Development stage and prospect analysis of cell therapy industry in my country

01 Industry Regulatory Analysis

(1) Supervision mode: still in the "dual-track" supervision mode

At present, China regulates cell therapy products in accordance with the "dual-track system" of drug and medical technology management

(2) Policy barriers: incomplete coverage and low stability

From the experience of Europe, the United States, and Japan, it is necessary for the cell therapy field to establish regulatory and policy frameworks at different levels from laws, regulations to industry guidelines, and to manage them by classification and classification, so as to form the pharmacy of cell therapy regulatory science from top-level design to specific medical technologies.

By sorting out the relevant policies of cell therapy supervision in China, it can be seen that in recent years, the drug regulatory authorities, health and health departments have frequently issued guidance documents for cell therapy products, showing their emphasis on such products, and hope that through the issuance of technical guidance documents Standardize and promote the development of cell therapy products in China

However, there are two major problems in the relevant documents issued at present, which do not cover the product life cycle in place and the stability of the policy documents is not high

Table 1: Analysis of relevant regulatory policies in the field of cell therapy in my country

Source: Flint Creation Arranged based on public information

02 Industry Path Analysis

(1) Path stage: The entire path to listing has been completed

1.

As of December 2021, two CAR-T products in China's immune cell field have been successfully approved for marketing by the NMPA, and have been officially used in clinical applications as drugs

Table 2: Details of two immune cell therapy products that have been marketed in China

Source: Flint Creation Arranged based on public information

Although two products have been launched, the field of immune cells is still in the early stage of research and development

Figure 1: Clinical staging of domestic immune cell therapy products

Source: Flint Creation Arranged based on public information

From the perspective of registration classification, most of the immune cell products are registered according to the category 1 innovative drug registration application, a total of 29, accounting for 81%, are the first products that have not been marketed at home and abroad

From the perspective of cell classification, CAR-T cells are the main immune cells, accounting for 89%, which highlights that China's CAR-T cell immunotherapy has developed rapidly in recent years, and clinical trials have shown a "blowout" state

Figure 2: Cell classification of domestic immune cell therapy products

Source: Flint Creation Arranged based on public information

2.

Stem cell therapy products are still in the clinical trial stage as drugs in China (although three stem cell drugs have been submitted for marketing applications in the early stage, but they have not been approved so far), and the number of registered drug clinical trials is only 13, and the most advanced is Clinical Phase II, according to the registration and filing trend of stem cell clinical trials over the years, after the peak of stem cell clinical trial registration in 2014, there was no stem cell clinical trial registration in China from 2015 to 2019, but the registration of stem cell clinical trials showed a recovery in 2020-2021.

Table 3: Information on domestically registered stem cell clinical trials

[Note: Although three stem cell therapy drugs were submitted for marketing in 2004 and 2005, the drug regulatory authorities have not yet approved them, so they are not included in the scope of stem cell clinical research in China

Source: Flint Creation Arranged based on public information

Figure 3: Number of registrations of stem cell drug clinical trials in my country over the years

Source: Flint Creation Arranged based on public information

To sum up, at present, China's cell therapy products have gone through the entire route of being marketed as drugs in China, but two immune cell therapy products have been listed.

Figure 4: The industrialization path and progress stage of cell therapy products in China

Source: Flint Creation Arranged based on public information

Figure 5: The industrialization path and progress stage of Achilles injection in China

Source: Flint Creation Arranged based on public information

Figure 6: The industrialization path and progress stage of Ruiki Aurenzai injection in China

Source: Flint Creation Arranged based on public information

(2) Path cost

1.

In terms of product research and development investment, the research and development cost of immune cell therapy products is in units of 100 million yuan, of which the research and development cost of akirenxe injection exceeds 600 million yuan

In terms of corporate R&D expenditure, among the listed cell therapy companies, Legend Bio's annual R&D expenditure of more than 1 billion yuan in 2019 and 2020 is the best

Figure 7: my country's listed cell therapy companies have invested in R&D over the years (100 million yuan)

Source: Flint Creation Arranged based on public information

2.
Time cost: higher than the average level of domestic new drugs

Judging from the time-consuming clinical trials and marketing authorizations of the two domestically approved drugs, it takes about 3 years from the time the clinical trial approval is obtained to the final marketing approval of the product.
) is 14.
4 months higher than the average level of domestic new drug clinical trials in 2020 (it should be noted that the calculation of the average time-consuming of domestic new drug registration clinical trials only includes the current development time of each phase of clinical trials, excluding the interval time of each phase of clinical trials)
.

Figure 8: Clinical trials and market cycle (months) of marketed cell therapy products in my country

Source: Flint Creation Arranged based on public information

3.
Space cost: more than 10,000 square meters of manufacturing space

Since cell therapy products have high requirements for cleanliness, they have strict lower limit requirements for the size of the manufacturing space.
The single-story building area should generally not be less than 800 square meters, and the use area of ​​the clean area should not be less than 500 square meters
.
Judging from the space volume of the two cell therapy products already on the market, the R&D center needs to be larger than 2,000 square meters, and the production base needs to be larger than 10,000 square meters
.
For example, Fosun Kite completed a cell therapy R&D center in early 2019 with a construction area of ​​2,000 square meters, and its industrialization base located in Shanghai Zhangjiang Innovative Drug Industry Base has a construction area of ​​about 10,000 square meters, including dozens of production lines, which can be carried out in parallel at the same time.
Preparation of CAR-T products
.

Table 4: Pathway costs for cell therapy products to be marketed in China

Source: Firestone Creation is based on public information, the above is only based on the marketed cell therapy products

03 Industry Prospect Analysis

(1) There is a large gap between production capacity supply and market demand

2021 is the first year of commercialization of cell therapy in China.
In that year, two cell therapy products were approved and successfully applied in clinical practice
.
Judging from the production capacity disclosed by the company, the designed production capacity of the Suzhou production base for Ruiki Orenza Injection is no more than 5,000 people per year.
The annual supply of domestically marketed cell therapy products is less than 10,000
.

According to the "2020 Latest Global Cancer Burden Data" released by the World Health Organization's International Agency for Research on Cancer (IARC), there will be 4.
57 million new cancer cases in China in 2020, of which about 10% are hematological tumors, that is, about 460,000 blood Assuming that 10% of cancer patients are suitable for immune cell therapy and can be paid (individuals, medical insurance, etc.
), there is a market demand of about 46,000 people per year in China
.
Combined with the current production capacity of less than 10,000 people per year, there is a capacity gap of about 360%.
Therefore, companies that have entered this field are expected to quickly occupy the market and form a first-mover advantage
.

(2) Market pricing and access to medical insurance help increase product volume

In terms of market pricing, since autologous CAR-T therapy is a personalized treatment, the preparation process is cumbersome and the preparation cost is high
.
Yescarta is priced at US$373,000 in the United States, totaling RMB 2.
233 million
.
According to the market pricing disclosed by the two cell therapy products already listed in China, the single treatment cost of the two products is about 1.
2 million yuan (only the cost of drugs, excluding other expenses such as hospitalization expenses), which is relatively high compared to foreign pricing.
Certain competitive advantages are more favorable for patient penetration and medical insurance access
.

In terms of medical insurance access, many countries/regions have included CAR-T therapy in the national medical insurance system
.
The United States officially included CAR-T cell therapy in medical insurance in February 2019.
In August of the same year, the Centers for Medicare and Medicaid Services (CMS) announced that it not only pays the cost of CAR-T cell therapy, but also all related services and treatment costs
.
Japan also announced in May 2019 that it approved the inclusion of Kymriah in medical insurance.
On the basis of medical insurance payment, the patient’s out-of-pocket ratio is only 10%-30%
.
Subsequently, the United Kingdom, Canada and other countries have also included CAR-T in their medical insurance
.

According to the "2021 National Medical Insurance Drug Catalog Adjustment List of Drugs Approved by the Preliminary Formal Review" released by the National Medical Insurance Administration, Akilence injection has passed the preliminary formal review, but has not entered the negotiation link of the medical insurance catalogue, and has not been finalized.
Can successfully enter the "National Basic Medical Insurance, Work Injury Insurance and Maternity Insurance Drug Catalog (2021)"
.
Therefore, domestic cell therapy products are still mainly paid by the patient, supplemented by supplementary commercial insurance, and there is still time before China's national medical insurance payment
.

In terms of commercial insurance, Ping An Health announced on July 14, 2021, that CAR-T therapy will be added free of charge on the basis of the original 18 drug lists in the basic drug list, which is the first time in China that CAR-T therapy has been included in commercial insurance
.
In addition, after the approval of Yikaida, it has been included in Ping An Life, Fosun United Health, Fosun United Health (Chaobao 2020), Fosun United Health (Yaoshen No.
1 2021), Zhongan Insurance, etc.
Commercial medical insurance, but the specific coverage rate and reimbursement situation are not yet clear
.

(3) Local legislation to promote the development of the industry in the standard

1.
Legislative history

Nationally, Shenzhen took the lead in enacting legislation for the development of cell and gene industries
.
The first national free trade zone legislation "Shenzhen Special Economic Zone Qianhai Shekou Free Trade Pilot Zone Regulations", which came into effect on October 1, 2020, provides new impetus and space for the development of Shenzhen's cell and gene therapy industry
.
The regulations clearly stipulate that medical institutions and scientific research institutions in the free trade area can carry out research and transformation and application of new technologies such as stem cells, immune cells, gene therapy, monoclonal antibody drugs, and tissue engineering according to their own technical capabilities and relevant regulations
.

In the same year, the General Office of the Central Committee of the Communist Party of China and the State Council issued the "Shenzhen Construction of the Pilot Demonstration Zone of Socialism with Chinese Characteristics Comprehensive Reform Pilot Implementation Plan (2020-2025)" to provide policy basis and guarantee for the legislative work in Shenzhen's emerging fields such as cell and gene therapy.
The Implementation Plan clearly states that "support Shenzhen to expand the legislative space for the special economic zone, strengthen legislative exploration in emerging fields, and formulate special economic zone regulations and rules in accordance with the law
.
"

Strengthening legislative exploration in emerging areas is a new mission entrusted by the central government to Shenzhen's comprehensive reform pilot program
.
In June 2021, the "14th Five-Year Plan for Shenzhen's National Economic and Social Development and the Outline of the Vision for 2035" was officially released, making specific plans and arrangements for "building a socialist law-based demonstration city with Chinese characteristics".
Once again put legislation in emerging fields on the planning agenda, and proposed to accelerate the promotion of legislation in emerging fields such as artificial intelligence, unmanned driving, big data, biomedicine, medical health, information services, etc.
Legislative exploration experience in cutting-edge emerging fields
.

In order to promote the healthy, sustainable and high-quality development of the cell and gene industry, improve the overall development level of the biopharmaceutical industry, and better meet the people's needs for a healthy life, according to the annual legislative plan of the Standing Committee of the Municipal People's Congress, the Standing Committee of the Shenzhen Municipal People's Congress plans The Budget Working Committee began to organize the drafting of the "Shenzhen Special Economic Zone Cell and Gene Industry Promotion Regulations (Draft)" (hereinafter referred to as the "Regulations (Draft)") in December 2020
.

Since the emerging field of cell gene therapy has the typical feature of "technology ahead and policy behind", the "Regulations" took nearly a year from drafting to public consultation
.
After the "Regulations (Draft)" were reviewed at the meeting of the Standing Committee of the Seventh Municipal People's Congress, the Legal Work Committee revised and formed the "Shenzhen Special Economic Zone Cell and Gene Industry Promotion Regulations (Draft for Comment)" (hereinafter referred to as the "Regulations") according to the deliberation opinions of the Standing Committee.
(Draft for Comments)"), and will officially open to the public for comments in November 2021
.

2.
Innovation and deficiencies

Figure 9: Innovations and deficiencies of Shenzhen Cytogene's Regulations (Draft for Comment)

Source: Flint Creation Arranged based on public information

(1) Encouraging clinical research and clinical trials will help revitalize Shenzhen’s clinical resources

Clinical research and clinical trials are key links in the cell and gene industry, and the two complement each other
.
The "Regulations (Draft for Comment)" proposes to support enterprises, scientific research institutions, and medical and health institutions to cooperate in clinical trials in the field of cells and genes, as well as clinical research initiated by researchers
.
Previously, in accordance with national policies, clinical research or clinical trials of stem cells could only be carried out in medical institutions above the tertiary level
.
However, the qualified medical institutions in Shenzhen are far from those in Beijing, Shanghai, Guangzhou and other places
.
The "Regulations (Draft for Comment)" proposed to encourage tertiary medical institutions to carry out clinical research and clinical trials in the field of cells and genes, and to set up internal clinical research management institutions and research wards, which actually liberalized the level of hospital development.
The implementation is very beneficial to revitalizing the overall medical resources of Shenzhen
.
At the same time, the assessment indicators for medical institutions that carry out relevant clinical research and clinical trials are relaxed, and the professional and technical qualification evaluation and job employment of relevant medical and health personnel are inclined, and medical institutions and medical personnel will be mobilized to a certain extent to carry out cell gene clinical research and clinical trials.
positivity
.

(2) Promote drug expansion clinical trials to accelerate the commercialization of cell genes

At present, the country has not officially issued corresponding specific regulations for drug expansion clinical trials.
With reference to international experience, it is necessary to improve this policy to accelerate the process of industrialization
.
The "Regulations (Draft for Comment)" proposes that for cell and gene drugs that are undergoing clinical trials for the treatment of serious life-threatening diseases for which there is no effective treatment, they may benefit from preliminary observations and meet ethical requirements.
After consent, it can be used in other patients with the same condition in the institution conducting the clinical trial
.
At the same time, the use stage of cell and gene drugs for extended clinical trials is stipulated, and applicants for cell and gene drug registration are required to have completed the clinical trial stage to support the marketing registration of new drugs, and after submitting the application for marketing authorization to the State Drug Administration, they can follow the It is stipulated that the use of cell and gene drugs for extended compassionate clinical trials will be used to further improve drug accessibility on the basis of existing data supporting the safety and efficacy of cell and gene drugs
.
On the one hand, this measure will help to improve the availability and commercialization of drugs.
In the past, cell therapy drugs were not allowed to charge before obtaining the drug approval number, allowing cell and gene therapy products to complete clinical trials and apply for marketing.
Carrying out extended clinical trials from time to time will help improve drug accessibility and advance the time point of the company's commercial return, which is undoubtedly a trend and signal to accelerate commercialization
.
On the other hand, promoting drug-expanding clinical trials is actually a powerful measure to break through the standardization dilemma of the cell and gene industry.
It will encourage companies to spontaneously improve their own product standards, move closer to the drug listing standards, and ultimately promote the standardization of the industry
.

3.
Innovative biological product batch issuance and testing platform to help drug production

The "Regulations (Draft for Comment)" proposes to support the Shenzhen Institute for Drug Inspection to undertake the quality inspection and testing of cell and genetic products of the national drug testing agency, the formulation of local and group standards for tissue cells and genetic products, and technical arbitration
.
And support its application for the qualification of the national biological product batch issuing agency
.
Encourage the introduction and construction of qualified third-party inspection and testing institutions to undertake the quality inspection and testing of cell and gene products
.
Promote the establishment of Shenzhen cell and gene product inspection and testing platform, strengthen cell and gene product inspection and testing capabilities, and carry out research on inspection and testing methods, quality standards, and safety evaluation technologies
.
Support third-party inspection and testing platforms to provide testing services for biological products such as cells and genetic products, and promote the formulation of inspection and testing industry standards
.

4.
Design all-round industrial development guarantee

The "Regulations (Draft for Comment)" designed a comprehensive industrial development guarantee covering policies, funds, platforms, and space
.
In terms of policy, it is proposed to incorporate the development of the cell and gene industry into the development plan of the biomedical industry
.
In terms of finance, encourage financial institutions to provide financial support for the development of cell and gene industries, increase credit support, and reduce corporate financing costs
.
In terms of platform, it is proposed to support the development of cell and gene industry research and development, production outsourcing service platform
.
Relevant departments formulate special incentive measures to promote the development of cell and gene industry outsourcing service platforms
.
In terms of space, it is proposed to delineate areas to build cell and gene industry characteristic parks, encourage the development of cell and gene industry innovation clusters, and support major cell and gene industry projects, major platforms, and major carrier resources to incline to the park.
Because of the industrial positioning of the professional park will be a major positive
.

However, compared with the "Regulations (Draft)", the "Regulations (Draft for Comment)", some of the industry's more concerned content is not covered, such as the risk classification management system and cost charges and other content did not appear in the final version of the "Draft for Comments"
.
However, it also shows that the introduction of any local industry promotion regulations requires a balance of development and regulation
.

references:

[1] According to the "Technical Guidelines for Research and Evaluation of Cell Therapy Products (Trial)" (No.
216 [2017] of the State Food and Drug Administration)
.

[2] According to "Administrative Measures for Clinical Application of Medical Technology" (Weiyizhengfa [2009] No.
18), "Administrative Measures for Clinical Research and Translational Application of Somatic Cell Therapy (Trial)" (Draft for Comment) (National Health Commission)
.

[3] In 2017, the General Office of the General Administration of China publicly solicited opinions on the "Administrative Measures for Expanded Compassionate Use of Drugs for Clinical Trials (Draft for Comment)"
.