Recently, I learned that Fosun Kate, a joint venture company of Fosun Pharma, is fully promoting the technology transfer and preparation verification of KitePharma’s first CAR-T product KTE-C19 (trade name Yescarta) approved by the FDA. The company has followed the national GMP standard and built an advanced ultra-clean laboratory for cell preparation in accordance with the Kite Pharma production process design concept. The laboratory has a large-scale production capacity and can achieve a production capacity of 500 people per year.
As one of the methods of tumor immunotherapy, CAR-T therapy has shown amazing therapeutic effects in the treatment of leukemia, lymphoma, and multiple myeloma. At present, the FDA has approved 2 CAR-T cell therapy products, and there are institutional estimates. The relevant domestic market space reaches tens of billions.
As of December 3, the number of CAR-T clinical trials registered on ClinicalTrials.gov in my country has reached 148, second only to 152 in the United States.
Although the development of CAR-T therapy is in full swing in China, a large number of entrepreneurial companies have emerged, and even many other non-pharmaceutical companies have invested in the layout. However, in terms of drug supervision and the trend of conforming to ICH international standards, CAR-T in the future The real commercialization of cell therapy products in China places higher demands on enterprises.
There are three major difficulties in the supervision of “living cell” drugs. How should they be monitored and how should they be declared?
CAR-T is an extremely personalized treatment that separates T cells from the patient’s blood supply, and uses genetic engineering technology to add a chimeric antigen receptor gene to T cells in vitro, so that it can specifically recognize and kill cancer cells. After being amplified in vitro, it is injected into the patient again to achieve the effect of eliminating cancer cells.
As a “living cell” drug, CAR-T therapy is very different from traditional drugs, which also brings a lot of challenges to supervision. At present, many regulatory agencies in various countries around the world have specific departments to review and control based on drug standards. This year FDA also plans to establish a CAR-T standardized database for multi-sample and standardized analysis, so as to better evaluate and recommend CAR-T therapy clinical trials and new drug applications.
An expert from the China Institute for Food and Drug Control said that from the perspective of pharmaceutical evaluation, CAR-T therapy as a drug supervision has three main difficulties: First, how to determine the dosage, batch and sample retention of patient cells prepared? Second, biological products such as proteins and vaccines have biological activity. This biological activity is related to clinical indications. The “living cells” used in CAR-T therapy have special features in terms of activity, preparation technology, and testing standards; Third, viruses, such as lentiviral vectors, are used in the cell preparation process. How to ensure that the cell products are not contaminated during the preparation process?
In December 2016, CDE issued the “Technical Guidelines for Research and Evaluation of Cell Therapy Products (Revised Draft)”, encouraging cell therapy products to be used as drugs for R&D and registration, and the industrialization path of cell therapy products has gradually become clear. According to people familiar with the matter, the official draft of the guidelines is expected to be announced in the near future, and the introduction of specific technical guidance documents for different types of cell therapy products will not be ruled out in the future.
“In terms of immune cell therapy, China has followed the world pace of such innovative therapies very quickly. We are very hopeful that we will narrow the gap in the field of R&D and industrialization, and even reach the world’s leading level. I think this is also the domestic immune system. One of the important driving forces for the development of treatment.” Dr. Liqun Wang, CEO of Fosun Kate, said that Fosun Kate will develop tumor immune cell therapy as a long-term undertaking, and the company will unswervingly apply Yescarta and other immune cell therapy products through the drug route. , So that it can be transformed and industrialized in China.
On October 18 this year, Yescarta was officially approved by the US FDA. This is the first CAR-T therapy approved by the US FDA for specific types of large B-cell lymphoma. This product is also the first to declare EMA (European Medicines Agency). ) The CAR-T drug applied for marketing is mainly used for the treatment of adult patients with specific types of large B-cell lymphoma who have received at least two or more other treatment options and have failed or relapsed. In Kite Pharma’s registered clinical trial, 51% of patients with refractory relapses have achieved complete remission, that is, all tumor cells have been eliminated.
In view of the fact that CFDA has joined ICH to gradually conform to international standards, and the clinical effectiveness and safety data accumulated by KitePharma may be conditionally accepted, Yescarta is expected to become the first cell therapy product to achieve transformation and approval in China, and promote domestic CAR-T cells Standardization and industrialization of treatment.
Too much attention to clinical trial results, ignoring key industrialization steps such as quality control
According to public reports, in the process of carrying out CAR-T therapy clinical trials, Juno’s JCAR015, KitePharma’s KTE-C19, and Cellectis’ UCART123, which is dedicated to the development of general-purpose CAR-T therapy, have all experienced deaths during treatment. event.
The difference is that Juno finally gave up JCAR015 and fell out of the first international CAR-T therapy team; KitePharma successfully completed the clinical trial after confirming that the cause of death of the patient has nothing to do with KTE-C19, becoming the world’s second approved CAR-T therapy; Cellectis The clinical trial was suspended, and the clinical trial can be continued after fully communicating with the FDA to redesign the plan.
“Patients receiving CAR-T treatment are often incurable. We often do not know whether the safety incident is caused by the patient’s disease itself or CAR-T treatment.” Zhang Dan, chairman of Fangen Medicine, said that in response to these For security incidents, there is currently a lack of assessment by third-party institutions in China, and there is no independent committee to testify. At present, the biggest challenge for the CFDA and ICH standards is safety evaluation. The two parties are inconsistent in terms of processing systems, reporting definitions, coding, and database structure. This is directly reflected in the quality of CRA-T clinical trials.
Because in the past, the threshold for companies to carry out CAR-T clinical trials according to the third type of medical technology was low, many hospitals did not have the conditions to prepare standardized cells, and the quality of research was uneven, and most of them were difficult to meet the latest drug development and production. standard.
Zhang Dan pointed out that with drug standards as the evaluation criteria, the current irregularities of CAR-T clinical trials carried out in China are mainly reflected in two aspects: the unclear dose and the lack of collection and processing of safety events. He believes that if companies want to apply for CAR-T therapy according to the drug route, they need to further plan in the future how to re-screen the test population with reference to the drug clinical trial entry and discharge standards, define the safety incident reporting standards, and develop a complete set of risk management plans for timely handling Side effects such as cytokine storm and central nervous system toxicity.
The reporter learned at the CAR-T cell therapy scientific seminar that most companies involved in the CAR-T field now pay too much attention to the results of clinical trials, such as how effective they are and how many patients are cured, but how to prepare CAR-T cells However, the key industrialization steps such as quality control are almost blank.
An expert engaged in drug safety evaluation emphasized that the pharmacy part is the focus of the clinical evaluation of CAR-T therapy. If the company aims to market the product, it must specify the entire process of cell preparation in strict accordance with the drug standards and maintain the production process of each link. Consistency, to ensure data compliance, reliable and traceable. “I think that if the design goals are controlled and achieved during the operation, plus preclinical animal experiment evaluation, etc., the effectiveness and safety can actually be guaranteed to a certain extent.”
“Whether it is pre-clinical data or clinical data, one of the most concerned aspects of review and approval is CMC, production and preparation, but it is often ignored by enterprises.” According to Wang Liqun, Kite Pharma invested a lot of energy in the process when applying for listing. In terms of process development and optimization, including reliability, repeatability, quality parameters, and cost reduction, Fosun Kate also attaches great importance to achieving a unified high standard and high quality with Kite Pharma products during the process of technology transfer. Currently, the company only produces Quality control staff accounted for nearly half.