With the "disease" running wild for 30 years, can the life and death bureau of Chinese medicine injection be solved?

Chinese medicine injections, which were eager to prove their "innocence", were poured with cold water.

On January 11, 2022, the State Food and Drug Administration announced that it decided to cancel the traditional Chinese medicine injection Lianbizhi after re-evaluation after marketing. It is also the first product to be delisted for this reason since China announced its post-market reappraisal plan for injections in 2017.

It has been 17 years since the State Food and Drug Administration first prompted adverse reactions such as kidney function damage in 2005 and ordered it to revise the instructions.

In order to prove their innocence, the company has made a lot of efforts. At the end of March 2018, Jiuxu Pharmaceutical's Lianbizhi injection entered a randomized, double-blind, multi-center clinical trial of efficacy and safety, and the company also posted a congratulatory article on its official website.

According to this annunciation article, for more than ten years, Jiuxu Pharmaceutical has invested a lot of manpower and material resources in the production process of Lianbizhi, and the experts and institutions that carry out clinical trials are well-known in China.

From the perspective of the time, the result of the final delisting was unexpected by enterprises and experts.

Do not do the listing after the evaluation can not prove their innocence, product focus monitoring, kick out the medical insurance market shrinkage, is a dead end; after the listing of the evaluation can not avoid death, once the results are not good, will only accelerate the delisting.

The delisting of Lianbizhi due to the re-evaluation of the listing is considered to be the beginning of the large-scale delisting of Traditional Chinese medicine injections. From a realistic point of view, this incident has also unveiled the dilemma that Chinese medicine injections cannot get out of for more than ten years.

Image from Visual China

Since the birth of the first Chinese medicine injection - Chai Hu Injection in the Taihang Mountains in the 1940s, the development of Chinese medicine injections has experienced ups and downs from fiery to controversial to dying in the past 80 years. How did they get here? Is there still a chance to turn over?

A fate that has long been predestined

The dilemma of Traditional Chinese medicine injections today, as early as more than a decade ago, has been doomed.

The main component of the delisted Libizhi injection is sodium bisulfite andrographolide, which is mainly used for the treatment of bacterial dysentery, pneumonia and acute tonsillitis, and there are two kinds of intramuscular injection and intravenous infusion.

According to clinicians, this drug has been used less.

In April 2005, the State Food and Drug Administration published the Phase 8 Adverse Reaction Monitoring Circular, which suggested the risk of acute renal function damage of this product.

In response to the monitoring results, in November 2006, the State Food and Drug Administration asked Libizhi to revise the instructions. In fact, according to people familiar with the matter, there was a proposal for direct delisting at that time, but it was not adopted.

The storm of Lian Bizhi, because it occurred in the context of the "banning" of another Chinese medicine injection, became an inconspicuous background. And this incident also laid the groundwork for the plight of chinese medicine injections today.

In February 2006, 10 months after the renal toxicity problem of Lianbizhi was announced, a 4-year-old girl in Jinhua City, Zhejiang Province, was injected with Houttuynia cordata injection intravenously in the hospital due to respiratory infection, and in the process, she convulsed and comatose, and although she was rescued from danger, she was still in a coma for 3 months.

Immediately after that, on May 27, 2006, the same tragedy was staged in Wuhan, Hubei Province, and the 3-year-old girl involved developed anaphylactic shock during the injection of Houttuynia cordata injection and died.

Three days later (June 1), the State Food and Drug Administration announced that it would suspend the clinical use of seven chinese medicine injections such as Houttuynia cordata nationwide, and suspend the acceptance and approval of various registration applications for these seven injections.

According to the monitoring data released by the State Food and Drug Administration at that time, from 1988 to April 13, 2006, there should be more than 5,000 cases of adverse diseases related to houttuynia injections reported nationwide, of which 222 cases of serious adverse reactions and 35 cases of death.

Chinese medicine injection was born in the era of lack of medical treatment, and in the 1970s, a nationwide research and development boom was set off, "At that time, even the commune health center was developing Chinese medicine injections." "There are experts in the field of traditional Chinese medicine who told Eight Points Jianwen.

According to the statistics of He Yijing and Li Xiaodong of the School of Pharmacy of Fujian University of Traditional Chinese Medicine, a total of 1154 document numbers were approved in the year with the largest number of approved Chinese medicine injections, and the total number of approval numbers approved or reissued from 1999 to 2007 reached 1290. There are more than 700 varieties, involving more than 400 enterprises.

During the fight against SARS in 2003, the former Ministry of Health also recommended 8 kinds of Chinese medicine injections, including Houttuynia cordata injection.

According to Medicin's sampling and analysis of 1412 hospitals at all levels in 21 provinces and cities across the country, from January to October 2005, among the mainstream proprietary Chinese medicine products used by hospitals, the top 20 products were 16 injections, accounting for 80%, and a total of 8 varieties with sales of more than 100 million yuan, 6 were injections.

According to the report of the Prospective Industry Research Institute, from 1999 to 2005, the average growth rate of the national traditional Chinese medicine injection market reached 30%.

It seems that overnight, Chinese medicine injections have changed from "upstarts" in the Chinese medicine industry to "flood beasts", and even Chinese medicine has been affected. According to the Magazine of the President of Chinese Hospitals, the public does not even dare to eat houttuynia cordata with medicinal and food homology. Famous Chinese pharmacists Zhou Chaofan and Sun Zhongzhong also specially refuted the rumors.

In the following years, there have been serious adverse reaction events of large varieties of double yellow lian, yin gardenia yellow, eleutherococcus, safflower, and heyonite, and even fatal incidents have been exposed.

"If you should withdraw from the market, you must quit", and even the call for complete withdrawal of Traditional Chinese medicine injections is endless.

Although Later, Chinese medicine injections were not really delisted, but this incident and monitoring data have made the public and industry people clearly realize that Chinese medicine does not mean safe and no side effects. The safety and effectiveness of Chinese medicine injections, which are commonly used in clinical dosage forms and the "upstart" of modern Chinese medicine, have not been fully confirmed by research.

"It 's [the adverse reaction] is like a label that can't be torn off on a Chinese medicine injection." Fu Dexing, former director of the Pharmacy Department of Beijing Hospital, pointed out in an interview with Capital Medicine in his early years.

The resulting huge pressure has also made hospitals, doctors, and even regulatory authorities cautious in dealing with the issue of Chinese medicine injections.

The seeds of industrial decline were sown.

Run wild with "sickness"

Although it has suffered continuous heavy blows and launched a post-market re-evaluation in 2009, chinese medicine injections have not declined, and the industry has entered a stage of rapid growth. According to forward-looking industry research data, in the five years from 2008 to 2012, the compound annual growth rate of Chinese medicine injections was about 21%, higher than the growth rate of the entire pharmaceutical market of 18.23%.

According to the statistics of The Intranet, the market size of Traditional Chinese medicine injections reached 104.8 billion yuan in 2016. Far exceeding the industry's expectation of 60 billion yuan.

Some products such as Danhong, Hemosetong, Thrombosis injection and other cardiovascular and cerebrovascular drugs, the peak of the annual sales of a single variety exceeded 8 billion yuan. There are not a few listed companies that mainly focus on large varieties of traditional Chinese medicine injections.

Some clinicians pointed out to Eight Points that in a specific historical period, Chinese medicine preparations, including Chinese medicine injections, two systems of Chinese medicine and Western medicine, two ways of thinking, "according to the standard observation of Western medicine, Chinese medicine preparations may not be very scientific, there is no systematic and in-depth professional data", but it still solves some problems, and also meets various demands such as advocating tradition, maintaining employment, and low-cost payment, which is a realistic compromise.

As a thriving industry, the market for traditional Chinese medicine injections is indeed large, and the industrial chain involves many enterprises and personnel.

The market size of the seven houttuynia injections that were pressed the pause button alone reached 8.5 billion yuan, involving 195 companies and about 40,000 employees. If it is extended to the entire industrial chain, the scale can reach the level of tens of billions, and it will also affect 100,000 pharmaceutical farmers, with an estimated loss of at least 2 billion yuan.

From 2006 to 2010, China's economy was in a critical period of integration into the wave of globalization. As a representative of the modernization of Chinese medicine, Chinese medicine injections are also considered to be a sharp weapon for Chinese medicine to go abroad and connect with the world.

The State Food and Drug Administration announced the implementation of the re-evaluation of Traditional Chinese medicine injections after listing, and the withdrawal of products that did not meet the requirements caused great repercussions in the industry. Some scholars even believe that foreign-funded enterprises see the potential advantages of the Traditional Chinese medicine injection industry and deliberately create momentum to suppress it.

All this makes it difficult for the big knife of supervision to fall directly. A series of measures to raise the threshold for Chinese medicine injections introduced later, such as higher standards in 2007 and post-market re-evaluation in 2009, have not really been implemented.

In clinical use, injections have also been generally welcomed by patients because of their advantages such as fast onset of action, and many patients have also developed the habit of regular infusion of traditional Chinese medicine injections, especially cardiovascular and cerebrovascular diseases. "Elderly people often come to ask for the infusion of Traditional Chinese medicine injections to unclog blood vessels." There are clinicians who helplessly tell Eight Points.

Judging from the monitoring data of the drug regulatory department, the number of adverse reaction events reported in 2013 and 2014 was significantly higher than the overall level, and the safety of chinese medicine injections has been paid close attention.

"It is difficult to say whether the overall level of Chinese medicine injections has improved, and the increase in sales is mainly due to market reasons." Some industry veterans told Eight Points.

In fact, the early 21st century to 2016 was also the golden age of the rapid development of China's pharmaceutical market.

With the benefits brought by the new policies such as medical insurance payment and basic drug catalog, as well as the rapid expansion of the scale of China's pharmaceutical market, in the trillion market of China's public hospitals, Chinese medicine injections continue to run wild with "disease" for 10 years, rapidly growing into a force that cannot be ignored.

Until September 2017, the former State Food and Drug Administration once again intervened to stop safflower injection and Xiyanping injection, which was also due to serious adverse reaction events.

Subsequently, the State Office of the CPC Central Committee issued a document to re-mention the "post-market evaluation of injections", for traditional Chinese medicine injections, the head of the national drug regulatory department in addition to safety, further emphasized that the first thing to evaluate is to evaluate the effectiveness.

For the first time, the Chinese medicine injection market experienced negative growth.

Battle of the Trapped Beasts

Since 2017, the entire industry has entered a period of decline, the number of varieties of traditional Chinese medicine injections has dropped to more than 130, and the vast majority of products have been eliminated.

China's drug regulatory upgrade, from emphasizing pre-supervision to focusing on ex post facto supervision and whole-life cycle supervision, the punishment has also been greatly upgraded, the research has been deepened, the instructions have been revised, the use of Traditional Chinese medicine injections has become more standardized, and the scope of application is also shrinking.

There have been large varieties of the past affected by key monitoring and kicking out of the medical insurance directory, and sales have fallen sharply until they actively apply for cancellation of document numbers.

Chinese medicine injections must prove themselves if they want to keep the market.

Chinese medicine injections were born in the special era of lack of medical treatment and medicine, so there are problems such as blind development, imperfect process, low standards, and no strict pre-market research.

This situation is not exclusive to Chinese medicine injections, and a large number of generic drugs also face the same problem. Consistency evaluation has given many generic drugs the opportunity to regain their "legal status", and post-market re-evaluation has been placed high hopes.

In January 2009, the former State Food and Drug Administration issued a notice announcing the full launch of the re-evaluation of Chinese medicine injections after they are listed. According to this notice, Chinese medicine injections will be subject to a comprehensive "trial", from prescription to production to clinical use of adverse reactions, etc., are included in the reference, "the revocation of the standard, resolutely revoked."

Shuanghuanglian injection and ginseng wheat injection were tested in the first batch. In the following ten years, in the adverse drug reaction monitoring report, Chinese medicine injections are the key monitoring objects, and chinese medicine enterprises with damaged reputations have never stopped their efforts to correct the name of Chinese medicine injections.

According to the Times Weekly's previous interview with Buchang Pharmaceutical Zhao Chao, the company has completed more than 30,000 safety evaluation studies in accordance with the guidelines of the previous round of re-evaluation around 2014. Zhao Chao has publicly stated many times that he hopes to explore the clinical value of traditional Chinese medicine injections through the re-evaluation of injections.

Shenwei Pharmaceutical has also carried out more than 30,000 real-world research work on safety for Varieties such as Qingkailing Injection and Shenmai Injection. "We are strongly supportive and actively looking forward to it, and only in this way can we support and encourage the development of drugs with reliable quality and deterministic efficacy." Yu Weiya, deputy secretary of the party committee of Shenwei Pharmaceutical, told Eight Point Jianwen.

"We continue to improve the quality of Chinese medicine injections in accordance with the requirements of re-evaluation of Chinese medicine injections, and continue to conduct in-depth research in terms of basic material research, pharmacodynamic mechanism research and clinical research." Ju Aichun, general manager of Tianjin Tasly Zhijiao Pharmaceutical Co., Ltd., told Eight Point Jianwen, "A good product, we need to explain their safety and effectiveness clearly." ”

There are not a few companies that have the same idea, Shanghai Green Valley, Conlite, Zhongheng Group, Changbaishan Pharmaceutical, etc., have launched corresponding projects. Post-market re-evaluation is not only clinical research, but also the upgrading and transformation of processes and equipment. According to media reports such as interface, some companies have spent 500 million to 600 million yuan to upgrade production lines.

After investing a lot of manpower and material resources, the company found that the initial goal was difficult to achieve - Chinese medicine injections were evaluated after many years of listing, but the drug regulatory department never gave a clear affirmation. "There has been no outcome assessment or tiered policy support at the national level." Yu Weizha told Eight Points Kenwen.

During the two sessions of the National People's Congress in 2019, Xiao Wei, a deputy to the National People's Congress, also proposed to accelerate the re-evaluation of the safety of traditional Chinese medicine injections. He mentioned that the re-evaluation due to various reasons of slow progress, enterprise research results can not be recognized, has led to the chinese medicine injection bad currency expelled good money, coupled with the control of costs, drug proportion and other policies, Chinese medicine injection in the access, clinical use, encountered a very unfair treatment.

A manufacturer of Chinese medicine injections said that the state does not establish a credible "ruler", which is very unfavorable for Chinese medicine injections. "Now everyone has been looking at Chinese medicine injections with the original questioning eyes."

Chinese medicine injections seem to be caught in a dilemma - do not re-evaluate, wait for death; invest manpower and material resources to do evaluation, may not necessarily be able to avoid death.

It is precisely because of this that in the stalemate, except for a small number of enterprises that are trapped in animal fighting, there are not a few enterprises that have no action.

An industry expert pointed out to Eight Points that even now, many companies are hesitant to re-evaluate listings. On the one hand, there is no final plan for re-evaluation; on the other hand, if the product does not make money, the company prefers to sell health care products.

Pay for savage growth

In the past 10 years, Chinese medicine injections have been limited by medical insurance payment and clinical key monitoring in the absence of a conclusion on the safety and effectiveness of the problem, and since 2019, there have been pilots that have undercut their prices and no quantity, and in more radical provinces, there has been a precedent of medical insurance Class A Chinese medicine injection medical insurance not paying. These have a direct impact on the market for TCM injections.

What's worse is that the serious adverse reactions of Chinese medicine injections have frequently erupted, Chinese medicine injections have become sensitive words, as long as doctor-patient disputes, patient deaths and other events involve Chinese medicine injections, and even Chinese medicine injection manufacturers are involved in bribery incidents, the problem of adverse reactions to Chinese medicine injections will be revived by the old things, and hospitals and doctors will also face huge public opinion pressure.

"Western medicine will also have adverse reactions, but once there is a problem with Chinese medicine injections, the contradiction in speech is relatively large." Some clinicians told Eight Points Health, so many large tertiary hospitals do not use, by 2015, 2016, many hospitals have no need to use Traditional Chinese medicine injections.

At present, there are only more than 40 varieties of Chinese medicine injections that are still in the medical insurance list and are used in clinical practice. From the perspective of product sales, the focus of the industry has shifted from anti-infection to cardiovascular and cerebrovascular and anti-tumor fields.

It is undeniable that the situation of Chinese medicine injections is more complicated, and the core point is that their composition is complex - of the 109 Chinese medicine injections listed in the national standard, 57 are composed of more than 57 medicinal materials with more than three tastes, of which 6 kinds of constituent medicinal materials exceed 7 kinds, which makes it difficult to achieve quality consistency between batches and batches. Complex, understood ingredients are also more likely to have adverse reactions when used in combination with other drugs.

At present, the complex components of Traditional Chinese medicine preparations have not been clearly studied, but in the field of basic research, research on improving processes and quality control has been advancing.

Adverse drug reactions themselves are completely unavoidable, many drugs more or less have certain adverse reactions, the key is to achieve risk control. Liang Aihua, director of the Research Center for the Safety of Chinese Medicine Injections at the China Institute of Traditional Chinese Medicine, has been working on the re-evaluation of the safety of Chinese medicine injections since 2006, trying to find a solution.

She told Eight Points Health that the main adverse reactions of Chinese medicine injections are allergic reactions, and their occurrence may be related to people, medicines and use. "For example, reducing drug concentrations and the rate of infusion reduces the risk of allergies." Liang Aihua's research team has established a set of allergy-like detection and sensitizing substance screening methods. On the one hand, it can be used for product testing in enterprises to help control the risk of allergy-like products. On the other hand, the allergenic substance is found for the injection itself, and the allergenic substance is controlled in a targeted manner. In addition, through the study of allergy-like mechanisms, find prevention and treatment methods. In short, targeted solutions are proposed and solved. It doesn't matter if the problem lies in the patient, or which part of the production and use.

Liu Xuesong, executive deputy director of the Institute of Modern Chinese Medicine of Zhejiang University, director and chief scientist of Zeda Yisheng (Tianjin) Technology Co., Ltd., also told Eight Points Jianwen that on the basis of the research on the material basis and process optimization of traditional Chinese medicine, a series of technologies and advanced pharmaceutical equipment for quality control in the production process of traditional Chinese medicine injections have been developed, and breakthroughs have been made in issues such as impurities.

On December 6, 2007, the State Food and Drug Administration issued the "Basic Technical Requirements for Injections of Traditional Chinese Medicines and Natural Medicines", and the threshold for chinese medicine injections was greatly raised. "If this standard is strictly followed, a large part of the Chinese medicine injections can only be delisted." Some insiders told Eight Points.

In 2011, the State Food and Drug Administration issued technical guidance documents for the post-market evaluation of 7 Chinese medicine injections in one go.

For the re-evaluation of Chinese medicine injections after listing, more and more industry insiders realize that it is imperative, just like the consistency evaluation of chemical drugs, which requires a final evaluation conclusion. Ju Aichun believes that the modernization of Chinese medicine needs valuable Chinese medicine injections, and the government, industry associations and enterprises need to jointly re-evaluate the risk and benefit of Chinese medicine injections after they are listed. At the same time, the development of the national re-evaluation method for traditional Chinese medicine injections requires the joint efforts of enterprises, industry associations and relevant national departments, so as to provide patients with higher quality products, create better social benefits, and meet clinical needs.

For the dosage form, Liang Aihua believes that "if there is a clinical demand and can solve clinical problems, there is a need to exist." ”

Shi Lin, director of the Zhejiang Provincial Engineering Research Center for the Modernization of Traditional Chinese Medicine Compound Preparations and the chairman of the Traditional Chinese Medicine Preparation Branch of the Zhejiang Association of Traditional Chinese Medicine, also told Eight Points Jianwen that due to the limitations of current laws and regulations, it is difficult for old products to have a qualitative breakthrough in the process, "The approval and supervision requirements are strict, but they should not be one-size-fits-all, but should be based on scientific and reasonable post-marketing re-evaluation to achieve survival of the fittest." The state encourages the research and development of innovative chinese medicine drugs, as long as it can meet clinical needs, the benefits are higher than the risks, and Chinese medicine injections are still a good choice. ”

In view of the possible results of the evaluation of Chinese medicine injections after they are listed, he believes that for Chinese medicine injections with low safety and effectiveness, it is not a good thing to clarify them as soon as possible and delist them as soon as possible. "If it leads to a large-scale serious adverse event clinically, the results must be worse." And the re-evaluation itself does not necessarily have to be recognized by the drug regulatory authorities. Most importantly, adequate research can give companies more confidence in their products.

Kang Zhen, deputy director of the National Licensed Pharmacist Development Research Center of China Pharmaceutical University, also told Eight Points Jianwen that injections that have no clear indications and many adverse reactions will definitely be eliminated, but whether Chinese medicine injections are going to be "killed with a stick" is still debatable.

There is no doubt that the degree of standardization of the Chinese medicine industry is getting higher and higher, but how long will it take for the confidence damaged by barbaric growth to recover?

Written by Chen Guangjing and Li Linshu

Xu Zhuojun | responsible editor

This article was first published on the WeChat public account "Eight Points Health" (ID: HealthInsight)

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