How to navigate a cell or gene therapy through China’s two-tier regulatory system

Two independent pathways govern cell and gene therapy (CAGT) clinical trials in China. One is administered by the National Health Commission (NHC) and enables investigator-initiated trials (IITs) at universities and academic research hospitals. Ethical Committee review and current good manufacturing practices (CGMP) compliance requirements for IITs vary across provinces. Commercialization is not the aim of this pathway, and CAGTs are classified as “therapy techniques.” A majority of IITs are early-phase and first-in-human studies.

The other regulatory route classifies CAGTs as “drugs,” is under the National Medical Products Administration (NMPA) jurisdiction, and is designed to support product licensure. This traditional pathway is similar to those in the U.S. and EU: typically, preliminary communications with regulators (which may occur in person, by phone, email, or on web-based meeting apps) guide sponsors in filing an investigational new drug (IND) or clinical trial application (CTA). If clinical studies are successful, companies can file a marketing submission. 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. 

Our recent search of clinicaltrials.gov suggests that, as of May 15, 2023, more than 1,000 clinical trials of CAGTs have been initiated in China, and the number of IITs far exceeds the number of industry-sponsored (IND-registered) trials.  More than 80 percent of the CAGT studies in China are in early-phase development.

While the high volume of trials means that the base of investigators and sites with experience conducting CAGT research is increasing, foreign companies planning studies in China must carefully manage risks and navigate a complex, nuanced environment. For example, an IIT trial is more flexible and may provide a valuable early readout on safety and efficacy. Still, costly and time-consuming rework may be necessary if trials are not compliant with good clinical practice (GCP) and CGMP. Many top research centers in large cities such as Shanghai conduct initial studies with the adequate ethical review, informed consent, and CGMP compliance: but it is essential to know the landscape. For most sponsors, IND-registered trials are the safest route because they receive regulatory scrutiny throughout development. 

¹ On May 15, 2023, we searched clinicaltrials.gov for stem cell, CAR T-cell, and gene therapy trials in China. We found 645 CAR T-cell trials (50% IIT, 90% early phase); 937 stem cell trials (75% IIT, 80% early phase); and 576 gene therapy trials (70% IIT, 85%+ early phase). In this analysis, IIT trials are those sponsored by non-industry entities, such as individuals, universities, or other organizations.

Developing CAGTs in China demands a savvy, tailored approach.

China remains a strategic priority for many biopharmaceutical companies due to its large population of treatment-naïve patients, lower study costs, and faster recruitment times. At Parexel, we have conducted clinical trials in China and the greater Asia/Pacific region for more than 25 years. During that time, we have witnessed a complete overhaul of the Chinese pharmaceutical regulatory system, bringing it in closer alignment with the U.S. and Europe. But the legal framework continues to evolve, and keeping on top of changing regulations is critical to success. For CAGT developers in China, we currently see several challenges:

• The lack of a well-established, preictable technical solution for scaling up manufacturing from the CAGTs used in IITs and laboratories to clinical trial- and commercial-grade products can hamper development, just as it does in the U.S. and Europe
• The executives leading CAGT companies often are researchers who may not know the complexity and criticality of CMC work and CGMP compliance.
• Many CAGT-focused companies operating in China are small, emerging firms and do not have adequate internal resources or expertise for sound CMC investment.

Despite these challenges, companies with a strong presence in China, including connections with local hospitals and investigators, familiarity with regulatory requirements, and sufficient cultural and linguistic competencies, can leverage opportunities with the right strategy. At Parexel, we have helped numerous clients address CAGT-specific regulatory considerations in China so they can generate data for a globally relevant clinical dossier. For example, we recently helped an international biopharmaceutical company hoping to enter the Chinese market with a CAR T-cell therapy clarify the technical requirements for a CMC control strategy. We also advised a client on key CMC considerations for their first-in-human CTA to test an oncolytic virus product. In China, regulatory guidance is sometimes unavailable and rapidly evolving, so it is crucial to devise a well-informed development strategy.

Contributing Expert