SHANGHAI – The CFDA recently released "Guiding Principles for the Research and Evaluation of Cell Therapy Products" for trial implementation. This hotly anticipated move now adds cell therapies – such as stem cells and chimeric antigen receptor (CAR T) therapies – under the umbrella of CFDA reforms that are aligning China's drug regulations with global drug markets. The guidelines set out standards for the approval of clinical trials for cell therapies and opens the door to a viable path to commercialization of cell therapies to be regulated by the CFDA, much like other new drugs.

"The new guidelines will increase the standard of China's cell therapy products and will move China closer to global standards," Jimmy Wei, venture partner at Kleiner Perkins Caufield & Byers, told BioWorld Asia. "It is a big change. In the past, it was mostly regulated through the Ministry of Health (MOH); now we are getting closer to the U.S. and European standard."

China's health ministry, the National Health and Family Planning Commission (NHFPC), as part of its responsibility for overseeing hospitals, has been regulating hospital procedures such as stem cell and CAR T treatments with a mandate to allow research while at the same time weeding out rogue clinics selling dubious treatments for profit (although the NHFPC had no jurisdiction over hospitals or research affiliated with the military.)

Chinese researchers and biopharmas have been able to launch CAR T studies in certain hospitals, if approved by the hospital and local health authorities, and collect data quickly one reason why China has as many if not more CAR T studies than the U.S. But this approach left fuzzy the question of nationwide market approval and commercialization.

Now, the answer to that question is coming into focus.

"Once you have CFDA review and clinical approval, you can obtain national approval; this will be much faster than the MOH route: going through the long process of getting approval hospital-by-hospital (to provide cell therapy treatment)" explained Wei.

Chinese CAR T spurred on by success in the U.S.

Last year the FDA approved two CAR T therapies: Kymriah (tisagenlecleucel, previously CTL-019) from Novartis AG to treat children and young adults with B-cell acute lymphoblastic leukemia (ALL) and Yescarta (axicabtagene ciloleucel, previously KTE-C19) for certain types of non-Hodgkin lymphoma (NHL) to treat adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. (See BioWorld, August 31, 2017 and Oct. 20, 2017.)

Without a regulatory path in China, no CAR T therapy has been approved by the CFDA. But this has not deterred ambitious researchers from studying CAR T treatments on Chinese patients.

According to a December paper in the Journal of Hematology & Oncology, there are 121 CAR T trials in China as listed on clinicaltrials.gov as of July 2017. Leaders in the field such as Juno Therapeutics Inc. and Kite Pharma Inc. have established joint-ventures with China players Wuxi Apptec and Fosun Pharmaceutical Group Co. Ltd. in an effort to compete with the dozens of local firms that have also entered the fray.

"The CFDA has been under pressure to initiate a cell therapy approval process," Peter Sun, head of global partnering at Beike Biotechnology of Shenzhen, told BioWorld Asia. "The U.S. has approved two CAR T therapies, and China had not accepted any clinical trial applications (CTAs); it created added pressure."

China also had a potential local champion on its hands after ASCO 2017 when Nanjing-based Legend Biotechnology Corp. shared data showing a 100 percent response rate in 35 Chinese patients with relapsed and/or refractory multiple myeloma. Data collected received hospital and health authority's relatively quick approval. Before last year, CFDA approval for first-in-human drug studies were backlogged, often taking years to green light.

Legend recently inked a $350 million cash deal with Janssen Biotech Inc., a subsidiary of Johnson & Johnson, for its bispecific CAR T therapy, LCAR-B38M, and was granted the national approval to conduct clinical trials before the CFDA's new guidelines were released. This approval came after Legend announced in September a death in their expanded trial of 74 patients. (See BioWorld, Jan. 3, 2018.)

Legend is the first company to get the CTA go-ahead from the CFDA but at least four other companies have announced that CAR T trial applications have been accepted by CFDA since December: Anhui Anke Biotechnology Inc., Carsgen Therapeutics Ltd., and Galaxy Biomed.

According to Sun, Beike Biotechnology has several subsidiaries involved in CAR T therapy, some of which are currently preparing their applications to the CFDA.

"We are forming a team to start preparing documentations for the application; everybody is doing this," said Sun. "It is like a bus, if the bus is here you better catch it. Who knows when is the next bus will come?"

Regulations still a work in progress

The trial guidelines set out to regulate cell therapy products "in accordance with the norms of drug management research, development and evaluation."

Further, they emphasize risk management and quality control and "propose(s) general technical requirements concerning the safe, effective and quality control of cell therapy products." For example, the guidelines include a product traceability management system to ensure the product can be tracked from donor to recipient.

However, those in the industry are expecting much more work will need to be done as the CFDA and China's Center for Drug Evaluation staff up to gain experience in a field that is relatively new to them.

"I think these guidelines are good for China, but the CFDA and the industry will need to work together to move this forward. The infrastructure for CAR T is still not mature yet, it will not be easy," noted Wei.

In particular, he pointed out the need for several steps in the manufacturing process will need to reach cGMP standards from virus to cellular production.

Sun also said the CFDA is working through its information requirements around manufacturing.

"I heard that the first application is only 100 pages. The CFDA will need more document support for CMC (chemistry, manufacturing and controls) data," said Sun.

MOH door still open

Although the new regulations allow for CFDA to regulate cell treatments, for the time being the human studies are still permitted if the health authorities and individual hospitals give the green light.

However, most companies with their own IP and concerned about meeting rigorous standards for clinical trial studies will likely avail themselves of the CFDA pathway.

"For the time being, people can still go through the MOH pathway and try to collect data that way, but I think more and more high quality companies will submit applications with the CFDA," said Wei.

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