China’s Dual-Track Regulatory System: Shaping the Future of Cell Therapy Research and Commercialization
Cell therapy has rapidly advanced, driven by the FDA’s 2017 approval of CAR-T therapies such as Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), which revolutionized treatment for B-cell malignancies. Subsequent approvals, including Breyanzi (lisocabtagene maraleucel) and Tecartus (brexucabtagene autoleucel) solidified CAR-T’s role in immuno-oncology.
Why did China implement a dual-track regulatory framework for cell therapy?
Since 2017, China has implemented a dual-track regulatory framework for cell therapy, providing distinct and clear requirements for investigator-initiated trials (IITs) and industry-sponsored trials (ISTs). This regulatory clarity has fueled substantial growth in China’s cell therapy pipeline, which now stands as the second largest globally, trailing only the United States. This rapid expansion highlights China’s commitment to developing innovative therapies, bolstered by the increasing approval of CAR-T products, such as Carteyva (relmacabtagene autoleucel), the first domestically approved CAR-T therapy in China.
Carteyva
China’s first domestically approved CAR-T therapy in China.
Landscape of Cell Therapy Clinical Trials in China (2005-2024)
Other somatic cells: 2.4% (e.g., cardiomyocytes: 0.4%)
China’s Registered Trials’ Top Target Indications:
Hematologic malignancies: 37.5% of trials – CD19 was the leading target, and 93.3% of CD-19 studies are CAR-T studies.
Infections: 4.0%
Immune disorders: 5.5%
Cell Therapy Trial Phases in China:
Phase I: 40.5%
Phase I/II: 21.2%
Emerging Focusin China:
Between 2021 and 2023: Recent increase in trials for solid tumour targets such as CLDN18.2, HER2, MSLN
While global clinical trials are increasingly exploring emerging targets such as CLDN18 (with a growth of over 400%) and KRAS (growing by 125%), Chinese trials predominantly focus on established targets like CD19 and BCMA. These two targets alone account for over 38.0% of Chinese trials, compared to 36.2% in global trials.
This emphasis on proven targets reflects a strategic approach to minimize costs and accelerate development timelines, leveraging existing clinical and regulatory knowledge.
Regulatory Agencies in China for Pharmaceuticals and Healthcare
Entering this market requires a thorough understanding of its regulatory framework, managed by two key agencies: the National Medical Products Administration (NMPA) and the National Health Commission (NHC).
1. National Health Commission (NHC)
China’s primary healthcare regulatory agency, previously known as the Ministry of Health and National Health and Family Planning Commission.
Responsibilities:
Oversees the operation of medical institutions, including those serving as clinical trial sites.
Plays a critical role in drug reimbursement policies, impacting access and affordability.
Key Differences Between Agencies
NMPA: Focuses on regulating pharmaceuticals and ensuring drug safety, efficacy, and compliance throughout their lifecycle.
CDE (under NMPA): Specializes in the technical evaluation of clinical and marketing applications for drugs and biologics.
NHC: Oversees healthcare delivery and infrastructure, including hospitals and clinical trial sites, and manages national drug reimbursement frameworks.
2. National Medical Products Administration (NMPA)
The NMPA is China’s primary regulatory body for pharmaceutical products, replacing the former China Food and Drug Administration (CFDA) after government reorganization in March 2018.
Responsibilities: Oversees all stages of the pharmaceutical product lifecycle:
Implements the same laws, regulations, and guidelines as the CFDA.
Sub-Agency: Center for Drug Evaluation (CDE)
Function:
Evaluates applications for clinical trials, marketing authorizations, and supplementary registrations for both domestic and foreign drugs.
Conducts technical reviews of drug and biological applications to ensure safety and efficacy.
Understanding China’s Dual-Track Regulatory System
China has a dual-track regulatory system for cell therapy like T-cell therapy clinical trials, distinguishing between investigator-initiated trials (IITs) and industry-sponsored trials (ISTs).
Cell therapy may be regulated either by the NHC as a Category III medical technology for clinical use or by the NMPA as a pharmaceutical product.
Track #1: The “National Health Commission (NHC)” Pathway for IITs
IITs are clinical trials initiated by investigators at universities or academic research hospitals,
The focus of IIT is on exploratory purposes, such as initial safety and efficacy evaluations, rather than to market a new drug.
Many IITs are early-phase studies, including first-in-human trials.
These trials are overseen by the NHC.
The NHC’s oversight of IITs requires compliance with ethical review and current good manufacturing practices (CGMP), although the exact standards and flexibility may vary across provinces.
IITs may not be subject to the same rigorous regulatory scrutiny as industry-sponsored trials (ISTs). The process is generally more flexible and focuses on advancing scientific knowledge rather than commercialization.
Track #2: The “National Medical Products Administration (NMPA)” Pathway for ISTs
ISTs are clinical trials sponsored by pharmaceutical companies, biotech or medical device companies.
Conducted to achieve drug approval and commercialization.
These trials are regulated by the National Medical Products Administration (NMPA), which manages the approval process for cell therapy products.
To pursue commercialization, an Investigational New Drug (IND) application must be submitted to the NMPA, followed by pivotal trials and New Drug Application (NDA) approval through the Center for Drug Evaluation (CDE) of the NMPA.
IND-registered trials offer the most secure route to commercialization, as they are continuously monitored by regulatory authorities during the development process.
Feature
NHC Pathway (IITs)
NMPA Pathway (ISTs)
Regulatory Authority
National Health Commission (NHC)
National Medical Products Administration (NMPA)
Type of Trials
Investigator-Initiated Trials (IITs)
Industry-Sponsored Trials (ISTs)
Initiation
Initiated by individual investigators or hospitals
Initiated by pharmaceutical, biotech or medical companies
Purpose
Primarily for scientific research, not for marketing
Focused on new drug approval, marketing and commercialization
Approval Process
Less stringent; requires compliance with ethical review and current good manufacturing practices (CGMP), although the exact standards and flexibility may vary across provinces.
More rigorous; requires Investigational New Drug (IND) application and approval from NMPA, followed by pivotal trials and New Drug Application (NDA) approval through the Center for Drug Evaluation (CDE) of the NMPA.
Structured and standardized process with strict guidelines
Data Collection
Can provide valuable early clinical data
Generally follows a more traditional clinical trial framework
This dual-pathway system ensures flexibility for early-stage academic research while providing a structured route for clinical development and commercialization in the cell therapy industry. Sponsors such as foreign entities should carefully consider their objectives when selecting a pathway. IITs offer a lower barrier to entry for initial research, while ISTs provide a clear route to market approval.
As of August 1, 2024, investigator-initiated trials (IITs) dominate the landscape, accounting for 90.2% (n = 2,519) of all trials, while industry-sponsored trials (ISTs) comprise only 9.8% (n = 275). Following the introduction of the 2017 NMPA guidelines, which clarified regulatory requirements for cell therapy products, there has been a significant rise in ISTs for stem cell and somatic cell therapies, growing from none before these guidelines.
Approval Process of IIT in the United States
IITs must still submit an Investigational New Drug (IND) application to the FDA before beginning clinical trials, ensuring more stringent oversight even for exploratory trials.
However, the approval process for IITs is less involved in regulatory scrutiny compared to industry trials.
If an IIT involves a new investigational product or significant modifications to an existing therapy, the FDA will oversee the process with a focus on safety and scientific validity.
If the IIT leads to a potential drug or product, it can transition into a more formal regulatory pathway under the FDA for further phases of development and commercialization.
Similar to China, IITs in the U.S. must comply with ethical review and Good Clinical Practice (GCP). While the FDA ensures that trials meet required safety and ethical standards, the level of oversight is not as extensive as in industry-sponsored trials.
The “NHC” Pathway for IIT Studies
Compared to pharmaceutical-sponsored trials, IITs in China face practical challenges due to the lack of experience among investigators and the immature regulatory framework. The NHC has established a series of guidelines to improve the quality of IITs.
Key Regulatory Framework by the NHC – Administrative Measures for Investigator-Initiated Clinical Trials by Medical and Health Institutions
On December 31, 2020, the NHC released the Draft Administrative Measures for Investigator-Initiated Clinical Trials by Medical and Health Institutions. This draft aimed to:
Standardizes IIT management.
Address organization, financial management, and trial implementation.
Improve oversight and streamline supervision.
Pilot and Implementation:
Trialled in Beijing and three other provinces in 2021, expanded to 12 provinces in 2022.
Pilots improved clinical research systems, professional support, digital management, and research quality.
Based on pilot results, the final version of the Administrative Measures was issued in September 2024, in collaboration with the State Administration of Traditional Chinese Medicine and the National Bureau of Disease Control and Prevention.
Scope of application:
The finalized Administrative Measures contain eight chapters and 49 articles:
primary responsibility of medical and health institutions during the conduct of the investigator-initiated clinical research
Core systems: Including scientific review, ethical review, project initiation and closure, and disclosure of research information.
Management principles: Incorporating classified management, prohibition of redundant research, and enhancing overall research efficiency.
Oversight mechanisms: Establishing a coordinated system of administrative and technical supervision.
Other Regulatory Frameworks by NHC
Administrative Measures on Stem Cell Clinical Research (2015)
Applicable to stem cell research conducted in medical institutions.
Institutions are prohibited from charging subjects any fees related to such research.
Advertising stem cell clinical research, even indirectly, is not allowed.
Somatic Cell Therapy Clinical Research and Transformation Application Management Measures (2019)
Hospitals can provide cell therapy treatments and charge patients, but only after obtaining price approval from provincial-level price authorities.
Enterprises developing somatic cell therapy products must apply for registration and marketing approval with the NMPA in compliance with drug administration regulations.
The “NMPA” Pathway for IST Studies
NMPA is the primary regulatory body overseeing cell therapy products in China. The NMPA regulates cell therapy products as biological drugs, which are subject to the same approval processes as other pharmaceutical products. This includes approval for clinical trials, IND (Investigational New Drug) applications, pivotal trials, and NDA (New Drug Application).
Like the FDA and EMA, the NMPA has issued multiple technical guidance documents outlining standards for Chemistry, Manufacturing, and Controls (CMC), non-clinical testing, and clinical requirements for CAGTs, among other issues.
Approval Process for ISTs
IND Submission:
Industry-sponsored cell therapy products are submitted for IND approval before clinical trials can begin. The NMPA’s Center for Drug Evaluation (CDE) is responsible for reviewing the safety and efficacy data before approving clinical trials.
Clinical Trials and Phases:
Clinical trials are typically conducted in phases (Phase I, II, III). Upon successful completion of each phase, the applicant must submit detailed reports and supporting materials for review by the NMPA before moving to the next phase. This process ensures that only safe and effective products progress through the clinical trial stages.
CDE’s Role in Evaluation:
The CDE conducts technical evaluations of drug applications, assessing safety, efficacy, and manufacturing quality. The CDE reviews the results from clinical trials and provides feedback on potential issues that may arise in later phases of development.
Regulatory Changes and Updates:
In line with the evolving regulatory landscape, the NMPA now allow clinical trials to proceed if the NMPA does not object within 60 days after the submission of an IND application. This has streamlined the approval process and helped expedite clinical trial timelines.
Approval for Subsequent Phases:
Once a clinical trial is approved, the applicant must submit updated protocols and supporting materials before initiating subsequent phases. If the NMPA has no objections to the revised protocol, the applicant can proceed to the next phase, ensuring that the study remains aligned with regulatory requirements.
Key Regulatory Framework
Technical Guiding Principles for Research and Evaluation of Cell Therapy Products (2017)
Scope: Provides guidelines for the medical study, non-clinical research, and clinical trials of cell therapy products and focuses on ensuring that cell therapy products meet drug quality management standards and follow Good Manufacturing Practices (GMP).
Pre-Clinical Research:
Emphasizes a “case-by-case analysis” for evaluating different products.
Requires preclinical safety studies to be conducted using cell therapy products intended for clinical trials, with consistent production processes.
Non-clinical studies should ideally simulate clinical administration and use appropriate animal species or alternatives to predict human responses.
Clinical Trials:
Must comply with Good Clinical Practice (GCP).
Includes safety evaluations, pharmacokinetics, pharmacodynamics, dose exploration, and confirmatory trials.
Specific trial designs can be adjusted based on the product’s pharmacokinetics and pharmacodynamics.
Technical Guidelines for Nonclinical Research and Evaluation of Genetically
Modified Cell Therapy Products (Trial) (2021)
Focuses on non-clinical research for genetically modified cell therapies
CAR- or TCR-Modified Immune Cells
Target-Related Toxicity: Evaluate antigen distribution in human tissues and verify the specific killing of target cells in vitro.
Off-Target Risks: Assess cross-reactivity for CAR’s extracellular domains and TCR’s self-antigen recognition using computational predictions, in vitro tests, and affinity measurements.
TCR Mispairing: Address risks of mismatching introduced and endogenous TCR chains with appropriate design strategies.
iPSC-Derived Cell Products
Tumorigenicity: Conduct preclinical tumorigenicity studies, including positive controls with undifferentiated iPSCs. Validate suicide mechanisms if used to reduce risk.
Epigenetic Changes: Assess potential functional and behavioural abnormalities arising from reprogramming-induced epigenetic alterations through nonclinical studies.
Gene-Edited Cell Products
On-Target and Off-Target Activity: Use computational analysis, deep sequencing, and whole-genome sequencing to confirm editing specificity and detect off-target mutations.
Phenotype and Function: Evaluate the potential impact of gene editing on cellular function and phenotype, accounting for differences in species, cell type, and physiological states.
Technical Guidelines for Clinical Trials of Immune-Cell Therapy Products (Trial) (2021)
Offers guidance on trial planning, protocol design, implementation, and data analysis.
Focuses on safety and efficacy evaluation while addressing the risks associated with clinical trials of immunocellular therapies.
Recognizes the gene therapy aspect of some cell products like CAR-T, guiding sponsors to ensure regulatory compliance and safety.
Key Steps for Foreign Cell Therapy Groups Wanting To Access China’s Cell Therapy Market
Establish Local Partnerships
Collaborating with Chinese academic institutions or hospitals can help navigate the IIT pathway.
These partnerships provide access to clinical trial sites, local expertise, and a better understanding of regional regulatory nuances.
Understanding local business practices and communication styles can strengthen partnerships and streamline negotiations.
Understand Ethical and GMP Standards
The dual-track system can be challenging to navigate. Seek local regulatory consultants to bridge knowledge gaps and ensure compliance.
For IITs: Standards vary across provinces, so early engagement with local authorities is crucial. Ensure compliance with ethical review processes and cGMP requirements.
For ISTs: Follow NMPA’s detailed guidelines on Chemistry, Manufacturing, and Controls (CMC) and clinical trial requirements.
Prepare an IND Submission (for ISTs)
The IND process with the NMPA is similar to the FDA or EMA but involves localized considerations:
Expect a 60-day review period, during which trials can proceed if no objections are raised.
Regulatory submissions and correspondence must be in Chinese. Employ professional translators familiar with technical and regulatory terminology.
. Focus on Proven Targets
Chinese trials prioritize established targets like CD19 and BCMA to minimize costs and leverage existing data.
Aligning your research with these trends can expedite approvals and reduce development timelines.
Supply Chain and Manufacturing
China’s GMP standards are evolving and now closely align with international norms. Ensuring compliance is vital for both IITs and ISTs:
Local Manufacturing Presence: Setting up a GMP-certified facility in China can reduce logistical challenges and demonstrate a long-term commitment to the market.
Partnerships: Collaborating with local contract manufacturing organizations (CMOs) can minimize upfront investment while ensuring compliance with local standards.
Cold Chain Logistics: Given the temperature sensitivity of cell therapy products, invest in robust cold chain systems to maintain product integrity across distribution channels.
Raw Materials: Ensure that critical raw materials, such as growth media and viral vectors, are either locally sourced or can be reliably imported without regulatory hurdles.
China’s cell therapy landscape is rapidly evolving, supported by a robust regulatory framework designed to foster innovation and maintain safety standards. With the approval of China’s first cellular product, CD19 CAR-T, and the significant growth in clinical trials for solid tumour cell and gene therapies, China is positioning itself as a global leader in this field.
The overhaul of the regulatory system, particularly since 2017, has aligned Chinese standards with international practices, enhancing the quality and efficiency of clinical trials. Despite some guidelines still being in draft form, the continuous improvements and updates to the regulatory environment aim to address emerging challenges, ensuring that China remains competitive in the fast-paced global cell therapy market.
With the NHC and NMPA providing clear pathways for both investigator-initiated and industry-sponsored trials, the future of cell therapy research and commercialization in China is bright, driven by innovation, collaboration, and a commitment to international standards.
References:
Yin et al. Gene and cell therapies in China: booming landscape under dual-track regulation. J Hematol Oncol. (2022)
Du et al. Mapping the cell therapy landscape: insights into clinical trials and regulatory advances in China, Journal of Hematology & Oncology (2024)
Administrative Measures for Investigator-Initiated Clinical Trials by Medical and Health Institutions 2017 《医疗卫生机构开展研究者发起的临床研究管理办法》: http://www.nhc.gov.cn/qjjys/s3577/202409/aac9e22582104baba5ccfa06f8b67652.shtml
Administrative Measures on Stem Cell Clinical Research (2015) 《关于印发干细胞临床研究管理办法》: https://www.nmpa.gov.cn/yaopin/ypfgwj/ypfgbmgzh/20150720120001607.html?type=pc&m=
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