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 Shanghai-based WuXi AppTec.
Analysts have noted recent health care reform
developments and a favorable landscape for in licensing and partnering of
foreign cell therapies in China, especially CAR-Ts, describing the Kite Fosun
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 Shanghai-based 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 non-Hodgkin’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.
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’s degree in
journalism from Ball State University and lived in China from 2001-2004. Follow
Alaric on Twitter @AlaricD_BPI