By: Jason She, Steve Winitsky, Mo Heidaran, Regulatory & Access, Parexel
In 2003, State Food and Drug Administration (SFDA), the Chinese national regulatory authority, upon its Institutional reform, drafted a guideline for human cell therapy, which was finally released in 2008 (1).The guidance discussed Chemistry, Manufacturing, and Controls (CMC), non-clinical, and clinical aspects of cell therapy. It pointed out the challenges of cell manufacturing, inspection of cells, and quality control of cells. It also outlined the requirement for sponsors to follow GMP, GLP, and GCP standards. However, despite the guidance, the majority of hospital-employed investigators still considered themselves not to be companies, which would mean that they were under no obligation to receive approval from SFDA for administering cell therapies as part of their medical practice. In 2013, a survey was carried out by the China Medicinal Biotechnology Association (CMBA), which revealed that out of a sample of 150 hospitals in Beijing, Shanghai and other major cities, all 150 of the hospitals had “cytokine-induced killer cells” (CIK)* programs. Among them, 88 hospitals also provided options for “dendritic cell-cytokine-induced killer cell” (DC-CIK)** therapy. Altogether, 54,094 patients received hospital-based CIK and DC-CIK treatments in 2013, with the cost per course of treatment ranging from CNY 5,500 to CNY 54,000.
It wasn’t until April 2016, when an incident caused by “immune cell therapy” that was widely reported in most Chinese newspapers resulted in an immediate government “shutdown” of almost all cell-therapy centers in mainland China. A young man named ZheXi Wei, an undergraduate student, received DC-CIK treatment for his late stage "synovial sarcoma." Mr. Wei’s doctor had apparently told him that the DC-CIK treatment would quite possibly result in a cure; however, the cancer continued to progress. In the final days of his life, Mr. Wei left several messages on his social media (WEIBO) account criticizing the doctor for deliberately lying to him about the efficacy of the treatment. This unapproved therapy not only stripped him of an opportunity to seek other treatments, but also left his parents with a substantial amount of debt that was very hard for them to pay off. This incident aroused public sympathy and indignation, spurring the government to take action (2).
In 2017, FDA approved two chimeric antigen receptor (CAR) T-cell products: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). Also, Emily Whitehead, who received the breakthrough CAR-T therapy, became the most famous cancer patient internationally (3). This “glimmer of dawn” eventually reached the CGT sector in China. However, this time, the China National Health Commission (NHC) issued a regulation to restrict hospitals from charging patients for unapproved cell therapy projects, emphasizing the difference between clinical research and approved clinical treatment. Furthermore, it required hospitals with cell therapy programs to obtain qualification from NHC before conducting cell therapy research. With this dramatic change, many biotech companies that had previously built up business partnerships with hospitals to charge patients for their unapproved cell products began to submit clinical trial applications (CTAs) to the Center of Drug Evaluation (CDE) of the National Medical Product Administration (NMPA) -- the new name for SFDA starting in September, 2018.
Fosun Kite Biotechnology Co., Ltd. ("Fosun Kite") was established in April 2017 in Shanghai as a joint venture of Shanghai Fosun Pharmaceutical (Group) Co., Ltd and U.S. Kite Pharma (4). Juno and WuXi AppTec also set up another joint venture, JW Therapeutics (Shanghai) Co., Ltd (5). Following the creation of these two pioneers, hundreds of biotech companies in this field were founded starting in 2018 and have since been actively developing CGT pipelines. In the beginning, pipelines from those companies mainly focused on targeting CD19 antigen with CAR-T products that used a 4-1BB/CD28 co-stimulatory design, but gradually, the products and treatment indications have diverged. As of May 31, 2020, a total of 28 companies had sent 41 CAR-T CTA applications to CDE/NMPA. Among these companies, 19 (67.9%) received approval of at least one application, with CAR-T targets including: CD19, BCMA, CD30, CD269, GPC3, and CLDN18.2 (source: http://www.chinadrugtrials.org.cn). In addition, Chinese biotech companies have started studying next generation products, such as fast CAR-T, UCAR-T (Universal CAR-T, or off the shelf version of CAR-T), TCRT, Tumor Infiltrating Lymphocytes (TILs), Induced Pluripotency Stem Cells (IPSCs)-derived CAR-T, and CAR-NK, but to date, those product classes remain underdeveloped, with many of those programs not having progressed past the non-clinical stage.
Accompanying this trend, NMPA also released six key regulation documents related to CGT products in the past three years (6,7,8,9,10,11). In the “GMP appendix - cell therapy products” document, NMPA clearly describes its requirements for cell therapy products, with regard to nine categories: scope, principles, personnel, “plant, facilities and equipment,” “materials and substance,” “production management,” “quality control,” “product traceability system,” and “collection of donor materials and use of products.” There are also three new guidelines that outline best practices for clinical trials that administer immune cells, human stem cells and their derived cell therapeutic products, and oncolytic viruses (9,10,11).
As reported by “Chinabiotoday.com”: “Nanjing Legend Biotech, a subsidiary of GenScript (HK: 1548), has filed for an IPO on a US exchange. In 2017, Legend surprised the world when its CAR-T therapy produced a 94% response rate in pretreated multiple myeloma patients. Six months later, Johnson & Johnson (NYSE: JNJ) partnered the treatment in a deal that paid Legend $350 million upfront, plus unspecified milestones and royalties (12). The CAR-T candidate, JNJ-4528, is now in Phase II trials in the US” (13). However, it’s clear that not every company in China can attract a development partner with the stature and know-how of Johnson & Johnson.
As a global leader in the Contract Research Organization (CRO) industry, Parexel has the resources and experience for companies who are aiming for global development of their Cell & Gene Therapies. We have provided assistance to numerous biopharmaceutical clients in China and around the world with a wide array of clinical development services, including regulatory support, preparation for early engagement interactions with US FDA, such as INTERACT PreIND and IND submission support, to late-phase activities, such as pre-BLA meetings and BLA authoring. Parexel also facilitates product development by providing technical support with product manufacturing and compliance services. Our 1,000+ strong consulting team includes over 80 former regulators / inspectors who have helped develop guidance across the world. To learn more, download our brochure or connect with one of our experts today.
* cytokine-induced killer cells (CIK)
Cytokine-induced killer (CIK) cell therapy, a growing option in the field of cancer immunotherapy, encompasses therapeutic strategies based on manipulating and co-opting a patient's or donor's cells to treat cancer. CIK cells are a heterogeneous subset of ex-vitro expanded, polyclonal T-effector cells with both natural killer (NK) and T-cell properties, which present potent non-major histocompatibility complex-restricted cytotoxicity against a variety of tumor target cells.
Cell-based immunotherapy with cytokine-induced killer (CIK) cells: From preparation and testing to clinical application Guirong Zhang et.al. Hum Vaccin Immunother 2017
**dendritic cell-cytokine-induced killer cell (DC-CIK)
Cytokine-induced killer (CIK) cells that are stimulated using mature dendritic cells (DCs), referred to as (DC-CIK cells) exhibit superior anti-tumor potency.
Safety and activity of PD-1 blockade-activated DC-CIK cells in patients with advanced solid tumors Jian-Chuan Xia et.al. Oncoimmunology 2018
1 Technical guideline for human cell therapy research and preparation quality control. SFDA 2008
6 Technical guidelines for research and evaluation of cell therapy products. NMPA 2017
7 GMP appendix - cell therapy products | NMPA 2019
8 Guiding principles for pharmaceutical research and evaluation of gene therapy products NMPA 2020
9 Technical guidelines for clinical trials of immune cell therapy products NMPA 2020
10 Technical guidelines for clinical trials of human stem cells and their derived cell therapeutic products
11 Guiding principles for clinical trial design of oncolytic viruses NMPA 2020
13 Week in Review: Nanjing Legend Files to Stage IPO in the US