Western CAR-Ts face Chinese Development Hurdles Due to Regulatory Uncertainty

Western-origin chimeric antigen receptor T-cell (CAR-T) therapies being developed in China face an uncertain regulatory landscape at the national level, as well as disparities between hospitals’ practices at the local level, experts said.

While regulation of cell therapies like CARTs may fall under Chinese Food and Drug Administration (CFDA) regulations, details of these regulations remain unclear, experts said. However, Ministry of Health-imposed restrictions on commercialization of cell therapies -- put in place after a scandal last year -- appear likely to be lifted, experts said, and potential approval of CAR-Ts in the US may spur the Chinese government to liberalize policies. Meanwhile, widely different hospital-level skillsets and approaches to institutional review board (IRB) approvals mean CAR-T manufacturers must be careful about which centers they use, experts said.

Kite Pharma (NASDAQ:KITE) announced 10 January the formation of a Shanghai-based joint venture (JV), Fosun Pharma Kite Biotechnology, with Fosun Pharmaceutical (SHA:600196), to will license and develop Kite’s axicabtagene ciloleucel (axi-cel) in China. The deal gives the JV options to license other Kite CAR-Ts and T-cell receptor (TCR) therapies. Juno Therapeutics (NASDAQ:JUNO) announced 7 April 2016 a similar JV, JW Biotechnology, with Shanghaibased WuXi AppTec.

Analysts have noted recent health care reform developments and a favorable landscape for inlicensing and partnering of foreign cell therapies in China, especially CAR-Ts, describing the KiteFosun JV as positing substantial cell therapy development opportunities there.

A Kite spokesperson noted the CFDA has drafted guidelines for cell therapies that are under review, but it does not currently regulate them, and the company has not disclosed timing or other details regarding clinical trials in China. The spokesperson added the 50/50-owned JV will be a separate Chinese company that will manufacture and develop axi-cel there. Juno did not address specific inquiries, and neither Fosun nor WuXi AppTec responded to requests for comment.

Uncertain regulatory landscape

A hurdle remaining to be cleared is Ministry of Health-imposed restrictions on commercial use of cell therapies in cancer - though clinical trials are still allowed - following a high-profile scandal last year in which a synovial sarcoma patient died after receiving dendritic cell cytokine-induced killer (DC-CIK) therapy, noted Alex Chang, professor, School of Medicine, Tongji University, Shanghai, and Lung-Ji Chang, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville. Despite being ineffective, the therapies had become widespread in China, leading to many patients being defrauded, Lung-Ji Chang added.

However, based on documentation, the government appears to be moving toward allowing commercialization, said Jianqiang Li, formerly Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, and now working on a startup in China. Dr Weidong Han, Department of Hematology, Chinese People’s Liberation Army Hospital, Beijing, said the government is treating CAR-T development as a priority.

Draft guidance that the CFDA released for public comment on 16 December 2016 proposed a CFDA-led regulatory framework for stem cell therapy, immune cell therapy and gene editing. The draft guidance has sparked industry debate and indicates the CFDA is gradually establishing a more flexible and pragmatic approach to cell therapy, according to a 20 December press release by Innovative Cellular Therapeutics, a Shanghaibased CAR-T company.

Thus, cell therapy development, which previously fell under the authority of the Ministry of Health, will likely now fall specifically under CFDA oversight, Jianqiang Li said. In general, cell therapies had previously not been regulated much, Lung-Ji Chang said.

FDA approval of CAR-Ts would be proof of concept for clinical application and could thus spur the Chinese government to open the market faster, said Peng Li, principal investigator, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences. This news service previously reported that axi-cel would likely win FDA approval for aggressive nonHodgkin’s lymphoma, while acute lymphoblastic leukemia (ALL) data on Novartis’ (VTX:NOVN) opened a decent approval path for tisagenlecleucel-T.

But for the moment, there are no specific development regulations for CAR-T, Lung-Ji Chang said, thereby presenting a hurdle to Western CARTs entering the market. For example, it is unclear if initiating a clinical trial would require filing an IND-type application, and who would look at such an application if it was filed, he said.

Given regulatory uncertainties and the greater difficulties of developing drugs in China than in the US, Kite and Juno were smart enough to know it would not be a good idea to try and enter the Chinese market by themselves, Alex Chang said. A lot of companies previously opened research facilities in China when the government opened the pharmaceutical market, but closed them after discovering drug development there was more difficult than anticipated due to unpredictable regulations, Lung-Ji Chang said.

Hospital practice disparities

Beyond regulatory hurdles, there are also development disparities in terms of different hospitals’ practices during trials, Lung-Ji Chang said. While some will make sure to get IRB approval before starting a study, others will not until after the study has started, he explained, adding some still will not seek IRB approval at all, he explained.

With time, he said, hospitals in China may catch up to international standards and ensure IRB approval before enrolling patients. But until then, companies developing CAR-Ts will have to be very picky about which hospitals they use for clinical trials, he said, adding that even working with CROs in China can sometimes be hectic because they do not do a good enough job facilitating communication between trial sites and sponsors.

Many hospitals have also insisted on doing manufacturing on-site, whereas others do not, Peng Li said. Because of this, he said, the CAR-T development program he is running set up central GMP facilities in Guangzhou and Changsha, as well as smaller facilities at some of the centers. ClinicalTrials.gov lists one Phase I study (NCT02822326) -- in which he is taking part -- of a CD19-targeting CAR-T in acute leukemia, sponsored by Guangdong General Hospital.

In terms of centers’ abilities to handle the toxicities associated with CAR-T and required inpatient care, Peng Li, Lung-Ji Chang and Alex Chang agreed there were significant disparities between some hospitals, with some being exemplary in their treatment of patients and others ill-equipped to handle CAR-T toxicities due to lack of skills, while doctors at other hospitals were too harried to communicate efficiently with sponsors.

April 3, 2017

Alaric DeArment

Reporter, New York

Alaric DeArment covers cancer drug development for BioPharm Insight. He served as associate editor of Drug Store News from 2008 to 2014, covering branded and generic drugs from development to distribution, retail and specialty pharmacy and regulatory affairs. In 2011-2012, he edited the book Contestation and Adaption: The Politics of National Identity in China. A native of Seattle, he graduated with honors with a bachelor degree in journalism from Ball State University and also lived in China from 2001-2004. Follow Alaric on Twitter @AlaricD_BPI