The Role and Challenges of Investigator‐Initiated Trials in the Cell and Gene Therapy Products Boom in Mainland China

ABSTRACT

As cutting‐edge technologies in biomedicine, cell and gene therapy (CGT) products demonstrate immense potential in treating cancer, rare diseases, and genetic disorders, thereby driving the importance of clinical research in this area. This study analyzes the growth trends and key characteristics of 1033 Investigator‐Initiated Trials (IITs) conducted by mainland Chinese institutions in the CGT field. The results show that IITs have played a positive role in the early proof‐of‐concept of CGT products, helping to obtain preliminary safety and efficacy data, and exploring the combination of CGT products with other therapies. Additionally, this study discusses the regional distribution, therapeutic areas, and challenges faced by IITs in the development of CGT products in China. Based on these findings, policy suggestions are proposed to optimize the regulation of IITs in mainland China, such as improving regulatory frameworks and enhancing technical guidance. It is hoped that these measures will further improve the efficiency and quality of IITs, fully utilize the large patient base and abundant clinical resources, and support the development of high‐quality CGT products in mainland China.

Summary.

• What is the current knowledge on the topic?

  • ○
    Cell and gene therapy (CGT) products offer promising treatments for cancer, rare diseases, and genetic disorders, driving substantial clinical research.
  • ○
    In China, a quasi‐dual‐track regulatory system has further propelled the expansion of investigator‐initiated trials (IITs) in CGT.
• What question did this study address?

  • ○
    This study examines the growth trends and characteristics of CGT‐related IITs in mainland China, with comparisons to IND trials, and explores the impact of China's regulatory environment on CGT trial development.
  • ○
    Specifically, it addressed the following:

    • The development trends and driving factors of CGT‐related IITs in China.
    • The regional distribution, indications, and target diseases of IITs in China.
    • The role of IITs in generating high‐value preliminary data for assessing safety, efficacy, and therapeutic potential.
    • The key challenges facing IIT development in China and potential directions for future regulatory optimization.
• What does this study add to our knowledge?

  • ○
    The study provides a unique data set distinguishing CGT‐related IITs from IND trials, documenting a rapid rise in IITs since 2015, predominantly driven by gene‐modified cell therapies.
  • ○
    The analysis reveals that single‐center IITs, though smaller in patient numbers, have nearly doubled total patient enrollment compared to IND trials, emphasizing the role of IITs in early drug development.
  • ○
    Importantly, the study emphasizes the need for improved regulatory frameworks and enhanced participant protection in IITs.
• How might this change clinical pharmacology or translational science?

  • ○
    This study underscores the critical role of IITs in early‐stage CGT development, particularly in a rapidly evolving regulatory environment.
  • ○
    It calls for improvements in trial standardization, regulatory oversight, and participant protection, which could enhance the scientific validity and ethical conduct of CGT research.
  • ○
    These insights may lead to more rigorous clinical research, accelerating the translation of CGT discoveries into effective therapies.

1. Introduction

Cell and gene therapy (CGT) products, as cutting‐edge biomedicine technologies, have garnered significant attention in global medical research and drug development. By utilizing cell engineering and gene editing technologies, CGT offers groundbreaking treatments for refractory diseases, particularly cancer, rare diseases, and genetic diseases [1]. The distinctive attributes of CGT products include a long development cycle, high cost, and technical intricacy [2]. This raises a pivotal question: how can development and commercialization be expedited through effective clinical research methods?

The United States, with its robust regulatory infrastructure and extensive research and development (R&D) resources, holds a preeminent position in the global advancement of CGT products. By 2023, the Food and Drug Administration (FDA) had approved multiple CGT products, including CAR‐T cell therapy for the treatment of B‐cell acute lymphoblastic leukemia (B‐ALL) and diffuse large B‐cell lymphoma (DLBCL), as well as gene therapy for the treatment of Leber congenital amaurosis (LCA), spinal muscular atrophy (SMA) and hemophilia A and B [3, 4]. The European Medicines Agency is also actively engaged in promoting the R&D and market access of CGT products through the Advanced Therapy Medicinal Products (ATMPs) regulatory framework [5]. With the support of national funding programs and public health initiatives, European countries have made significant progress in research and clinical applications in the CGT domain [6]. Other nations, including Japan, South Korea, and Australia are also vigorously fostering R&D and the commercialization of CGT products [7, 8, 9]. Notably, Japan has streamlined CGT product approval via the Regenerative Medicine Safety Act, fostering innovation and expanding its global R&D presence [10].

The development of CGT products in mainland China started relatively late; however, significant progress has been made in terms of policy support, R&D investment, and technological innovation over the past few years. As of August 2024, a total of 7 CGT products have been granted market approval, including 5 CAR‐T‐cell products, 1 oncolytic virus product, and 1 viral‐vector gene therapy product [11]. The prosperous development of CGT in mainland China is attributed to the adjustment of regulatory systems, especially the issuance of the “The Notice on the Cancellation of Approval for Clinical Application Access of Third‐Category Medical Technologies” in 2015 by the National Health and Family Planning Commission of the People's Republic of China, followed by the National Medical Products Administration (NMPA), which issued a series of technical guidelines to guide the development of CGT products [12, 13, 14]. Furthermore, unlike Japan's regulatory framework, China employs a quasi‐dual‐track system for regulating CGT. This system includes the “drug track” for marketing applications managed by NMPA and the “therapeutic track” overseen by the National Health Commission (NHC) for investigator‐initiated trials (IITs). However, products in the therapeutic track can only transition to the drug pathway by submitting an Investigational New Drugs (IND) application. This quasi‐dual‐track regulation allows IITs to exhibit greater flexibility and autonomy, significantly supporting the clinical evaluation of CGT products [15].

IITs are typically initiated by clinical researchers (mainly physicians), which is one or a series of clinical studies driven by medical development and clinical treatment needs. With the growth of the CGT field, IITs have expanded from targeting specific issues of postmarket drugs to early research on the safety and efficacy of investigational products [16]. Through IITs, researchers can quickly obtain preliminary safety and efficacy data, which is crucial for assessing the potential of CGT products and guiding subsequent R&D, thus accelerating their development [15].

There are abundant patients and rich clinical resources in mainland China, particularly in oncology and rare diseases, providing a vast research population for IITs. Numerous large hospitals and research institutions actively engage in IITs, accumulating extensive clinical research experience. However, despite significant policy support for IITs, there remains a lack of a risk‐based management system during the application and implementation. Overall, the research quality and management of IITs in mainland China remain suboptimal, and the international recognition of domestic IIT data still requires further improvement [17, 18].

This study examines IIT research data on CGT products in mainland China, exploring the role and challenges of IIT in CGT development. It also analyzes the current situation of IIT regulation both domestically and internationally, as well as the actual implementation of IIT in mainland China. This allows for a comprehensive evaluation of the limitations and conflicts in existing regulations, and proposal policy recommendations to optimize IIT regulation in mainland China. The results provide reference information on standardizing IIT implementation and improving the clinical quality of IITs, thereby leveraging China's clinical resources to support the growth of the emerging pharmaceutical industry.

2. Methods

2.1. Retrieval and Screening of Relevant Registered Trials

This cross‐sectional study includes interventional CGT trials registered on ClinicalTrials.gov and IND trials on chinadrugtrials.org.cn from January 1, 2000, to April 30, 2024. The trials from ClinicalTrials.gov were obtained by using the advanced search terms of different categories of CGT products, with “China” as the location. CGT‐related IND trials on chinadrugtrials.org.cn were sourced using keywords on different CGT products. These data were imported into the Excel table, and key information (start date, research objectives, investigational drugs, and participant enrollment criteria) was manually reviewed to exclude irrelevant data. All data were downloaded on April 30, 2024, for analysis conducted between May and July 2024.

2.2. Data Extraction

The following information was extracted from ClinicalTrials.gov and chinadrugtrials.org.cn: (1) tracking information: submission date, first posted date, study start date/date enrollment, primary completion date, and key time nodes; (2) descriptive information: titles, detailed description, study type, study phase, and study design; (3) recruitment information: estimated enrollment/target size; and (4) administrative information: NCT number, sponsor, collaborators, and registered address. Additional cell information, including origins, cell types, target spots, disease area, and indications, was manually reviewed. Moreover, we categorized cell therapy products (CTPs) into five types based on cell sources (pluripotent stem cells, adult stem/progenitor cells, perinatal, fetal, and functional mature/differentiated cells) and gene therapy products (GTPs) into four types based on technology and mechanism of action (oncolytic viruses, therapeutic vaccines, vectors expressing transgenes, and gene‐modified cells) according to FDA recommendations.

3. Results

3.1. Screening and Included Trials

A total of 1204 trials were identified on ClinicalTrials.gov, from which eight trials conducted overseas were excluded, including seven IND trials registered by manufacturers from mainland China and one IIT. Additionally, a separate data set comprising 329 IND trials was sourced from the chinadrugtrials.org.cn. By cross‐referencing key information (investigational drug, manufacturers, start dates, and research purposes), 163 domestic IND trials were filtered out from the 1196 CGT‐related trials. This resulted in a final IIT data set of 1033 trials conducted by medical institutions or manufacturers in mainland China (Figure 1). Among these, 347 trials were irregularly registered manufacturers as sponsors. To ensure accuracy, the authors verified the research institution details through additional registered information, finalizing the IIT data set.

FIGURE 1.

Flowchart of data selection, up to April 30, 2024. (A) CGT‐related trials on ClinicalTrials.gov; (B) CGT‐related trials on chinadrugtrials.org.cn.

3.2. Growth Trends of IIT on CGT in Mainland China

From the standpoint of the total number of CGT clinical trials, IND trials in mainland China experienced a rapid growth phase beginning in 2018 (Figure 2A). In comparison, the growth of IITs commenced 3 years earlier (in 2015) (Figure 2C), with the number of IITs registered on ClinicalTrials.gov reaching 207 by 2023, an increase of 11.2 times compared with 2015.

FIGURE 2.

The growth trends of CGT products in mainland China. (A) Annual trend of IND trials, (B) Composition of IND trials by different product categories (2018–2023), (C) Annual trend of IITs, (D) Composition of IITs by different product categories (2015–2023). (1) The red stars in A and C indicate the starting point of the rapid growth stage. (2) For the purpose of comparative analysis, the cases in D did not include the single fetal case in 2017 (NCT03296618). (3) The trials registered in 2024 were not included in this figure.

The rapid growth period of IITs can be divided into three distinct stages: 2015–2017, 2018–2020, and 2021–2023, each characterized by unique driving factors. Figure 2B,D shows the proportions of different categories of products in IND trials and IITs, respectively. Figure 2D reveals that the proportion of gene‐modified cell‐related IITs has consistently remained above 50% since 2015, even exceeding 80% in 2016, 2017, and 2020. During stages 1 and 2, the surge of IITs was predominantly driven by gene‐modified cell products, with the regulatory adjustments serving as the primary catalysts. These included the policy shifts in July 2015 that excluded stem cell therapy‐related technologies from the third category of medical technologies management and the issuance of the “Technical Guidelines for Research and Evaluation of Cell Therapy Products” by the NMPA in December 2017 [12, 13, 14]. Moreover, the growth of IITs may have stagnated between 2020 and 2021, potentially due to the impact of COVID‐19.

In Stage 3, the increase in IITs exhibits new characteristics. After 2021, the clinical studies on CGT products witnessed a new growth phase, with the gene‐modified cell products still experiencing a 44% increasing in total number, compared with stage 2. Yet, their share among all CGT categories diminished from 85% in 2020 to 51% in 2023. Similarly, the proportions of oncolytic virus and vectors expressing transgene products increased to 10% and 15%, respectively. This trend was more significant in IND trials, where the proportion of gene‐modified cells decreased from 73% in 2018 to 24% in 2023, while vectors expressing transgene products increased from 9% to 26%, and no significant change in oncolytic virus products was detected. This suggests that the rapid development of CGT products in Stage 3 was also influenced by technological advancement, allowing a broader spectrum of innovative CGT products to enter early‐stage proof‐of‐concept and IND phases. Vectors expressing transgene products may emerge as a new competitive frontier soon.

3.3. Distribution of IIT on CGT in Mainland China

A total of 1033 IITs were conducted in mainland China, of which 929 were single‐center clinical trials. Geographically, the top five provinces/municipalities in terms of the number of IITs were Shanghai (15.9%), Beijing (14.1%), Zhejiang (11.9%), Jiangsu (11.1%), and Guangdong (8.5%). The Yangtze River Delta economic zone centered around Shanghai and the Capital Economic Zone centered around Beijing accounted for 39.0% and 22.9% of the total, respectively. Additionally, the Central China region (Henan, Hubei, and Anhui) also demonstrated significant potential (12.8%, 119/929) (Figure 3A). In terms of clinical recruitment numbers, the Yangtze River Delta, Jing–Jin–Ji (Beijing–Tianjin–Hebei), and Guangdong emerged as core regions, with Beijing leading with 4744 cases, followed by Shanghai with 3641 cases, and Guangdong with 2759 cases (Figure 3B). The geographic distribution of IND trials sponsors mirrored that of the IIT research institutions, with Shanghai (28.6%, 94/329), Beijing (20.7%, 68/329), and Guangdong (12.8%, 42/329) being the top three, followed by Jiangsu (11.2%, 37/329) and Zhejiang (6.7%, 22/329) (Figure 3C). These results indicate that Shanghai and Beijing are the core hubs for CGT product development and IIT research in mainland China. Moreover, Shanghai influences the Yangtze River Delta economic zone, while Beijing affects the Capital Economic Zone, with Guangdong also playing a significant role, fostering CGT development in North, East, and South China. Although Central China and Southwest China have fewer R&D enterprises, their strong clinical resources and medical infrastructure support the clinical translation of CGT products. From an economic zone perspective, the Yangtze River Delta leads the Capital Economic Zone by a margin of 1.42–1.78 times in both IND trials and IITs (Table 1), which may be attributed to the region's economic openness and supportive policies.

FIGURE 3.

Distribution of Cell and Gene Therapy Research and Trials in Mainland China. (A) Geographical distribution of IIT study numbers (statistics of single‐center studies conducted in mainland China). (B) Geographical distribution of IIT recruitment numbers (statistics of single‐center studies conducted in mainland China). (C) Geographical distribution of sponsors for IND trials. (D) Distribution of research phases for different products in IND trials. (E) Varieties of phase III IND trials. (F) Distribution of research phases for different products in IITs. (G) Proportion of single‐agent and combination therapies in IITs.

TABLE 1.

Clinical research activities for CGT products across different economic zones.

Economic zone	Province/municipality	IIT		IND
		No. of clinical trials a	No. of cases	No. of clinical trials b
Capital economic circle	Beijing	131	4744	68
	Tianjin	44	1048	15
	Hebei	38	1174	3
	Total	213	6966	86
Yangtze river delta economic circle	Shanghai	148	3591	94
	Jiangsu	103	2538	37
	Zhejiang	111	3732	22
	Total	362	9861	153
Ratio		1.69	1.42	1.78

^a Based on the location of the clinical implementation institution.

^b Based on the location of sponsors/marketing authorization holders.

Further analysis reveals that 89% of the IND trials were phase I/II studies, with only 7% being phase III studies (including phase I/II/III), which focused primarily on vectors expressing transgenes (52%) (Figure 3D,E). These phase III clinical trials involved 20 CGT products submitted by 18 sponsors, of which 8 sponsors (44%) were based in Shanghai and 3 (17%) in Beijing. Similarly, in IITs, Phase I/II accounted for 90%, whereas Phase III (including Phases II/III) constituted only 1%. For the most popular IIT research category, gene‐modified cells, out of 701 studies, early phase I and phase I accounted for 22% and 44%, respectively, with an additional 20% being phase I/II (Figure 3F). Notably, 24% of IITs were exploratory studies of combination therapies, with 16%, 27%, and 25% of these conducted in the early phase I, phase I, and phase I/II stages, respectively (Figure 3G). These findings highlight the role of IIT in product development, not only in early proof‐of‐concept and obtaining preliminary safety and efficacy data but also in exploring the combined use of CGT products with monoclonal antibodies, radiotherapy, chemotherapy, and other treatments, demonstrating their significant value.

In terms of study scale, the enrollment numbers for IND trials involving pluripotent stem cells, oncolytic viruses, therapeutic vaccines, vectors expressing transgenes, and gene‐modified cells were significantly higher than those for IITs (p < 0.05). No significant differences were observed in functional mature/differentiated cells or perinatal or adult stem/progenitor cells (Figure 4A). Among IITs with known site location information, 92% are single‐center studies. For Gene‐modified cells, which had the greatest number of trials, single‐center IITs had significantly lower enrollment numbers than multicenter IITs and IND trials (p < 0.05). However, there were no significant differences in scale between domestic multicenter IITs and IND trials (Figure 4B). Notably, the 1033 IITs recruited approximately twice as many participants as the 329 IND trials, highlighting the need for greater focus on participant protection and trial quality in IITs.

FIGURE 4.

Comparison of patient enrollment between IIT and IND. (A) Comparison of IND and IIT enrollment, (B) comparison of single‐center and multicenter IIT data from gene‐modified cells with IND data. Each data point represents one separate clinical trial.

3.4. Therapeutic Areas and Diseases for CGT in Mainland China

On the basis of data from both IIT and IND trials, the most concentrated area of research for CGT products is currently in the field of oncology. Specifically, 43.5% of IITs target hematologic malignancies, whereas 32.9% focus on solid tumors (Figure 5A). In the domain of nononcological treatments, key areas of research areas include genetic disorders, autoimmune diseases, infections, cardiovascular diseases, and ocular diseases (Figure 5B).

FIGURE 5.

The application of CGT for clinical treatment. (A) Distribution of all diseases, (B) nononcological indications, (C) hematologic malignancies indications, (D) drug targets for B‐cell lymphoma treatment, (E) target distribution of single‐target drugs, (F) drug targets for T‐cell lymphoma treatment, (G) indications for solid tumors.

As the primary therapeutic area, hematologic malignancies represent the core competitive target for CGT products, specifically gene‐modified cell products. These products constitute 95% of the total 449 IITs target hematologic malignancies. In terms of specific therapeutic indications, B‐cell acute lymphoblastic leukemia/lymphoma (B‐ALL/LBL), plasma cell myeloma (PCM), and chronic lymphocytic leukemia (CLL) are the top three most common lymphoproliferative diseases and tumor indications, with percentages of 27.8%, 20.2%, and 12.4%, respectively. Moreover, acute myeloid leukemia (AML) has a significant representation at 14.7%. Conversely, research on lymphoid tumors originating from T and NK cells is relatively scarce. Among these indications, T‐cell acute lymphoblastic leukemia/lymphoma (T‐ALL/LBL) ranks the highest, accounting for 6.4% (Figure 5C).

Among the 343 IITs targeting B‐cell tumors, 248 disclosed target information. Of these, 70% of the studies used drugs targeting a single target, while the remaining 30% targeted dual or multiple targets. The most concentrated research targets included CD19 (66.5%), BCMA (23.0%), CD22 (14.5%), CD20 (9.7%), and GPRC5D (4.4%, 11/248) (Figure 5D). These five targets are also the most widely used in single‐target drugs, accounting for 57.2%, 23.7%, 4.0%, 4.0%, and 4.6%, respectively (Figure 5E). In comparison, relatively few studies disclosed target information for NK/T‐cell tumors, with the top three targets being CD7 (64.7%), CD5 (11.8%), and CD30 (5.9%) (Figure 5F). Notably, among the 34 studies with disclosed targets, 33 were single‐target drugs.

The utilization of gene‐modified cell products in the treatment of solid tumors is also extensive, accounting for 57.6% of the total 340 studies on solid tumors, followed by functional mature/differentiated cells (21.8%) and oncolytic viruses (13.5%). The most common indications are hepatocellular carcinoma, gastric cancer, and pancreatic cancer, accounting for 21.3%, 13.3%, and 12.7%, respectively. CGT products are also under investigation in IITs for urogenital system tumors, thoracic tumors, central nervous system tumors, and head and neck tumors (Figure 5G). In addition to the wide range of indications, the targets for products aimed at solid tumors are also quite diverse, with over 80 disclosed targets. The top five targets are PD‐1, CEA, CD3, claudin 18.2, CD70, and GPC3. Research on PD‐1, CEA, claudin 18.2, and GPC3 has focused on digestive system tumors, whereas CD70 has been studied primarily in urogenital system tumors such as ovarian and cervical cancers. CD3 has broader indications, including digestive system tumors, urogenital system tumors, soft tissue tumors, and bone tumors (Figure S1).

3.5. Positive Impact of IIT on IND Applications

Among the 1033 IITs, 54 have been completed, with an average study duration of 29.4 months (95% confidence interval: 25.6–33.3 months). Among the completed IITs, 68.5% of the study drugs were gene‐modified cells, and 27.8% were cell therapies. Information on 41 studies involving 34 products from 22 companies has been disclosed, with 21 products showing positive progress after completing IIT, including 15 gene‐modified cell products (Table 2). For 19 domestically registered drugs, the average duration from IIT initiation to IND acceptance was 27.2 months (95% confidence interval: 18.9–35.4 months); 52.6% (10/19) of the drugs were submitted for IND before completing IIT (based on acceptance date). Five products have been submitted for market approval in the United States and mainland China, with four receiving Orphan Drug Designation (ODD) from the FDA. Additionally, two products have FDA‐approved INDs but are not yet registered domestically: CAR‐T cells from the Cellular Biomedicine Group and TCR‐T cells from the Lion TCR. These findings suggest that IITs can provide preliminary safety and efficacy data for early drug development, support IND submissions, and even provide evidence for regulatory review.

TABLE 2.

IND application status of drugs with completed IITs.

No.	Manufacturer	Drug name	Type	IIT		NMPA		FDA
				Start date	Completion date	IND	Year	IND	Year	Expedited review
1	CARsgen	CT011	CAR‐T	2015/2017	2018	√	2019	/	/	/
		CT041	CAR‐T	2019	2024	√	2020–2023	/	/	/
2	Heyuan Biotechnology	CNCT19	CAR‐T	2016/2017	2018/2021	√	2020–2024	√	2022	ODD
3	BRL Medicine Inc.	BRL‐101	Hematopoietic stem cell therapy	2020	2023	√	2022	/	/	/
		BRL‐201 (Modified)	CAR‐T	2020	2023	√	2023	/	/	/
4	China Immunotech	HXYT‐001	CAR‐T	2020	2021/2022	√	2022	/	/	/
		YTS‐104	STAR‐T	2022	2022	√ (Implied License)	2024	√	2022	ODD
5	Regend Therapeutics	REGEND001	Cell therapy	2019/2021	2022/2023	√	2023	/	/	/
6	Beijing Imunopharm Technology	IM19	CAR‐T	2017	2019	√	2020–2022	/	/	/
7	Hebei Senlang Biotechnology	SENL101	CAR‐T	2020	2021	√	2023	√	2023	ODD
8	AbelZeta	C‐CAR066	CAR‐T	2019	2022 ~ 2023	/	/	√	2023	/
9	Simnova	F01	CAR‐NK	2022	2022	√	2024	/	/	/
10	Lion TCR	LioCyx‐M004	TCR‐T	2015/2016	2019/2021	/	/	√	2021	ODD/Fast Track
11	XiangXue Life Sciences	TAEST16001	TCR‐T	2017	2019	√	2020–2022	√	2020	/
12	Anhui Kedgene Biotechnology	PD‐1 knockout‐engineered T cells	Gene‐modified cell therapy	2017	2018	√	2024	/	/	/
13	Newishes Technology	Autologous Tcm injection	Cell therapy	2017	2019	√	2022	/	/	/
14	Shanghai iCELL Biotechnology	hAESCs injection	Cell therapy	2020	2023	√	2023	/	/	/
15	Shanghai Bendao Gene Technology	BD111	Gene therapy	2020	2022	√	2023	√	2023	ODD
16	Shanghai Sunway	H101	Oncolytic virus	2021	2023	√	2023	/	/	/
17	Innovent Biologics	IBI346	CAR‐T	2022	2023	√ (Implied License)	2023	/	/	/
18	Chengdu Meijesaier Biotechnology	PD‐1 knockout‐engineered T cells	Gene‐modified cell therapy	2016	2020	√ (Implied License)	2024	/	/	/

Abbreviation: ODD, orphan drug designation.

Notably, two IITs have been conducted on Brl Medicine Inc.'s CD19 CAR‐T products. The first study (NCT03232619) was initiated in August 2018 and utilized the drug BRL‐201. Another IIT was subsequently launched in March 2020 via a modified product incorporating a nonviral technique for site‐specific integration of the PD1 gene based on BRL‐201. This modified product was filed for IND in 2022 (Application No. CXSL2200465) [19]. These findings suggest that IIT data can provide valuable references for product modifications, aiding in the optimization of drug design and the development of superior innovation products.

Additionally, Immuno PHARM's IIT for the product IM23 was initiated in July 2018 for the indication of CD123+ AML and finished in October 2020. However, judging from the pipelines recently disclosed by Immuno PHARM, IM23 did not appear in the list of drugs under development, and it is speculated that the IIT data did not meet expectations or that there are other considerations so that the project has not been promoted [20]. This case underscores the importance of promptly terminating IITs with negative outcomes to avoid further investment, benefiting pipeline management and strategic adjustments. Whether the other 10 drugs used in completed IITs will be followed up with IND applications or considered separately deserves further attention.

3.6. Challenges of IITs Under the Quasi‐Dual‐Track Regulation Status in Mainland China

In 2021, the National Health Commission of China officially issued the “Management Measures for Investigator‐Initiated Clinical Research Conducted by Medical and Health Institutions (Trial Implementation)” as the first regulatory framework for IITs in mainland China. The regulation clarifies the basic principles, responsibilities, and regulatory requirements for stakeholders. According to this, IITs are divided into observational studies and interventional studies, and interventional studies must use drugs or medical devices that are already approved and marketed [21].

Since 2022, the aforementioned administrative measures have been implemented on a trial basis in 12 provinces and municipalities in mainland China [22]. In practical terms, the role of IITs in the clinical development of innovative drugs, especially CGT products, has long surpassed the scope of this document. Policies such as the “Administrative Measures for Stem Cell Clinical Research (2015)” and the draft “Administrative Measures for Clinical Research and Translational Applications of Somatic Cell Therapy (2019)” highlight that IITs for CGT products are not limited to postmarketing studies but serve as early exploratory studies preceding IND application. The officially issued “Guidelines for Clinical Research of Somatic Cells” further emphasize the national intent to encourage innovation and exploration in somatic cell IITs [23].

Local governments primarily regulate IITs based on the NHC's Notice No. 155 (Administrative Measures for Investigator‐Initiated Clinical Trials), while also introducing region‐specific regulatory, incentive, and policy measures to enhance IIT quality [24, 25, 26]. Despite progress, several risk points persist, requiring urgent attention. Our team surveyed the implementation and management of IITs in mainland China. The results indicate that IITs for CGT products are primarily driven by clinical needs and researchers' interests, yet unclear policies and an incomplete regulatory system constrain research quality. Most IITs face funding shortages, although some projects receive financial support from enterprises and industry associations. While most healthcare institutions have initiated IITs, few have comprehensive management systems or dedicated departments. In particular, ethical review and participant protection need urgent reinforcement. To address these challenges, the IIT regulatory system should be further improved by implementing risk‐based management to standardize the IIT research process and quickly establish sound regulatory standards and guidelines. Healthcare institutions should establish robust IIT project management systems, create dedicated clinical research management departments, and improve oversight to ensure the scientific and standardized conduct of IITs.

4. Discussion

This study provides an in‐depth analysis of IIT research data for CGT products in mainland China, revealing the current state and development trends of the CGT industry as well as the role of IIT research in CGT product development. Since 2018, IND trials for CGT in mainland China have entered a period of rapid growth, with IITs playing a pioneering role in promoting early‐stage research and innovation. The growth period of IITs can be divided into three stages: 2015–2017, 2018–2020, and 2021–2023, each driven by different factors, particularly policy and technological advancements. Notably, vectors expressing transgenes have emerged as a new competitive area, following gene‐modified cell products. This trend indicates that diversification and technological innovation in CGT, accelerating product progression into early proof‐of‐concept and IND applications, thereby fueling the sector's overall growth.

Geographically, the development and clinical research capacity of CGT products in mainland China exhibit significant regional characteristics, influenced by various economic zones. Shanghai, Beijing, Zhejiang, Jiangsu, and Guangdong lead IITs, with the Yangtze River Delta Economic Zone and the Capital Economic Zone playing dominant roles. Other regions, such as Central China, also show considerable potential. IND trial sponsors are similarly concentrated in Shanghai, Beijing, and Guangdong, indicating the robust development of research institutions in the North, East, and South China regions, with the Yangtze River Delta and Capital Economic Zones as core hubs. These findings highlight the pivotal role of Shanghai and Beijing, extending their influence to the Yangtze River Delta and Capital Economic Zones, in supporting the CGT development. Furthermore, the Central and Southwest regions, despite having fewer R&D manufacturers, offer valuable clinical resources and infrastructure for CGT translational studies.

CGT products are primarily applied in clinical research for antitumor treatment, with B‐ALL/LBL, PCM, and CLL being the top three indications [27]. In the treatment of hematologic malignancies, CGT products predominantly target single targets, with a gradual exploration of dual and multiple targets. The most focused targets include those for B‐cell tumors (CD19, BCMA, CD22, CD20, and GPRC5D) and those for NK/T‐cell tumors (CD7, CD5, and CD30). In the treatment of solid tumors, digestive system tumors such as liver cancer, gastric cancer, and pancreatic cancer are the most popular indications for CGT products. Additionally, numerous IITs target urogenital system tumors, thoracic tumors, central nervous system tumors, and head and neck tumors. These products exhibit high target diversity, with over 80 identified, including prominent targets such as PD‐1, CEA, CD3, and claudin 18.2 being prominent targets [28]. As CGT development advances, its clinical applications are expected to expand, offering hope to a broader patient population.

This study has highlighted the crucial role of IITs in early safety and efficacy evaluation and indication exploration for CGT products, providing essential evidence for R&D decision‐making. The research shows that most CGT products made positive progress post‐IIT, with over half submitting IND applications prior to IIT completion. This demonstrates the value of IITs in providing preliminary data, enhancing R&D confidence, and even facilitating the entry of domestic innovations into international markets.

IITs play a significant role in product optimization. For example, data from IITs of Brl Medicine Inc., CD19 CAR‐T‐cell products informed product modifications and strategic adjustment. These findings indicate that IIT data not only assess the safety and efficacy of a new product but also provide critical insights for optimization, thereby enhancing drug development efficiency. Furthermore, CGT‐related IITs are not only used to study single therapies but also to explore the combination use with monoclonal antibodies, radiotherapy, and chemotherapy, expanding their applications and prospects.

However, the IIT boom presents potential risks. The 1033 IITs in this study involve over 30,000 participants, twice the number in IND trials. Although individual IITs involve fewer participants than IND trials, their increasing number poses challenges to ensure research quality and participant protection. Our survey identified the current risks and issues in IITs, highlighting the need to optimize the regulatory system in mainland China with increased policy support and technical guidance.

However, this study, based on publicly available data and surveys, may not fully reflect the actual situation. The proposed improvement measures and policy recommendations should be further tested and optimized in practice. Our future research will explore IIT regulatory pathways, verify operational standards through pilot projects, and develop new regulatory tools to improve the quality of IITs and the level of evidence in the data.

In summary, IITs are crucial in early drug development, providing preliminary data for IND applications and guiding product improvements. However, challenges in IITs highlight the need for enhanced regulatory frameworks and technical guidance. Establishing national or regional centers CGT production centers could streamline processes and improve quality control. Furthermore, international agreements on IIT standardization would promote global cooperation and consistency in research standards, boosting the efficiency and quality of IITs. These improvements would support the development of high‐quality CGT products in China and advance the healthcare sector.

Author Contributions

Y.Y., L.B., and Y.C. wrote the manuscript. C.G. and T.C. designed the research. Y.Y., L.B., Y.C., Y.X., H.S., J.R., S.G., J.G., M.J., X.Z., L.L., S.M., and X.L. performed the research. Y.Y., L.B., and Y.C. analyzed the data.

Ethics Statement

As this study involved the analysis of publicly available data, no ethical approval was needed. However, the data were handled in accordance with the guidelines provided by ClinicalTrials.gov and the journal's ethical standards.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1.

Data Availability Statement

The data sets generated during the current study are not publicly available for privacy reasons but are available from the corresponding author upon reasonable request.