the traditional paradigm of disease treatments and may provide breakthrough opportunities for some severe diseases.¹ China, as one of the forerunners in advancing the development of innovative technologies, began research on CGTs at an early stage, conducting the world's first clinical trial for gene therapy in 1991 and approved the world's first gene therapy (Gendicine) in 2003.² However, due to loose and ambiguous regulation of CGTs, the development of CGTs was once in chaos in China, with unapproved CGTs being widely used for disease prevention and treatment in private clinics or even large hospitals.³

In 2016, the event of “Wei Zexi” alarmed the whole nation; a college student died from receiving unapproved DC-CIK cell therapy for synovial sarcoma.⁴ This tragedy resulted in an immediate government “shutdown” of almost all research of CGTs in China, which severely impeded research and development of CGTs.⁵ The application of unproven CGTs in patients has also perpetuated a global health problem leading to multiple patient injuries and deaths, threatening legitimate research efforts, and undermining regulatory authority to safeguard public health.⁶ All stakeholders on national and international levels must collaborate to efficiently address this complicated and multifactorial problem.⁷

The rapid advancements of CGTs worldwide coupled with their therapeutic potential in fulfilling unmet clinical needs of patients in China have prompted the Chinese government to establish effective regulatory frameworks for CGTs. Over the past few years, a series of technical guidelines related to CGTs have been released by the Chinese government to provide incentives and encourage investments in the field.⁸ Most recently, thanks to the government support, substantial progress in the field of CGTs have been achieved in China. Currently, China is ranked second in terms of the number of patent applications and registered clinical trials for CGTs worldwide, following the United States.⁹ On June 23, 2021, the first chimeric antigen receptor T (CAR-T) cell therapy, Yescarta, was approved in China for the treatment of relapsed or refractory large B cell lymphoma after two or more lines of systemic therapy in adult patients, which is a remarkable milestone for cell therapy in China.¹⁰

In this article, we aim to (1) provide an overview in the evolution of regulatory reforms related to CGTs in China, (2) present the current development states of CGTs for publications, patents, clinical trials, and products in China, (3) discuss key contributors for the growth of CGTs' development in China, and (4) explore what challenges remain for CGTs, and what efforts await to achieve its future success in China.

Regulatory Reforms for CGTS in China

Over the past three decades (1990–2020), over 30 national regulatory guidelines or standards for CGTs have been released by Chinese regulatory authorities (Supplementary Table S1). The regulatory reforms in China can be roughly divided into three periods: initial period, rectification period, and standardization and acceleration period. The milestones for the regulatory reforms and major events for CGTs in China are highlighted in Fig. 1.

Figure 1.

The major events and three regulatory development periods related to CGT in China from 1991 to 2020, including the key milestone events, important events affecting the regulatory reforms, three regulatory development periods and key regulatory guidelines and issues in each period. CFDA, China Food and Drug Administration; CGTs, cell and gene therapies; MOHC, Ministry of Health of the People's Republic of China; SFDA, State Food and Drug Administration; NHC, National Health Commission; NHFPC, National Health and Family Planning Commission of the People's Republic of China; NMPA, National Medical Products Administration.

Initial Period with Loose Regulation (1990s–2008)

In 1993, CGTs were first incorporated into the regulatory system in China, with the release of the first quality control guideline for clinical research of CGTs by the Ministry of Health of the People's Republic of China (MOHC).¹¹ In 1999, the State Food and Drug Administration (SFDA) stated that CGTs were supervised as new biological products.¹² In 2003, SFDA drafted the guidelines for human cell research, which included requirements for manufacturing, nonclinical research, and clinical trial of cell therapy.¹³ SFDA also issued the guidelines for human gene therapy research, which stipulated requirements for clinical trial application and quality control.¹⁴ That same year, MOHC and the Ministry of Science jointly issued ethical principles for research of human embryonic stem cells, and MOHC published the technical guideline for human-assisted reproductive technology, which prohibited the gene therapy for the purpose of reproduction.^15,16

During this period, Chinese authorities began to explore how to regulate CGTs' development. The regulatory environment was relatively loose.

Rectification Period with Strict Regulation (2009–2016)

In 2009, MOHC announced autoimmune cells (T cell and NK cell) and stem cells were included on the list of category III medical technology. Medical institutions with approvals from MOHC were allowed to conduct clinical applications of products on this list in routine clinical practice.¹⁷ However, due to the relatively loose regulatory system, many cell therapies without approvals were illegally applied in some medical institutions, thereby creating chaos in the CGT industry. As a result, in 2011, MOHC and SFDA jointly published a notice for the cessation of unapproved stem cell clinical research and applications, and the self-examination and self-correction for cell therapy for 1 year were performed in China.¹⁸

In 2015, National Health and Family Planning Commission of the People's Republic of China (NHFPC) cancelled the approval of clinical application of category III medical technology.¹⁹ Subsequently, NHFPC and China Food and Drug Administration (CFDA), previously known as SFDA, jointly issued the guidelines for clinical research of stem cell therapy, which stipulated that medical institutions needed to be recorded in both the NHFPC and CFDA before initiating stem cell clinical research.²⁰ In 2016, due to the death of Wei Zexi, NHFPC stopped all the clinical applications of unapproved immune cell therapy, which resulted in the stagnation of immune cell therapy development in China.⁵ That same year, the NHFPC issued measures for the ethical review of biomedical research involving humans, which required the responsibilities of Medical Ethics Committees and further specified the basic scope and operation procedure of informed consent.²¹

During this period, China took actions to rectify the CGT industry by tightening its regulatory policies. However, from an overarching perspective, the regulation of CGTs in China was far from standardized and clarified.

Standardization and Acceleration Period with Comprehensive Regulation (2017 to Present)

After experiencing several setbacks, China attempted to establish a stricter and comprehensive regulatory system for CGTs. In 2017, CFDA released the technical guidance on the research of cell therapy, in which the requirements for manufacturing, quality control, nonclinical trial, and clinical trial were specified. Additionally, this guideline stressed that the market authorization of CGTs should be regulated as biological products.²²

In 2018, a Chinese scientist called He Jiankui, announced that his team had used the CRISPR gene-editing system to edit DNA in human embryos to make them less susceptible to human immunodeficiency viruses. This scandal received widespread criticism from some of the world's top scientists.²³ Subsequently, the Chinese court sentenced him to 3 years in prison for illegal medical practice.²³ Affected by this event, China decided to impose stricter regulation for human gene editing and began to step up legislation in this area. In 2019, the National Health Commission (NHC) submitted a new draft of civil code, which required that scientific and medical studies pertaining to human genes or embryos must follow the relevant regulations and cannot harm people's health, breach moral or ethical standards, or violate public interests.²⁴ The civil code was adopted on May 28, 2020 and took effect on January 1, 2021, which first brought medical and scientific research related to human genes or embryos under civil legislation.²⁵

Around the same time, China also published several guidelines to standardize and promote the development of CGTs. In 2018, CFDA published key requirements of clinical trial applications for cell therapy to encourage the development of innovative drugs for diseases with unmet needs.²⁶ In 2019, the NHC also issued the guideline to permit that somatic cell therapy with safety and effective data could be delivered to patients in the form of clinical application in the recorded medical institutions.²⁷ In 2020, the National Medical Products Administration (NMPA), previously known as CFDA, published five technical guidelines (in consultation, currently) for CGTs in sequences. Two guidelines for clinical trials of immune cell therapy and stem cell-based therapy were released in July and August, whereas three guidelines for pharmaceutical research and evaluation of immune cell therapy, gene therapy, and gene transduction and modification system were released in September.^28

–32

To accelerate the access to drugs in urgent clinical needs, State Administration for Market Regulation established four expedited programs for marketing authorization of drugs in the latest version of the “Drug Administration Law,” including breakthrough therapy designation, priority review and approval, conditional approval, and special examination and approval (Supplementary Table S2).³³ The program of priority review and approval was first proposed in 2015 and updated in 2020; by the end of February 2021, five CAR-T cell therapies have been granted priority review designations (Table 1).¹⁰ The program of breakthrough therapy designation was first proposed in 2020, and the LCAR-B38M, a CAR-T product from Legend Biotech Corporation, was the first product to be granted a breakthrough therapy designation by CDE in China. By the end of February 2021, five CAR-T products were granted breakthrough therapy designations (Table 1).¹⁰ No CGTs have been granted conditional approval so far.

Table 1.

Cell and gene therapies with priority review and breakthrough therapy designations in China as of February 28, 2021

Registration ID	Product Name	Company	Target	Indication	Application Date	Publicity Date	Status
Priority review designation
CXSL1700201	LCAR-B38M	Nanjing Legend Biotech	BCMA	Multiple myeloma	December 11, 2017	December 18, 2017	Approved
CXSL1700203	CAR-GPC3T	CARsgen Therapeutics, Inc.	GPC3	Solid tumors	December 29, 2017	January 29, 2018	Approved
CXSL1700193	NA	Hrain Biotechnology Co., Ltd.	CD19	Lymphoma	December 25, 2017	January 29, 2018	Approved
CXSL1700122	NA	Marion Biotech Pvt. Ltd.	CD19	Lymphoma	December 25, 2017	January 29, 2018	Approved
CXSS2000036	JWCAR029	JW Therapeutics	CD19	Acute lymphocytic leukemia	August 9, 2020	September 9, 2020	Approved
Breakthrough therapy designation
CXSL1700201	LCAR-B38M	Nanjing Legend Biotech	BCMA	Multiple myeloma	July 10, 2020	August 5, 2020	Approved
CXSL1800002	JWCAR029	JW Therapeutics	CD19	Large B cell lymphoma	August 10, 2020	September 9, 2020	Approved
CXSL1800054	CT053	CARsgen Therapeutics Inc.	BCMA	Multiple myeloma	August 24, 2020	November 30, 2020	Approved
CXSL1800106	CNCT19	Heyuan Biotechnology (Tianjin) Co., Ltd.	CD19	Acute lymphocytic leukemia	November 3, 2020	December 11, 2020	Approved
CXSL1900060	CT103A	IASO Biotherapeutics and Innovent Biologics, Inc	BCMA	Multiple myeloma	December 11, 2020	February 9, 2021	Approved

In this period, China has made a lot of efforts to promote CGT development with more regulatory guidelines released to provide clarifications on the requirements for research and clinical trial for CGTs.

Current Development Landscapes of CGTS in China

Publications and patent applications for CGTs

According to the analysis from Chinese Academy of Sciences, China generated 24,199 publications and 4,850 patent applications related to CGTs between 1988 and 2017, which ranked second after United States with 36,901 publications and 14,573 patent applications.⁹

In China, the number of publications for CGTs began to increase rapidly between 2003 and 2007 (about 4,500), more than four times compared with that in the period of 1998–2002.⁹ The number of publications reached its peak between 2008 and 2012 (about 9,100) and a slight decrease was observed between 2013 and 2017 (about 8,900).⁹ Over the period of 1988–2017, two organizations from China were among the top 10 organizations generating the largest publications worldwide: Shanghai JiaoTong university ranking seventh with 795 publications and Huazhong University of Science and Technology ranking eighth with 757 publications.⁹ The top 10 organizations with most publications in CGTs in China were all from universities and public research institutes.³⁴

The patent application trend for CGTs in China was similar to that of publications, with a rapid increase during 2003–2007 (about 300) compared with that during 1998–2002 (about 100).⁹ However, unlike that of publications, the number of patent applications still increased dramatically in the period of 2013–2017 (about 3,000), three times higher than that in the period of 2008–2012 (about 1,000).⁹ During the period of 1988–2017, one organization from China was listed on the top 10 organizations with most patent applications over the world: Chinese Academy of Sciences ranking seventh with 280 patents.⁹ Among the top 10 organizations in China, Guangzhou SALIAI Stem Cell Technology, who ranked third with 131 patents, was an enterprise, and the other organizations were all universities and public research institutes.³⁴

Clinical trials for CGTs

Currently, the United States and China are leading the race in CGT development with 3,907 and 1,041 clinical trials registered on ClinicalTrials.gov website, respectively.³⁵ Although China is ranked second in the number of clinical trials for CGTs, there is a large gap between China and the top country, the United States, which conducts over three times clinical trials than China. From the Wiley database on Gene Therapy Trials Worldwide, the United States undertakes the most clinical trials for gene therapy globally with 1,643 trials, followed by China with 322 trials.³⁶ Among the 322 clinical trials for gene therapies in China, 276 of them (85.7%) are in the early phases (Phase 1 or Phase 1/2). The overwhelming majority of them (n = 291, 90.4%) target a treatment for cancer diseases. Among the 137 clinical trials reporting on vectors and delivery techniques, lentivirus vectors (n = 62) are the most adopted approach followed by adenovirus (n = 38) and CRISPR-Cas9 (n = 13) vectors.

China, however, has the leading position in clinical trials for CAR-T therapies, according to the registry on ClinicalTrials.gov website, which has surpassed the United States since June 2017.³⁷ By the end of 2020, 381 clinical trials for CAR-T therapy were identified in China on ClinicalTrials.gov website.³⁸ Our analysis showed that the number of clinical trials began to increase rapidly since 2016, and the year 2019 had the largest number of clinical trials (n = 87), followed by 2020 (n = 68) and 2017 (n = 64). Most clinical trials were for the treatments of blood tumors (n = 278, 73.0%) and solid tumors (n = 92, 24.1%). However, the indications targeted by CAR-T seemed to gradually become diversified over the past 3 years, even though the number of clinical trials for other indications was still small (Fig. 2a).

Figure 2.

The analysis of registered CART clinical trials on ClinicalTrials.gov in China by the end of 2020. (a) The distribution of CART clinical trials by type of disease from 2013 to 2020. (b) The distribution of CART clinical trials by type of clinical trial phase. (c) The distribution of CART clinical trials by type of sponsor. (d) The top 10 CART targets investigated in the CART clinical trials. (e) The top 10 CART targets investigated in the CART clinical trials for blood tumors. (f) The top 10 CART targets investigated in the CART clinical trials for solid tumors. HIV, human immunodeficiency virus; NMOSD, Neuromyelitis Optica Spectrum Disorder; POEMS, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes; SLE, Systemic Lupus Erythematosus.

Most clinical trials (n = 324, 85.0%) were still in the early phases (Phase 1 and Phase 1/2) (Fig. 2b). Only five clinical trials (1.3%) were in the late phases (Phase 2/3 and Phase 3). Among them, three trials investigated the CD19-targeted CAR-T for the treatments of acute lymphoblastic leukemia and B cell lymphoma, one trial investigated the CD123 and CLL1-targeted CAR-T for the treatment of acute myeloid leukemia, and one trial investigated the BCMA-targeted CAR-T for the treatment of multiple myeloma. The clinical trials were mostly sponsored by collaboration between industry and hospital (n = 157, 41.2%), followed by hospital (n = 99, 26.0%) and industry (n = 43, 11.3%) (Fig. 2c).

A total of 69 targets were investigated (Supplementary Table S3), either as single target or a combination of multiple targets. The top five most studied targets for all indications were CD19 (n = 178), BCMA (n = 49), CD22 (n = 39), CD20 (n = 32), and MESO (n = 20) (Fig. 2d). The top five most targets for blood tumors were CD19 (n = 173), BCMA (n = 45), CD22 (n = 37), CD20 (n = 31) and CD123 (n = 16), and the top five most targets for solid tumors were MESO (n = 19), GPC3 (n = 14), EGFR (n = 11), MUC1 (n = 10), and HER2 (n = 10) (Fig. 2e–f).

Investigational new drug applications for CGTs

On March 12, 2018, CFDA approved the first investigational new drug (IND) application of a CAR-T therapy from Nanjing Legend Biotech, which marked that the first CGT was officially licensed for clinical trial initiation in China.¹⁰ This is significant because clinical trials of CGTs not authorized by CFDA will not be accepted for application of market authorization in China.

By the end of 2020, a total of 78 IND applications of CGTs from 53 companies were identified from CDE website.¹⁰ The year 2018 had the most IND applications (n = 38), followed by 2020 (n = 25), 2019 (n = 11), and 2017 (n = 4). Among the 78 IND applications, 12 were approved after the review of CDE, 36 were granted implied approval without receiving rejection or question from CDE within 60 days of their submitted applications, and 30 are still under review. Among 48 IND applications receiving approval or implied approval, 31 were for CAR-T therapies targeting CD19 (n = 22), BCMA (n = 5), CD20 (n = 1), CD30 (n = 1), CLDN18.2 (n = 1), and GPC3 (n = 1). The remaining CGTs with IND approvals included 10 stem cell therapies, 2 gene therapies, and 5 other therapies.

On January 19, 2021, CDE approved the IND application for ET-01, an investigational CRISPR/Cas 9 gene-editing therapy for patients with transfusion-dependent β-thalassemia, which marked the first gene-editing therapy IND application approval in China.¹⁰

Key Contributors to Rapid Development of CGTs

In general, there are three key contributors for the rapid development of CGTs in China: (1) policy and funding support from national and regional governments, (2) investment support from venture capitalists, and (3) multilateral cooperation between biotech companies.

Policy and funding support from national and regional governments

Accompanied with a strict oversight system to standardize the regulation of CGTs, the Chinese government also issued a series of policies to promote the development of CGTs over the past few years. In 2017, the National Development and Reform Commission (NDRC) issued the “13th Five-Year Biological Industry Development Plan,” which stressed that the development of stem cell and CAR-T industry should be one of main focuses in the next 5 years.³⁹ In 2019, NDRC released the “Catalog for Guiding Industry Restructuring (2019 version),” which classified the varying industries into three categories (encouraged, restricted, and eliminated categories) for directing domestic and foreign investment and guiding government agencies to manage local investment projects.⁴⁰ In this document, CGTs were designated as “encouraged” category.

To respond to the national call, various regional governments successively issued policies to accelerate the development of CGTs. For example, the regional governments of Hebei, Shenzhen, and Shanghai have already released the related policies to encourage medical institutions to carry out the stem cell researches in the pilot-free trade zone.⁴¹

At the same time, the Chinese government also increased investments in the CGT industry. According to statistics, stem cell research has been one of the key projects supported by the central government for 3 consecutive years: $69.6 million for 25 projects in 2016; $136.2 million for 43 projects in 2017; and $84.1 million for 30 projects in 2018.⁴² In 2019, the Ministry of Science and Technology issued the guideline indicating that the government planned to allocate another $58.0 million to support additional 12 stem cell research projects.⁴²

This support from the government stimulated great progress with several “first” projects being implemented or in the development. For example, the first Chinese National Gene Bank was officially opened on September 22, 2016 after a 5-year development funded by the Chinese government.⁴³ It is the world's largest gene bank so far, which aims to promote public welfare, life science research, and industry innovation by supporting the CGTs' development. On August 17, 2018, China Gene Group and Luohu Hospital announced to build China's first specialized hospital for CGTs.⁴⁴ On July 31, 2020, the construction of Cell and Gene Therapy Innovation Center was initiated in Beijing and is expected to be put into use by May 2021, which aims to provide the professional services of R&D and clinical trials for biotech companies.⁴⁵ On September 28, 2020, the first Chinese cell therapy sharing industry support platform was initialized in Jinan and is expected to be put in use in 2023, which will be the first industrial support system integrating shared laboratories, shared contract development and manufacturing organizations (CDMOs), and shared clinical centers for cell therapy in China.⁴⁶ These reflect the Chinese government's interests and incentive toward the field of CGTs by investing extensively in building scientific and technological innovation infrastructure.

Investment raised from venture capital

Promoted by policy encouragement and huge market potential, more and more investments targeted to the Chinese CGT market have been made in recent years. By the end of 2020, about 105 venture-raising events for cell therapy occurred in China with a total amount of $2.5 billion (Supplementary Fig. S1a).^47,48 The amount of venture financing soared to $380.0 million in 2018 with a 706.8% increase compared with 2017 (Supplementary Fig. S1a). This may have been promoted by several technical guidelines and encouraging policies for cell therapy issued in 2017 and 2018, along with the approval of two CAR-T cell therapies (Kymriah and Yescarta) in 2017 by Food and Drug Administration (FDA) in the United States. Among the 105 venture-financing events, 16 of them (15%) were in the angel round, 35 of them (33%) were in the A round, 20 of them (19%) were in the B round, 8 of them (8%) were in the C round or above, and 3 of them (3%) were in the initial public offering (IPO) round (Supplementary Fig. S1b).^47,48

In the face of COVID-19, there were still 41 venture-raising events for CGTs with a total amount of $2.4 billion in China in 2020.⁴⁸ The top 10 venture-financing events with largest raised funds for cell therapy in 2020 are summarized in Supplementary Table S4. Nanjing Legend Biotech with raising $423.84 million in US IPO, was the biggest winner in 2020, which also emerged as one of the largest public raises in biotech history.

Partnerships with multinational companies

The multilateral cooperation between biotech companies also accelerated the development of CGTs in China. The multinational companies usually build up collaborations with domestic biotech companies in the form of licensing and joint venture partnerships or establish international clinical research centers to accelerate the layout of Chinese CGT market.

Several pharmaceutical giants or pioneering CGT developers have established partnerships with Chinese biotech companies in the past 5 years (Table 2).⁴⁹ Some examples include (1) Juno Therapeutics and its joint venture with WuXi AppTec, named JW Therapeutics, in the development of novel cell-based cancer immunotherapies in 2016; (2) Kite Pharma's joint venture with Shanghai Fosun, named Fosun Kite, for the development of CAR-T in 2017; (3) Nanjing Legend's collaboration with Janssen in granting a world license for the development of LCAR-B38M in 2017; (4) Cellular Biomedicine and its strategic licensing agreement with Novartis to manufacture Kymriah in 2018; and (5) MilliporeSigma establishing a strategic alliance with GenScript focusing on the manufacturing of CGTs in 2019. CAR-T cell therapy for cancer was one of the major focuses in their partnership agreements between Chinese and foreign companies (Table 2). The three companies with approved CAR-T cell therapies, Novartis, Kite (a Gilead Company), and Juno (a Bristol-Myers Squibb Company), all have established alliances in China for the manufacturing and commercialization of their products.

Table 2.

Partnerships between Chinese and foreign cell and gene therapy companies from 2014 to 2021

Date	Chinese Companies or Organizations	Foreign Companies or Organizations	CGTs Types	Disease Areas	Type of Partnership
April 23, 2014	China Cord Blood	Cordlife	Cell therapy	Blood disease	Collaborative R&D
September 30, 2014	Tianhe Stem Cell Biotechnologies	CORD:Use	Cell therapy	Endocrine diseases	License agreement
June 11, 2015	Wuxi Apptec	Regenxbio	Gene therapy	Not specified	Contract service
January 13, 2016	Shenzhen Yuanxing Bio-Pharm Science & Technology	Medifocus	Seed virus	Cancer	Contract service
April 7, 2016	Wuxi Apptec	Juno Therapeutics	CAR-T and TCR	Cancer	Joint venture
May 24, 2016	Jiangsu Hengrui Medicine	Oncolys BioPharma	Oncolytic virus	Cancer	Distribution and Commercialization
June 7, 2016	3SBio	TNK Therapeutics	CAR-T	Cancer	Joint venture agreement
July 11, 2016	Huapont Pharma	Angionetics	Gene therapy	Cardiovascular disease	Distribution and Commercialization
September 28, 2016	Huapont Pharma	Histogen	Cell therapy	Aesthetic and cosmetics	Distribution and Commercialization
November 28, 2016	China Southeast University	Boehringer Ingelheim	Cell therapy	Otorhinolaryngology	Collaborative R&D
January 6, 2017	SunTerra Biotechnology	F1 Oncology	CAR-T	Cancer	Distribution and Commercialization
January 11, 2017	Fosun Pharmaceutical	Kite Pharma (Gilead)	CAR-T	Cancer	Joint venture
March 28, 2017	Zhaotai Group	Malaghan Institute	CAR-T	Cancer	Joint venture
April 10, 2017	Cellular Biomedicine	GE Healthcare	CAR-T	Cancer	Collaborative R&D
November 8, 2017	Cellular Biomedicine	Thermo Fisher Scientific	CAR-T	Cancer	Collaborative R&D
December 1, 2017	Legend Biotech	Johnson & Johnson	CAR-T	Hematologic malignancies	Collaboration and licensing
January 16, 2018	YOFOTO (China) Health Industry	Replicel Life Sciences	Cell therapy	Dermatology	Distribution and Commercialization
March 21, 2018	Wuxi Apptec	Nohla Therapeutics	Cell therapy	Not specified	Contract service
June 7, 2018	Luye Pharma Group	Elpis Biomed	CAR-T	Cancer	Collaboration and licensing
June 7, 2018	Guangzhou Xiangxue Pharmaceutical	GE Healthcare	TCR	Cancer	Contract service
July 2, 2018	Guangzhou Xiangxue Pharmaceutical	Axis Therapeutics	TCR	Cancer	License agreement
July 11, 2018	YOFOTO (China) Health Industry	Replicel Life Sciences	Cell therapy	Aesthetic and cosmetics	Distribution and Commercialization
July 17, 2018	Tasly Pharmaceuticals	Mesoblast	Stem cell therapy	Cardiovascular disease	Distribution and Commercialization
September 20, 2018	China Medical System	Vaximm	Cell therapy	Cancer	Distribution and Commercialization
September 27, 2018	Cellular Biomedicine	Novartis	CAR-T	Hematologic malignancies	Distribution and Commercialization
March 19, 2019	GenScript Biotech (services)	MilliporeSigma (Merck)	Multiple CGTs	Not specified	Collaborative R&D
April 9, 2019	Fosun Pharmaceutical	ReNeuron	Stem cell therapy	Not specified	Distribution and Commercialization
April 17, 2019	Hong Kong Baptist University	Golden Meditech	Cell therapy	Central nervous system	Collaborative R&D
June 13, 2019	China-Singapore Guangzhou Knowledge City	Tessa Therapeutics	CAR-T	Cancer	Joint venture
September 30, 2019	Tianjin CanSino Biotechnology	Ocugen	Gene therapy	Ophthalmics	Contract service
October 1, 2019	Wuxi Apptec	Trakcel	Cell therapy	Not specified	Contract service
January 9, 2020	Regenerative Medicine of China	Zhittya Genesis Medicine	Not specified	Mixed indications	Distribution and Commercialization
May 12, 2020	Legend Biotech	Noile-Immune Biotech	CAR-T	Cancer	Collaboration and licensing
May 27, 2020	ImmunoChina Pharmaceuticals	EdiGene	CAR-T	Cancer	Collaborative R&D
February 3, 2021	JW Therapeutics	Thermo Fisher Scientific	CAR-T	Cancer	License agreement

CAR-T, chimeric antigen receptor T; CGTs, Cell and gene therapies.

The interests of foreign companies in investing CGTs in Chinese companies are foreseeable because of the large market potential, local resources, and research capabilities.

Challenges and Suggestions for CGTS in China

Due to the nature of CGTs, many countries face several challenges in common for the development of CGTs such as great heterogeneity and variation in manufacturing and limited availability of nonclinical data. Besides the common challenges, the clinical development of CGTs in China also faces several specific challenges.

Regulation framework

Even though China has released a series of regulations, the current regulatory framework still cannot meet the rapid development of CGTs in China. Currently, unlike the United States and Europe, CGTs in China follow a “dual-track” regulatory scheme; companies could achieve market authorization from NMPA with proved safety and effectiveness evidence from clinical trials and medical institutions could conduct clinical research within regulatory of NHC. However, the regulatory jurisdictions between NMPA and NHC deserve more clarity, especially for clinical research for somatic cells. Nevertheless, China still has not established comprehensive ethical supervision for CGTs even though many efforts have been made. Some Ethics Committees lack the necessary practical experience and theoretical knowledge, making it difficult to keep their independence.⁵⁰ To enhance systematic trainings for Ethics Committees is suggested to instruct and supervise in research protocol and informed consent.

Manufacturing and supply chain

Unlike conventional therapies, the development, manufacturing, and transport of CGTs require consideration and care, including temperature controls and tracking and verifying the chain of custody, which could significantly influence the translational success of these products.⁵¹

In China, the virus vectors usually come from a laboratory's small-scale packaging, which cannot ensure the quality level of carrier uniformity, titer, purity, and infection efficiency of vital vectors.⁵² The cells used for clinical research are usually developed in the laboratories of hospitals and research institutions and few of them could meet the requirements of Good Clinical Practice (GCP).⁵² Some companies usually work with CDMOs to accelerate the clinical and commercial programs of CGTs. However, the majority of CDMOs for CGTs are located in Europe and North America.⁵³ In China, the development of CDMOs is in the infancy stage, which lacks the full-lifecycle services from R&D, production to forensic listing. More effects are encouraged from public and private sectors to establish standardized manufacturing, supply chain infrastructure, and professional CDMOs in China.

With the first approval of CAR-T, China needs to address how to develop a standardized and robust good manufacturing practice-compliant manufacturing process for CAR-Treg cells to increase success rate and decrease the costs of CAR-T therapies. Further improvements on optimization of CAR constructs, delivery techniques (viral or nonviral systems), potency testing, and manufacturing automation platforms are suggested.⁵⁴

Long-term clinical efficacy and safety evidence

So far, most cell therapies are in the preclinical and early phases of clinical development and long-term clinical evidence is relatively limited, which requires some time to achieve clinical validation. The published Chinese clinical data for CGTs are usually obtained from single center, nonrandomized clinical trials with limited enrolled patients, which increase the uncertainty of trials' outcomes.⁵⁵ CAR-T therapies are usually criticized for their severe and occasionally lethal toxicities such as cytokine release and neurological toxicity.⁵⁶ A major safety concern for gene therapy is their potential to stimulate immune reactions, which usually requires the usage of immunosuppression.⁵¹ Some gene therapies rely on the use of modified infectious virus, which also increases the risks of life-threatening viral infection.⁵¹

Chinese regulators are suggested to establish dialogue with companies at the early stages of clinical development to address the issues regarding clinical trial designs, risk management plan development, and pharmacovigilance activities, including postauthorization efficacy or safety studies.⁵⁷

Pricing and reimbursement

Compared with conventional drugs, CGTs usually require relatively high prices considering the high costs associated with manufacturing, the small market size (especially for orphan products), and life-long clinical benefits through a potential one-time cure. In the case of Yescarta, the first CAR-T therapy in China, the one-time treatment cost is $373,000 in the United States, which equals 35.6 times per capita GDP in China ($10,484 in 2020).^35,58 How to price and reimburse CGTs to ensure patient accessibility is a big challenge for payers in China.

With the increasing approved number of CGTs, Europe and the United States have provided valuable exemplars of innovative payment models to address the concerns of high treatment cost, upfront payment burden, and uncertainty in clinical outcomes for CGTs. For example, in the case of Yescarta, England and France use coverage with evidence development schemes to reimburse it where the future price and reimbursement reassessment will be based on a combination of both longer-term follow-up from the ongoing trials, and real-world data; Italy and Spain have introduced an outcomes-based staged payment scheme, whereby payments (adjusted for a confidential discount on the list price) will be made in instalments linked to individual patient outcomes.⁵⁹

Payers in China are suggested to learn from the valuable experience in other countries to explore the reimbursement plan suitable for China's national conditions. Companies could try to find different funding options such as charity organizations, commercial insurance agencies, and patient assistance programs to decrease affordability gaps.

Conclusion

China lost the advantage of being one of the frontrunners in CGTs and is now engaged to catch up with other leading countries. After a long period of unregulated field, CGTs are entering a much more policy-regulated environment in China. While there is more to be done, the necessary legal environment is there and continues to improve. Important investments have been initiated to establish a public infrastructure to stimulate and support the emergence of a performing CGT industry in China. This is translated through fast growth of scientific production and patent filings. Public and private funding are growing fast, showing the high expectations from investors and central/regional governments. The large domestic market as well as the research capability and infrastructure have encouraged foreign companies to enter partnerships with Chinese companies for research, manufacturing, and commercialization.

The future development of CGTs in China will rely more on the multilateral cooperation between governments, companies, and research institutions at the national and regional levels than just private company initiatives. Chinese regulatory authorities are suggested to issue more targeted practical guidelines for the development, production, and application of CGTs to form a comprehensive framework. Research institutions should increase the quality and innovation levels of publications and patents to promote the clinical application and transform of their research. Domestic companies should pay more attention to the trends of market, deeply integrate therapies and new-generation medical innovation technologies, and explore the diversification of products. They also need to explore more possibility to forge strategic alliances with developers of CGTs in other countries, which China will benefit from more extensive exchanges of knowledge and technologies to strengthen their own capability, in addition, to promote the exportation of domestic technologies and CGT products to other countries. The example of Nanjing legend, which successfully completed the IPO, has clearly showed how innovation will attract foreign players, and how it will in turn stimulate the future investments.

Footnotes

Acknowledgments

The authors acknowledge Tarek El-Maghrabi for providing medical writing supports.

Author Disclosure

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Figure S1

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

References

Salzman

, Cook

, Hunt

, et al. Addressing the value of gene therapy and enhancing patient access to transformative treatments. Mol Ther, 2018; 26:2717–2726.

Wang

, Wang

, Cai

. An overview of development in gene therapeutics in China. Gene Ther, 2020; 27:338–348.

Cheng

, Lu

S-l

, Fu

X-b

. Regenerative medicine in China: main progress in different fields. Military Med Res, 2016; 3:24.

Li AH-f. Whom to Trust When Sick? The Wei Zexi Incident, the Chinese Internet, and the Healthcare System in China. China Perspect, 2016; 2016:79–83.

The National Health and Family Planning Commission of the People's Republic of China held a video and telephone conference on standardizing the management of medical institutions' departments and medical technology management. National Health and Family Planning Commission of the People's Republic of China. www.gov.cn/xinwen/2016-05/05/content_5070534.htm (last accessed December 28, 2020 ).

Master

, Matthews

KRW

, Abou-el-Enein

. Unproven stem cell interventions: a global public health problem requiring global deliberation. Stem Cell Rep, 2021; 16:1435–1445.

Bauer

, Elsallab

, Abou-El-Enein

. Concise review: a comprehensive analysis of reported adverse events in patients receiving unproven stem cell-based interventions. Stem Cells Transl Med, 2018; 7:676–685.

, Wang

, Tang

, et al. Regulatory oversight of cell therapy in China: government's efforts in patient access and therapeutic innovation. Pharmacol Res, 2020; 158:104889.

Chinese Academy of Sciences & Technology. Global Science & Technology Trends Report: Gene and Cell Therapy Research & Development. https://www.cas.org/resources/whitepapers/gene-cell-therapy (last accessed January 10, 2021 ).

10.

Center for drug evaluation. www.cde.org.cn/index.jsp (last accessed June 20, 2021 ).

11.

Key points for quality control of human somatic and gene therapy clinical research. Ministry of Health of the People's Republic of China. www.elinklaw.com/zsglmobile/lawView.aspx?id=86561 (last accessed December 28, 2020 ).

12.

New measures for the examination and approval of biological products (council order 1999 no. 3). State Food and Drug Administration. https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/fgwj/bmgzh/19990422094901576.html (last accessed December 28, 2020 ).

13.

Technology guidelines for the quality control of human cell therapy research and preparations. State Food and Drug Administration. https://wenku.baidu.com/view/fed10980abea998fcc22bcd126fff705cc175cfe.html (last accessed December 28, 2020 ).

14.

Technical guidelines for human gene therapy research and formulation quality control. State Food and Drug Administration. http://law.pharmnet.com.cn/laws/detail_845.html (last accessed June 20, 2021 ).

15.

Ethical guiding principles for the research of human embryonic stem cell. Ministry of Health of the People's Republic of China and the Ministry of Science. www.scrcnet.org/download/eccr_31.pdf (last accessed June 20, 2021 ).

16.

Ethical principles for human assisted reproduction technology and human sperm bank. Ministry of Health of the People's Republic of China. www.nhc.gov.cn/qjjys/s3581/200805/f69a925d55b44be2a9b4ada7fcdec835.shtml (last accessed June 20, 2021 ).

17.

The first to allow the clinical application of the Third Category of Medical Technology Directory. Ministry of Health of the People's Republic of China. www.gov.cn/gzdt/2009-06/11/content_1337464.htm (last accessed December 28, 2020 ).

18.

Notice on carrying out clinical research and application of self-examination and self-correction of stem cells. Ministry of Health of the People's Republic of China. www.nhc.gov.cn/zwgkzt/pkjjy1/201201/53890.shtml (last accessed December 28, 2020 ).

19.

Notice of the National Health Commission on the Cancellation of the relevant work on the approval of access to medical applications for the Third Category of Medical Technology. National Health and Family Planning Commission of the People's Republic of China. http://www.nhc.gov.cn/yzygj/s3585/201507/c529dd6bb8084e09883ae417256b3c49.shtml (last accessed December 28, 2020 ).

20.

Notice about application as a Stem Cell Clinical Research Institution. National Health and Family Planning Commission of the People's Republic of China and China Food and Drug Administration. www.nhc.gov.cn/qjjys/s3581/201512/a8ef28444b8e4d4382f06353bb09909c.shtml (last accessed December 28, 2020 ).

21.

Measures for the ethical review of biomedical research involving human subjects. National Health and Family Planning Commission of the People's Republic of China. http://www.nhc.gov.cn/fzs/s3576/201610/84b33b81d8e747eaaf048f68b174f829.shtml (last accessed June 20, 2021 ).

22.

Technical guidelines for research and evaluation of cell therapy products (trial). China Food and Drug Administration. http://www.scrcnet.org/download/eccr_33.pdf (last accessed December 28, 2020 ).

23.

Cyranoski

. What

CRISPR-baby prison sentences mean for research

. https://www-nature-com-s.web.bisu.edu.cn/articles/d41586-020-00001-y (last accessed June 20, 2021 ).

24.

China: Therapeutic/stem cell. Global Gene Editing Regulation Tracker. https://geneticliteracyproject.org (last accessed June 20, 2021 ).

25.

Civil Code of the People's Republic of China. National Health Commission. http://www.npc.gov.cn/npc/c30834/202006/75ba6483b8344591abd07917e1d25cc8.shtml (last accessed June 20, 2021 ).

26.

Key considerations for cell therapy product application for clinical trial pharmaceutical research and application materials. China Food and Drug Administration. www.cde.org.cn/news.do?method=largeInfo&id=ffacd65c6758298d (last accessed December 28, 2020 ).

27.

Somatic Cell Therapy Clinical Research and Transformation Application Management Measures (Trial) (Draft for comments). National Health Commission. www.nhc.gov.cn/wjw/yjzj/201903/01134dee9c5a4661a0b5351bd8a04822.shtml (last accessed December 28, 2020 ).

28.

Technical guidelines for clinical trials of immune cell therapy products (draft for comments). National Medical Products Administration. www.cde.org.cn/zdyz.do?method=largePage&id=579b0e71dbe89489 (last accessed December 28, 2020 ).

29.

Technical Guidelines for clinical trials of human-derived stem cells and their derived cell therapy products (draft for comments). National Medical Products Administration. www.cde.org.cn/zdyz.do?method=largePage&id=c641b96eaadd68d5 (last accessed December 28, 2020 ).

30.

Technical guidelines for pharmaceutical research and evaluation of gene therapy products (draft for comments). National Medical Products Administration. www.cde.org.cn/news.do?method=largeInfo&id=b167edc6058fc23e (last accessed December 28, 2020 ).

31.

Technical guidelines for pharmaceutical research and evaluation of immune cell therapy products (draft for comments). National Medical Products Administration. www.cde.org.cn/zdyz.do?method=largePage&id=607291fb0b3ee019 (last accessed December 28, 2020 ).

32.

Technical guidelines for pharmaceutical research and evaluation of gene transduction and modification systems (draft for comments). National Medical Products Administration. www.cde.org.cn/zdyz.do?method=largePage&id=2e2336e1fc34169c (last accessed December 28, 2020 ).

33.

Drug Administration Law. National Medical Products Administration. https://www.nmpa.gov.cn/directory/web/nmpa/hudong/zxft/20190918161201286.html (last accessed June 20, 2021 ).

34.

Chai

, Fang

, Cynthia

, et al. Analysis of gene and cell therapy research & development trend. China Biotechnol, 2019; 39:43–52.

35.

Deloitte. Winning in the cell and gene therapies market in China. https://www2.deloitte.com/content/dam/Deloitte/cn/Documents/strategy/deloitte-cn-strategy-and-operation-china-cgt-white-paper-en-200520.pdf (last accessed December 2020 ).

36.

Gene Therapy Trials Worldwide. The Journal of Gene Medicine. https://a873679.fmphost.com/fmi/webd/GTCT (last accessed June 2021 ).

37.

Wang

, Gao

, Wang

, et al. Clinical development of CAR T cell therapy in China: 2020 update. Cell Mol Immunol, 2020; 18:792–804.

38.

NIH. ClinicalTrials.gov. https://clinicaltrials.gov/, (last accessed January 10, 2021 ).

39.

13th Five-Year Biological Industry Development Plan. National Development and Reform Commission. https://www.ndrc.gov.cn/xxgk/zcfb/ghwb/201701/t20170112_962220.html (last accessed December 28, 2020 ).

40.

Catalogue for Guiding Industry Restructuring (2019 version). National Development and Reform Commission. www.gov.cn/xinwen/2019-11/06/content_5449193.htm (last accessed January 10, 2021 ).

41.

Nuwacell. The national and local authorities' cell industry encouragement policies in 2019. www.nuwacell.com/index.php?c=content&a=show&id=507 (last accessed January 10, 2021 ).

42.

Forward the Economist. A panoramic map of the stem cell medical industry in 2021. https://www.qianzhan.com/analyst/detail/220/201207-8cfce57d.html (last accessed December 28, 2020 ).

43.

BGI. China National Genebank Officially Opens. https://www.bgi.com/%E5%85%B3%E4%BA%8E%E6%88%91%E4%BB%AC/careers/china-national-genebank-officially-opens (last accessed January 10, 2021 ).

44.

BIOTECH. China's first gene and cell therapy hospital will be located in Shenzhen. www.biotech.org.cn/information/155581 (last accessed January 10, 2021 ).

45.

Invest. The Life Garden Cell and Gene Therapy Innovation Center is launched to accelerate the transformation of scientific research. http://invest.beijing.gov.cn/tzbj/tzxm/ssmtjxyxw/202008/t20200803_1969610.html (last accessed January 10, 2021 ).

46.

Jinan Science & Technology Bureau. The country's first cell therapy sharing industry support platform is settled in Jinan. Jinan Science & Technology Bureau. http://jnsti.jinan.gov.cn/art/2020/9/29/art_11657_4680138.html (last accessed January 10, 2021 ).

47.

Vcbeat. The full spectrum of domestic cellular immunotherapy companies in China. https://vcbeat.top/47190 (last accessed December 28, 2020 ).

48.

eMedClub. In 2020, China's cell and gene therapy financing transactions exceed 15.5 billion yuan CAR-T is still hot. https://wemp.app/posts/49dbf81d-59c2-483a-bb22-4668c0e260c1 (last accessed December 28, 2020 ).

49.

Insight Pharma Reports. https://www.insightpharmareports.com (last accessed April 8, 2021 ).

50.

, Walker

, Nie

, et al. Experiments that led to the first gene-edited babies: the ethical failings and the urgent need for better governance. J Zhejiang Univ Sci B, 2019; 20:32–38.

51.

Abou-El-Enein

, Elsanhoury

, Reinke

. Overcoming challenges facing advanced therapies in the EU Market. Cell Stem Cell, 2016; 19:293–297.

52.

Gao

. The development status of cell therapy industry and supervision in China. Chin Med Biotechnol, 2019; 14:193–198.

53.

Sartotius. How CDMOs can digitalize their cell and gene therapy processes. https://www.sartorius.com/en/knowledge/science-snippets/how-cdmos-can-digitalize-their-cell-and-gene-therapy-processes-751642 (last accessed June 20, 2021 ).

54.

Fritsche

, Volk

, Reinke

, et al. Toward an optimized process for clinical manufacturing of CAR-Treg cell therapy. Trends Biotechnol, 2020; 38:1099–1112.

55.

Wang

, Tan Su Yin

, Zhao

, et al. CAR-T cells: the Chinese experience. Expert Opin Biol Ther, 2020; 20:1293–1308.

56.

Siegler

, Kenderian

. Neurotoxicity and cytokine release syndrome after chimeric antigen receptor T cell therapy: insights into mechanisms and novel therapies. Front Immunol, 2020; 11:1973.

57.

Exley

, Rantell

, McBlane

. Clinical development of cell therapies for cancer: the regulators' perspective. Eur J Cancer, 2020; 138:41–53.

58.

KNOEMA. China—gross domestic product per capita in current prices. https://knoema.com/atlas/China/GDP-per-capita (last accessed June 20, 2021 ).

59.

Jørgensen

, Hanna

, Kefalas

. Outcomes-based reimbursement for gene therapies in practice: the experience of recently launched CAR-T cell therapies in major European countries. J Mark Access Health Policy, 2020; 8:1715536.

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