Abstract
The booming of gene and cell therapy (GCT) worldwide in recent years has been observed, especially in the field of cancers. In order to provide the comprehensive GCT landscape in China with a focus on differential development pathways under the current dual-track regulation mode, we analyzed 953 clinical trials initiated by March 2021 including Investigational New Drugs (IND) registered trials and investigator-initiated trials (IITs). We classified GCT products into three categories and analyzed the clinical development by phases and regulation tracks, disease areas, indications, and targets. We found that CAR-T therapies from ex vivo category and stem and somatic cells from non-gene category are two most studied therapy types and GCT mostly focused on cancers. The number of IITs far exceeded IND-registered trials except for in vivo category. After 2017, when the cell therapy guideline issued, products of all categories boomed, especially the ex vivo categories. These data showed that current dual regulation tracks in China complemented each other and together facilitated the GCT development, especially after 2017. More consistent technical standards and risk-based regulation will help bring more GCT products to patients.
To the Editor
Differential development paths for the three GCT categories
The dual-track regulation mode of GCT in China enables GCT to initiate clinical development by IND-registered trials or IITs. IIT trials are more flexible and can provide valuable early human data. First starting an IIT and then submitting an IND to CDE as a drug is the frequently chosen development path for lots of GCT products in China. The 2017’s “cell therapy guideline” issued by NMPA [3] with more clarified technical standards and the marketing approval of CAR-T therapies abroad in 2017 together stimulated the overall pipelines’ development. The technical standards for IIT trials also became strict and clarified recently [8], more and more equivalent to that of IND trials. Before 2017, less risky cell therapies like non-gene edited MSC therapies conducting IITs took more proportion. After 2017, both IND-registered and IIT trials boomed, especially the trials testing ex vivo categories (Fig. 1d). In vivo category displayed different trend, given that it was defined as drug since early years. The developer distribution also showed similar patterns (Additional file 1: Fig. S1).
Outlook
We can see that current dual regulation tracks in China complemented each other and together facilitated the GCT development, especially after 2017. The regulation mode of China is different from the US mode. In the USA, GCT should apply for IND or Investigator-IND, both requiring IND application to FDA. However, regulation in China and the USA both strive for the consistent and strict standards which are the basis for steady development of GCT. Also, in the USA the biologics are regulated under section 351 and section 361 of the Public Health Services Act, and products regulated under section 361 (with relatively lower risks) need not to apply for Biologics License Application (BLA). Recently, an FDA expert’s mention of considering an intermediate regulatory pathway for some products regulated under section 361 [9] also revealed the future trend. In the future, more risk-based and stratified regulation of GCT will nurture innovation while managing risks.
IIT can provide more flexibility during R&D and IND-registered trials are more standardized. How to better connect these two pathways and keep their advantages remains a challenge. As we mentioned above, consistent technical standards and risk-based approach is the key to the GCT regulation. Thus, we suggest further issuance of consistent technical guidelines and stratified regulation based on risk for GCT clinical trials. Strengthened ethnic review is also vital for subject protection. Specific expert consensus and guidelines for GCT ethnic review were published recently in China [10, 11], and we expect more attention to be attached to patient protection. Besides regulation, greater encouragement on medical need driven R&D, and more efforts in establishing manufacturing infrastructures will help bring more novel GCT products from bench to patient in China.
