On the one hand, it is relatively extensive operation; On the other hand, there are constantly tightened "import" pockets. After 2011, China has not introduced monkey seeds from abroad, but the cynomolgus monkey commonly used in experiments is from Southeast Asia, which has led to the aging of experimental monkeys in China in recent years, and the aging has reduced the fertility rate. At the same time, the inability to introduce species abroad has led to the genetic uniformity of the domestic experimental monkey population, which in turn has led to the degradation of the overall population. "What we are seeing today is an increase in monkey prices, but 'freezing three feet is not a day's cold', which is the result of the accumulation of various ills over the years."
In the monitor, a monkey that appeared to be anesthetized was picked up and brought into the laboratory, it looked like an ordinary monkey, but the price was comparable to the price per square meter in the center of Beijing, Shanghai, Guangzhou and Shenzhen, China.
230,000 yuan, which is the price of an experimental monkey when it was speculated to the highest; 8,000 yuan, which is the approximate cost of raising an experimental monkey for three years. Laboratory monkeys mainly refer to monkeys used for medical experiments, or social experiments. They are characterized by their large numbers, no risk of extinction in nature, ease of domestication and low difficulty in farming. Because experimental monkeys need to achieve high conditions in all aspects, they must be bred in captivity, and wild monkeys need to be reproduced through artificial intervention for two generations before they can be used as experimental monkeys.
Preclinical research often requires multiple experimental animal studies to verify each other, generally using a rodent and a non-rodent (including dogs, rabbits, miniature pigs, and monkeys) to complete animal evaluation experiments on the efficacy, metabolism and toxicology of drug candidates. The experimental monkey is a non-rodent experimental animal with the highest cross-reaction and relatively more accurate experimental effect. In 2019, a report of cross-reactivity in laboratory animals against 39 monoclonal antibody drugs showed that cross-reactivity was 82% in cynomolgus monkeys, 67% in velvet monkeys, 17% in rabbits, 11% in dogs, 7% in mice, and 0 in rats. In addition, cynomolgus monkeys weigh less (male weight 5~7kg, female weight 3~4kg) and are easier to operate, so cynomolgus monkeys are the most widely used experimental monkey species in preclinical research.
Cynomolgus monkeys are named for their love of crabs, mainly produced in Thailand, Laos and other Southeast Asian countries, like to inhabit tropical rainforests and other tropical areas, therefore, China's monkey farms are mainly distributed in the southeast coast with a warm climate.
According to the "China Institute of Food and Drug Control Cynogus Monkey Procurement Project Bidding Announcement" published by the Chinese government procurement website in April 2023, the budget purchase price of this batch of cynomolgus monkeys is 22.4 million yuan. In the end, the winning bid price of 120 cynomolgus monkeys was 20.4 million yuan, and the unit price of cynomolgus monkeys was 170,000 yuan per monkey. Previously, according to the results released by the Chinese government procurement network "China Institute of Food and Drug Control Experimental Cynomolgus Monkey Procurement Project" in 2022, the prices of the two purchases of cynomolgus monkeys were 184,000 yuan per monkey and 194,000 yuan per monkey respectively. In the 2020 project announcement, the budget for the purchase of 400 experimental cynomolgus monkeys was 12 million yuan, or 30,000 yuan each.
The unit price of cynomolgus monkeys in the "China Institute of Food and Drug Control Cynoguls Procurement Project Winning Announcement" released in April 2023. Image source: Chinese government procurement website
The "cause" behind the sharp rise in monkey prices
It seems difficult to tease out a simple and intuitive chain of causal prices for experimental monkeys.
Jin Hairong, general manager of Hainan Yuling Biotechnology Co., Ltd. (hereinafter referred to as "Yuling Biotechnology"), has been engaged in the CRO industry in Japan (contract research organization, mainly refers to the organization or institution that provides professional outsourcing services for pharmaceutical companies through contracts), and has many years of management and practical experience in CRO, animal experiment technology, experimental animal breeding. He remembers that about 10 years ago, buying an experimental monkey in China cost only about 10,000 yuan. Since the pandemic, the price of experimental monkeys in China has risen all the way, and records show that in 2022, when an experimental monkey was sold for a maximum of 230,000 yuan. Jin Hairong believes that this is mainly because after the outbreak of the epidemic, the demand for scientific research and drug research has increased, the supply and demand relationship between the upstream and downstream of the industry has been imbalanced, and the market gap is large.
But beyond the change in supply and demand, there seems to be more to it.
Many industry insiders said that the annual feeding cost of an experimental monkey is about 2000-3000 yuan, and an experimental monkey needs to be raised for at least 3 years before it can be sold, so the cost of an experimental monkey from breeding to sale is about 8000 yuan. According to Liu Wei, director of the experimental animal management department of Kanglong Chemical (Beijing) New Drug Technology Co., Ltd. (hereinafter referred to as "Kanglong Chemical"), most of the experimental monkeys raised for a long time belong to disposable laboratory consumables. For example, in the toxicological test of the detection drug, the organ slice of the monkey needs to be studied, and at the same time, the cynomolgus monkey is a national second-class protected animal, and the breeding needs to apply for the "domestication and breeding license" and "wild animals or their products business license" according to the regulations.
This does not include the cost of introduction, which is to introduce new monkey species from other places or abroad and mate with local monkeys to maintain the high-quality development of monkeys. Zhang Hong, chief scientist of Shanghai Puling Biotechnology Co., Ltd., said metaphorically: "It's as if human beings have been marrying close relatives will increase the probability of disease in offspring." "Seed introduction is a more complex process. Zhang Hong introduced: "The state has strict management of related industries, designated quarantine sites to manage the import of monkey animals, the quarantine time is 3-4 months, and the customs are stationed on site and supervise the whole process. In terms of administrative approval, imported animals must be approved in advance, and factors such as the origin of the animal and the epidemic situation need to be considered. In terms of time cost, after the farm introduces the breeding monkey for two generations, its offspring can be used as experimental monkeys, because wild monkeys imported from Southeast Asia may have bacteria and viruses, and it takes about 9 years to continuously weaken the wildness of wild monkeys through manual intervention and enhance their experimentability. ”
Many insiders said that some people chose to take risks and smuggle monkeys from Southeast Asia, and in the early years, some monkey farm owners paid more attention to border trade and did not pay attention to monkey farm management, burying "hidden dangers" for the quality of experimental monkeys. In addition, this is also closely related to the development of China's biomedical industry, China's pharmaceutical industry started late, and experimental monkey breeding is a basic industry, coupled with the early years of unscientific breeding, lack of upper management and other phenomena.
On the one hand, it is relatively extensive operation; On the other hand, there are constantly tightened "import" pockets.
At the end of January 2020, the State Administration for Market Regulation, the Ministry of Agriculture and Rural Affairs, and the State Forestry and Grassland Administration jointly issued the Announcement on Banning the Trade in Wild Animals. Earlier, in 2011, the State Forestry and Grassland Administration issued the Notice on Matters Related to the Licensing Quota for Experimental Monkeys in 2011-2012, stating: "The introduction of cynomolgus monkey seeds from abroad will be suspended." If each breeding unit needs to adjust the seed source of cynomolgus monkeys, it can be solved by introducing seeds from domestic breeding units. ”
On August 19, 2018, Beijing, on August 23, the Chinese Academy of Sciences announced that the research team of the Institute of Zoology and the Institute of Biophysics of the academy achieved the whole body knockout of SIRT6, which is considered to be a classic "longevity protein", in non-human primates for the first time through joint research, obtained the world's first model of a specific longevity gene knockout, and further research revealed the key pathways for primate development and life regulation. Visual China infographic
Since then, China has not introduced monkey seeds from abroad, but the cynomolgus monkeys commonly used in experiments are native to Southeast Asia, Jin Hairong said, which has led to the aging of experimental monkeys in China in recent years, and aging has reduced the fertility rate. At the same time, the inability to introduce species abroad has led to the genetic uniformity of the domestic experimental monkey population, which in turn has led to the degradation of the overall population.
As a result, CRO companies that have survived have begun to compete for monkey resources through equity participation, acquisition, and signing long-term agreements. In 2020, WuXi AppTec, a leading CRO enterprise in the pharmaceutical industry, acquired Guangdong Chunsheng Monkey Farm, becoming one of the enterprises with the largest breeding inventory of cynomolgus monkeys in China; In 2021, Kanglong Chemical successively acquired a 50.01% controlling stake in Zhaoqing Chuangyao Biotechnology Co., Ltd. and a 100% stake in Ankai Yibo (Zhanjiang) Biotechnology Co., Ltd. (formerly Kangruitai (Zhanjiang) Biotechnology) for RMB 110 million and RMB 206 million respectively. Among them, Zhaoqing Chuangyao has an 18-year history of raising experimental animals, and operates the domestication and breeding of macaques and cynomolgus; In April 2022, Beijing Zhaoyan New Drug Research Center Co., Ltd. acquired Yunnan Yingmao Biotechnology Co., Ltd., whose core assets are experimental monkeys, and 100% of the shares of Guangxi Weimei Biotechnology Co., Ltd., with a total acquisition amount of more than RMB 1.8 billion.
Large CRO companies acquired head monkey farms and targeted a large number of high-quality experimental monkeys, resulting in a decrease in the quality of experimental monkeys currently in circulation. At the same time, there is the problem of overselling. Jin Hairong introduced that many monkey farms and enterprises are rushing to sell monkeys in order to strive for more profits, he gave example: for example, according to the monkey production volume of a certain enterprise, only 1,000 monkeys are sold a year, but in order to meet customer needs, many monkey breeding enterprises will expand their sales ratio by about 50% in recent years, and will also sell breeding monkeys used to introduce seeds.
The person in charge of a small and medium-sized CRO enterprise said that although from the overall quantitative point of view, there are not many monkey farms acquired by CRO enterprises, but from the perspective of quantity and quality, local large-scale monkey farms and relatively high-quality seed sources are basically controlled directly or indirectly by various CRO enterprises, and most of them do not carry out external sales, which makes the quality of monkeys currently circulating in the market not very good, and at the same time, many small and medium-sized CROs or related enterprises and scientific research institutions that "enter" late are difficult to obtain the supply guarantee of experimental monkeys.
An industry insider told The Paper: "Everyone is talking about hoarding monkeys, but how many experimental monkeys are really healthy and young and have good reproductive ability?" "Lack of monkeys leads to competition, and excessive competition leads to lack of monkeys. However, the intervention of capital not only brings about the situation of "the strong and the strong", but also brings funds, standardized breeding methods and high-end talents.
"What we are seeing today is an increase in monkey prices, but 'freezing three feet is not a day's cold', which is the result of the accumulation of various ills over the years." Kim Hairong said.
Monkeys become a strategic resource?
In that case, can you experiment with other animals without monkeys?
Zhang Hong said that with the development of biomedicine in the post-gene era, various major therapeutic technologies, such as antibodies, small molecule nucleic acids (a class of low molecular weight compounds, usually have better permeability, stability and selectivity than traditional nucleic acid hybridization tools. and so on, all need human-like experimental systems. In particular, the development of innovative drugs and innovative drug targets, non-human primate disease models have become a rigid need.
Because monkey disease models are closer to human physiology and pathology than other animal models such as mice, their response to drugs and side effects are closer to human conditions. In addition, the clinical endpoints, clinical tests, and markers of monkey disease models are consistent with human clinical trials, so the data generated are more reliable, which can provide more accurate prediction and clinical trial design reference for drug clinical development, and improve the success rate of clinical development.
According to Zhang Hong, from another perspective of promoting the development of the biopharmaceutical industry, the stage results of monkey model experiments can become the cornerstone of clinical efficacy trials, enhance the confidence of pharmaceutical companies in follow-up clinical trials, and actively promote drugs to enter late-stage clinical trials. On the other hand, new drug research and development is inseparable from the relay of funds, and the data results of the monkey model experimental stage can provide the closest evaluation of the real situation to the transaction of "new drug technology products", help to form a benign sustainable development of development to pay for R&D, and provide an evaluation of "scientific and technological value" with predictive reference for investment such as the innovation board and the science and technology innovation board.
Previously, China was a major exporter of experimental monkeys. Zhang Hong introduced that China imports wild monkeys from Southeast Asia, cultivates and cultivates experimental monkeys, and then exports them to developed countries such as the United States, and the Chinese market accounts for almost 60% of the world's experimental monkey market. Therefore, the fluctuation of the Chinese market has also caused shocks in the world market. Some industry insiders said that it is said that in the US market recently, experimental monkeys were once speculated to $60,000.
In order not to be "stuck" in the "raw materials" link, many countries have gradually begun to import wild monkeys directly from Southeast Asia. According to Kim Hae-young's observation, in the past, people who went to Southeast Asia and other countries were mainly Chinese, and now Koreans, Japanese, etc., are fighting for monkey resources, and correspondingly, Cambodia, Vietnam and other countries have also significantly strengthened the management of export experimental monkeys.
Jin Hairong said that Southeast Asia and other countries have strictly managed the issuance of monkey farm licenses, and only qualified institutions can open monkey farms. In addition, the relevant government departments have begun to take action to enact stricter regulations to limit the disorderly growth of the monkey farm population in the country, with the aim of strengthening the overall competitiveness of the domestic industry. "Everyone is aware that monkeys are becoming a scarce resource, and the global biomedical industry has entered the fast lane of development, with macromolecular drugs and new pharmaceutical technologies such as gene therapy are booming, and it is necessary to use a species closer to humans - monkeys, to evaluate drug safety and efficacy." Therefore, everyone has intensified the grabbing of monkey resources. ”
On January 5, 2020, the China Experimental Primate Breeding Development Association submitted a "2020 Experimental Monkey Census Instructions" to the Department of Zoology and Flora of the State Forestry and Grassland Administration, which reads: "1. By the end of 2018, the number of experimental cynomolgus monkeys was 211171 (34,714 in 2018); The total number of experimental macaques was 28,806 (2,640 sold in 2018). Stable large-scale farmed stocks have been reached. 2. The unstable factors and problems between industries are becoming more and more prominent, mainly manifested in vicious competition between enterprises, vicious price reduction by middlemen, and false data reported by individual aquaculture enterprises. ”
A year later, statistics from the China Experimental Primate Breeding Development Association in 2021 showed that there were more than 240,000 cynomolgus monkeys and rhesus monkeys in the country, with an annual production of only about 30,000, while domestic demand was as high as 40,000. Zhang Yuchao, secretary general of the China Experimental Primate Breeding and Development Association, said in an interview that in addition to juvenile monkeys and seed monkeys, there are currently about 100,000 actual commercial monkeys in the country, and if you remove the young or "menopausal" monkeys that have been booked and underwritten overseas, the number of monkeys in the country is only about 30,000.
How many monkeys does a country have to reach in a year to meet the normal operation of the market? Jin Hairong said: "I have also thought about this problem, it is meaningless to simply look at the number of experimental monkeys, it depends on the quality." In terms of quantity, first of all, it is roughly estimated that the number of monkeys used in our country is about 30,000 per year, while the United States needs 70,000. If we want to meet the demand of 50,000 experimental monkeys a year on the mainland, according to the fertility rate of 35%-40%, we need at least 150,000-200,000 seed monkeys, and they are healthy breeding monkeys. ”
Previously, the Chinese market accounted for almost 60% of the world's experimental monkey market.
The role of business and government
It is forbidden to introduce seeds from abroad, can China breed itself to solve the problem?
When the Chinese Society of Laboratory Animals released the work progress of the 2019 National Laboratory Animal Seed Center (National Laboratory Animal Resource Bank) in 2020, it said that as of 2010, a total of 8 national experimental animal resource centers have been established, and the main responsibilities are to introduce, collect and preserve experimental animal breed strains, research new technologies for experimental animal breeding, cultivate new experimental animal breed strains, and provide standard experimental animal seeds for domestic and foreign users.
But the seed center can only solve "yes or no", not "how much". For example, Liu Wei may need to consume 100-200 mice for a project, but the seed center can only provide three pairs of mice at a time, "Of course, they also have difficulties, because laboratory animals are not consumables in the short term, maybe only once a year to sell seeds, but if you want to meet this transaction, you may need to keep thousands of (mouse) species, so it is difficult to achieve a balance." ”
And experimental monkeys have both "experimental attributes" and "animal attributes", which determines that there is more than one relevant management department.
According to the Wildlife Protection Law, the General Administration of Customs and other departments manage import and export, the State Forestry and Grassland Administration manages the breeding, sale and transportation of experimental animals, the Ministry of Agriculture and Rural Affairs is responsible for the filing and supervision of animal receipt, and the Science and Technology Commission is responsible for issuing laboratory animal facilities and use permits.
The National Office of the Administration of Endangered Species is mainly responsible for the issuance of international trade licenses for the examination and approval of imported and exported protected animals and samples. Non-human primate pharmacodynamic tests require further use of human drugs, clinical instruments and equipment, so they also involve the management of departments such as the Drug Administration and the Health Commission.
In 2011, the Shanghai Municipal Science and Technology Commission issued the Notice on the Establishment of Shanghai Laboratory Animal Management Office and the Change of the Name of Shanghai Laboratory Animal Management Committee, announcing the establishment of Shanghai Laboratory Animal Management Office, which is located in the Conditional Finance Department of Shanghai Municipal Science and Technology Commission, to undertake the management responsibilities of Shanghai Laboratory Animals, and rely on the Shanghai Laboratory Animal Research Center for daily work. At the same time, the original "Shanghai Experimental Animal Management Committee" was renamed as "Shanghai Laboratory Animal Guidance and Coordination Committee", retained the "Shanghai Laboratory Animal Management Committee" non-established institution, and renamed it "Shanghai Laboratory Animal Guidance and Coordination Committee" to guide and coordinate the city's experimental animal management and emergency handling of emergency laboratory animals.
The terms of reference and responsibilities of each department are different, which is related to laws and regulations. Matters related to wild animals are governed by the Forestry Law, and import and export trade is governed by the Foreign Trade Law of the People's Republic of China, but there is no relevant law on the management of laboratory animals, only the Regulations on the Management of Laboratory Animals, which also determines that the relevant departments cannot play a greater role.
For example, in terms of transportation, the State Forestry and Grassland Administration stipulates that animals in the breeding industry can only choose to be slaughtered or not slaughtered after delivery, and cannot be moved at will, but experimental animals need to be repeatedly transported in different locations such as hospitals and enterprises. Therefore, this is a cumbersome process that involves the approval and coordination of multiple relevant departments, which is not only inefficient, but also often produces various contradictions to meet different regulations.
What are the respective roles of enterprises and government departments in this industry?
Jin Hairong believes that on the whole, this industry belongs to the more basic link in the biomedical industry chain, and the state can be used as a superstructure to give policy support, and the specific implementation is done by the industry and enterprises. Because if the national department, such as the Academy of Sciences system, into the specific breeding work, this is inconsistent with their functions, after all, from the nature, professionalism and other aspects, the scientific research and utilization of monkeys and monkey breeding are two concepts that are very different, and enterprises have more systematic planning and richer practical experience in this regard.
Zhang Hong suggested that in order to develop the industrialization of innovative biomedical non-human primate technology, it is necessary to design at the top level, optimize relevant regulations and policies, and take the lead of a leading department to formulate relevant rules for experimental monkeys and improve the rationality and efficiency of cross-departmental approval.
Liu Wei believes that government departments can support them in terms of funds and policies, and let enterprises develop in the rest, "Just like performance appraisal, you put forward your demands, and I am responsible for meeting them reasonably and legally." ”
In his view, policy support is the focus. "Private capital has investment strength, but it is limited by the lack of policy support and has nowhere to do it. For example, the introduction involves cross-border transportation, so the first problem is to coordinate the relevant customs procedures of the two countries, consider reasonable transportation methods, and if you choose air transportation, you also need to coordinate with airlines. ”
Even if these hurdles are cleared, there are still a number of challenges to face when returning to the local farming industry. Agricultural land needs to be approved again, and the policy of returning farmland to forest is currently being implemented, the amount of forest land is limited, and according to the relevant quarantine law, monkey farms and distance and other specific site restrictions, it is difficult to find suitable forest land, "These problems need the help of the government to solve, in a good investment environment, private capital can exert its strength." This requires simplifying the approval process, reducing administrative licensing, 'loosening' for enterprises, and letting the market solve market problems. Liu Wei said.
Zhang Hong said that the scale of experimental monkey breeding can be expanded in an orderly manner by national planning, and at the same time, experimental monkey breeding can be carried out in places with suitable climate in the south and southwest, and reasonable introduction and breeding can "maybe also alleviate poverty."
Liu Wei did not suggest that the state intervene in expanding monkey farm farming, "It is like at the beginning when everyone did not have enough to eat, they proposed 'filling lakes and reclaiming fields', but later it turned out that they could not rudely lack anything to make up for anything, and now the lack of monkeys will set up monkey farms, first of all, it will disrupt the market order, and secondly, the quality of monkey farms is difficult to guarantee." The industry needs a process of recovery and adjustment. ”
There are different suggestions for industrial development, but everyone has the same view on the trend of monkey prices: it will fall, but it will not fall to the original price. Some people said it may remain around 50,000 yuan. The importance of experimental monkeys is already self-evident, it is reported that before the new crown pandemic, the number of laboratory monkeys consumed in the world every year was around 80,000, of which the United States accounted for about half.
In the future, "compared with nearly 200 million mice used in preclinical research and development of biomedicine every year and tens of millions of people participating in various clinical trials, the application of 100,000 experimental monkeys is still very limited, and as a strategic resource for high-end research, it can bring new opportunities for innovation and in-depth development of the biomedical industry." Zhang Hong said.