Interface News Reporter | Huang Hua
Interface News Editor | Xie Xin
On December 19, the State Food and Drug Administration announced on its official website that it had convened the inaugural meeting of the expert working group on post-marketing research and evaluation of marketed traditional Chinese medicine injections.
The aforementioned meeting announced the establishment of an expert working group on post-marketing research and evaluation of marketed traditional Chinese medicine injections, and the first batch of expert working groups includes 28 members, led by Zhang Boli, academician of the Chinese Academy of Engineering. At the same time, the meeting said that it is necessary to promote the holder to accelerate the post-marketing research and evaluation of traditional Chinese medicine injections, clarify the relevant technical requirements, and guide the holder to improve the evidence of safety and effectiveness.
In short, for the traditional Chinese medicine injections that have been marketed, the State Food and Drug Administration once again proposed to do a good job in the research and evaluation of such products, and the specific way is to urge the holders, that is, pharmaceutical companies, to improve the evidence of the safety and effectiveness of their own products, and have the expert group check it.
In the past ten years, the State Food and Drug Administration has repeatedly proposed to conduct post-marketing evaluation of traditional Chinese medicine injections. In the process of carrying out this work, a large number of products have been eliminated in China. At the same time, among the survival of the fittest, the competitive advantage of leading pharmaceutical companies is becoming more and more obvious. However, in the face of the adjustment of the "National Medical Insurance Drug Catalogue" and the continuous rollout of centralized procurement, traditional Chinese medicine injections, which have long been on the cusp of public opinion, need to quickly prove that they are safe and effective.
Perennial "dominant" adverse drug reaction reports
Traditional Chinese medicine injection is a special class of traditional Chinese medicine products, and it is also a product of special historical background, and it is also a class of drugs with great controversy in China. The core of the controversy is whether the product is safe and effective, and whether the product can provide sufficient evidence-based medical evidence to support its use in clinical patients. This is also the key reason why this type of product should be re-evaluated after marketing.
In clinical application, deaths after injection of traditional Chinese medicine injections still occur today. At the beginning of November this year, according to China News Weekly, a patient treated at the Third People's Hospital of Taiyuan City unfortunately suffered shock and acute liver failure after being infused with Phlegm Reqing injection, and eventually died.
If you look at the "National Adverse Drug Reaction Monitoring Annual Report" in the past ten years, traditional Chinese medicine injections are mentioned in each year's report.
For example, in 2013, the National Adverse Drug Reaction Monitoring Network received a total of 530,000 reports of adverse reactions/events of national essential drugs, of which 26,000 cases were seriously reported, accounting for 4.9%; Xuesaitong (lyophilized) and Danshen injection for injection.
Moreover, only the annual reports from 2013 to 2015 are counted, and the varieties of traditional Chinese medicine injections that have been named have also covered the mainstream varieties of this category in clinical application. This reflects that the adverse reactions of traditional Chinese medicine injection products are not only in individual varieties, but also not a problem of individual manufacturers, but a common risk in this category of products.
Since 2016, the State Food and Drug Administration has no longer separately disclosed the monitoring of TCM injections in the Annual Report on National Adverse Drug Reaction Monitoring, but will still mention relevant statistics in TCM adverse reactions. For example, in 2022, 24.8% of the adverse reactions/events were reported by injection, 62.5% by oral administration, and 12.7% by other route of administration, while 97.1% were intravenously administered and 2.9% were administered by injection.
Based on the continuous adverse reactions of clinical application, the regulatory authorities have proposed more than once at the policy level to carry out research and evaluation of traditional Chinese medicine injections. That is, the State Food and Drug Administration said on December 19 that it would carry out post-marketing research and evaluation of marketed traditional Chinese medicine injections, which is an ongoing event in the history of domestic drug regulation.
What to do with re-evaluation?
If we count from 2009, this work has been carried out for 15 years now. However, the focus of this research evaluation has always been on how to carry out research evaluation in order to be scientific and credible.
As early as July 2009, the former State Food and Drug Administration issued the "Letter on Soliciting Opinions on the Technical Requirements for the Safety Re-evaluation of Traditional Chinese Medicine Injections", which put forward the re-evaluation of traditional Chinese medicine injections for the first time.
The above-mentioned document proposes that the manufacturers of traditional Chinese medicine injections are required to comprehensively investigate the risks that may arise in the production process of traditional Chinese medicine injections in accordance with the "Key Points of Quality Control for the Safety Re-evaluation of Traditional Chinese Medicine Injections", and the manufacturers of traditional Chinese medicine injections are required to actively carry out research in accordance with the "Basic Technical Requirements for the Safety Re-evaluation of Traditional Chinese Medicine Injections", and the State Bureau will carry out a comprehensive evaluation of the quality control and risk benefits of traditional Chinese medicine injections in batches and stages.
Under this notice, the regulatory authorities have formulated the "Key Points for Quality Control of Safety Re-evaluation of Traditional Chinese Medicine Injections" (Draft for Comments) and the "Basic Technical Requirements for Safety Re-evaluation of Traditional Chinese Medicine Injections" (Draft for Comments). In fact, in 2007, the State Food and Drug Administration issued the "Basic Technical Requirements for Injections of Traditional Chinese Medicine and Natural Medicine". The 2009 research and evaluation work has been clearly aimed at "re-evaluation".
Subsequently, in March 2010, the State Food and Drug Administration issued the "Letter on Soliciting Opinions on the Guiding Principles for Technical Evaluation Related to the Safety Re-evaluation of Traditional Chinese Medicine Injections". This document is a continuation of the aforementioned management actions. Compared with the previous document, the evaluation system has been further extended.
Specifically, in the notice in March 2010, the State Food and Drug Administration stated that it had organized the formulation of the "Technical Principles for Non-clinical Research of the Safety Re-evaluation of Traditional Chinese Medicine Injections", "Technical Principles for the Re-evaluation of the Safety of Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of Production Process for the Re-evaluation of the Safety of Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of the Quality Controllability of the Safety Re-evaluation of Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of the Risk Control Ability of Enterprises for Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of Risk Control Ability of Enterprises for Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of the Risk Control Ability of Enterprises for Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of the Risk Control Ability of Enterprises for Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of the Risk Control Ability of Enterprises for Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of Risk Control Ability of Enterprises for Traditional Chinese Medicine Injections", "Technical Principles for the Evaluation of Risk Control Ability of Enterprises for Traditional Technical Principles for Risk and Benefit Evaluation of Safety Re-evaluation of Traditional Chinese Medicine Injections" and "Guiding Opinions on Risk Management Plan for Traditional Chinese Medicine Injections".
It can be seen that for the evaluation of traditional Chinese medicine injections, the regulatory authorities have formulated multi-dimensional evaluation guidelines from various aspects such as non-clinical research, clinical research, production process, quality control, and risk control. Correspondingly, the research and evaluation work of pharmaceutical companies should also be carried out in accordance with these documents.
Based on this understanding, if a TCM injection product has undergone complete research and evaluation in accordance with this set of guidance documents, it can become a product recognized by this evaluation system. Conversely, if a product cannot be evaluated according to this system, or if it is not recognized, it may be eliminated.
The above seven technical guidelines should be regarded as a framework document for the research and evaluation of Chinese medicine injections in China. Subsequently, in the process of continuing to carry out the research and evaluation of traditional Chinese medicine injections in China, some products were also announced to be eliminated.
For example, at the end of October 2012, the State Food and Drug Administration issued the "Letter for Soliciting Opinions on the Proposed Elimination of Some Traditional Chinese Medicine Injection Varieties", which included Chaixin Cold Injection, Chuanshanlong Injection, Ganjing Injection, Ganxintai Injection, Tianjihuang Injection, Lemahui Injection, Hanjisong Injection, Tufritillary Senoside Injection, Painconine Injection, Aconitum Injection, and Naoxinkang (Lyophilized) for Injection in the "List of Traditional Chinese Medicine Injections to be Eliminated".
In the second half of 2019, the interface news reporter learned from a traditional Chinese medicine injection company that the State Food and Drug Administration would officially carry out the re-evaluation of traditional Chinese medicine injection around the end of that year, but then there was no follow-up on this matter.
How many businesses can get through?
As the specific implementers of the research and evaluation of traditional Chinese medicine injections, pharmaceutical companies are important parties under this policy.
For pharmaceutical companies, the research and evaluation of traditional Chinese medicine injection products must be carried out. In the short term, enterprises need to take out a part of the funds for research and evaluation investment, theoretically there is also a risk of evaluation failure, but in the long run, if the product evaluation is successful, it will be conducive to product sales promotion. If you look at the announcements of listed pharmaceutical companies, if the products involve traditional Chinese medicine injections, the re-evaluation of their products is continuously carried out.
For example, Jiuzhitang stated in this year's semi-annual report that it would continue to carry out the re-evaluation research of Shuxuetong Injection, KPC said that it would continue to carry out the re-evaluation and secondary development of core products, and Yibai Pharmaceutical also proposed that the company would carry out the safety re-evaluation research of Ginkgo Damol Injection and Eddie Injection during the period, and preliminarily completed the research on the improvement of the quality standards of Aidi Injection and the improvement of the quality standards of Ginkgo Damol Injection.
For another example, Zhendong Pharmaceutical said in this year's semi-annual report that the company's Shuxuening injection is a classic ginkgo biloba extract preparation, which is used for the prevention and treatment of ischemic cardiovascular and cerebrovascular diseases, and was approved for marketing in 2002.
Zhenbaodao said in the "Investor Relations Activity Record Form" at the end of October that the company's production and R&D of traditional Chinese medicine injections have always been at the forefront of policies and regulations, such as the secondary development, standard improvement and re-evaluation of Xuesaitong and Shuxuening injection for injection are ahead of national policies and regulations, and the company has good expectations for the future performance of traditional Chinese medicine injections.
In addition, in the CXO (pharmaceutical R&D outsourcing) industry, more and more companies have voiced that they can carry out post-marketing re-evaluation services and research and development of traditional Chinese medicine injections.
From the perspective of commercial ability, many traditional Chinese medicine injections belong to "large single products". Among these products, there are many products with annual sales of more than 100 million yuan, and there are many products with annual sales of more than one billion and billions. At the same time, relying on these products, a series of listed pharmaceutical companies have also been born.
For example, Qingkailing Injection, Shenmai Injection, Shuanghuanglian Injection, Xuesaitong Injection, Shu Xuening Injection, Thrombotong Injection, Danshen Injection, Xiangdan Injection, Shengmai Injection, and Phlegm Reqing Injection are all traditional Chinese medicine injections with considerable sales scale in China. In addition to listed pharmaceutical companies, there are countless unlisted companies behind these products, which jointly participate in this market.
According to data from Minenet, since 2016, the market size of traditional Chinese medicine injections in China's public medical institutions has exceeded 100 billion. Even affected by the policy, in the days when the use was tightened, the annual sales of traditional Chinese medicine injections in 2017 were 102.15 billion yuan. Throughout the period from 2015 to 2022, the compound annual growth rate of this type of product is -10.29%.
Although the disclosure of sales data of TCM injections by domestic listed pharmaceutical companies has weakened in recent years, at the beginning of the listing of these companies, the sales information of core products disclosed in their prospectuses can still show the huge volume of TCM injections.
For example, according to the prospectus of Dali Pharmaceutical, from 2014 to 2016, the company's sales of Xingnaojing injection were 225 million yuan, 170 million yuan and 166 million yuan, and the sales of Shenmai injection were 90.5632 million yuan, 92.3758 million yuan and 107 million yuan.
At the same time, from 2014 to 2016, there were three main production enterprises in the country that produced Xingnaojing injection, in addition to Dali Pharmaceutical, Wuxi Jemincare Shanhe Pharmaceutical Co., Ltd. (hereinafter referred to as "Jemincare") and Henan Tiandi Pharmaceutical Co., Ltd. During this period, according to the statistics of the competition pattern of Chinese patent medicine terminals in the public hospitals of the Southern Medical Research Institute of the State Food and Drug Administration, Jemincare's sales were at an average annual level of 300 million yuan, and the corresponding market share was 80%, while the market share of Dali Pharmaceutical was only 10%.
Also from 2014 to 2016, there were mainly 7 production enterprises in the country that produced ginseng wheat injection, and according to the statistics of Minenet, Dali Pharmaceutical's market share in public hospitals in key cities was between 5% and 6%. These two sets of data information also revealed that whether it is Xingnaojing injection or Shenmai injection, the sales scale of the entire market is more than one billion yuan.
The prospectus of Yisheng Pharmaceutical also shows that from 2008 to 2010, the company's sales revenue of Shengmai injection was 129 million yuan, 170 million yuan and 180 million yuan respectively, accounting for 41.43%, 40.99% and 35.06% of the company's main business income in the same period. During the same period, the company's sales of Qingkailing injection were 21.2367 million yuan, 47.8232 million yuan and 112 million yuan.
In 2009, the market share of Yisheng Pharmaceutical Shengmai Injection was 24.77%. According to this estimate, the size of this market is also more than 600 million yuan. During the same period, there were also players in the Shengmai injection market, such as Jiangsu Suzhong Pharmaceutical Group Co., Ltd., Shanxi Taihang Pharmaceutical Co., Ltd., and Ya'an Sanjiu Pharmaceutical Co., Ltd.
In the Qingkailing injection market, from 2008 to 2010, in addition to Yisheng Pharmaceutical, there were Shenwei Pharmaceutical, Guangzhou Baiyunshan Mingxing Pharmaceutical Co., Ltd., Shanxi Taihang Pharmaceutical Co., Ltd. and Beijing University of Chinese Medicine Pharmaceutical Factory. Among them, the industry leader is Shenwei Pharmaceutical, whose annual sales of Qingkailing injection are 324 million yuan, accounting for 53.7% of the market share. In other words, Qingkailing injection has a market with annual sales of 600 million yuan.
From the perspective of sales, the annual sales volume of traditional Chinese medicine injection products is also very large, and it is very common to have hundreds of millions of dollars a year. According to the 2019 annual report of Furen Pharmaceutical, which has been delisted, the company sold 195 million salvia injections that year.
If you want to look at the recent sales data, in the first three quarters of this year, Buchang Pharmaceutical's Danhong Injection achieved revenue of 1.859 billion yuan, accounting for 18.65% of the company's revenue. The sales of Danhong injection reached 4 billion yuan in 2015, and at the end of 2021, the medical insurance contract of the product was successfully renewed, and the condition of "limited to hospitals above the second level" was lifted.
During the same period, Kangyuan Pharmaceutical's Retoning Injection achieved revenue of 980 million yuan, accounting for 28.04% of the company's total operating income (unaudited), and the company's other exclusive variety Ginkgo diterpene lactone meglumine injection achieved revenue of 596 million yuan, accounting for 17.06% of the company's total operating income (unaudited).
In addition, in the first three quarters of this year, the operating income of Jiuzhitang Shuxuetong Injection was 488 million yuan, accounting for 20.59% of the company's revenue.
In recent years, the development of traditional Chinese medicine injection has also experienced several ups and downs. Before the current establishment of a working group to carry out the research and evaluation of traditional Chinese medicine injections, the state has had a round of obvious adjustments to the use of traditional Chinese medicine products.
For example, in the 2017 edition of the National Medical Insurance Drug Catalogue, for the first time, the use of traditional Chinese medicine injections was strictly restricted, and 26 varieties of traditional Chinese medicine injections were limited to hospitals above the second level, and some of them also attached disease restrictions. In 2019, traditional Chinese medicine injection was "named" again. At the same time, the National Medical Insurance Drug Catalogue also put forward clearer and stricter requirements for traditional Chinese medicine injections, and the restricted varieties continued to expand, and some types were directly eliminated, and only medical institutions above the second level were required to use them, and at the same time, it was stipulated that they could only be used for severe cases or specific diseases.
However, in the newly adjusted "National Medical Insurance Drug Catalogue", the medical insurance payment conditions for traditional Chinese medicine injections have been relaxed. At the same time, the centralized procurement of traditional Chinese medicine injections is also continuing. This also means that more patients may be prescribed TCM injections in the future. Therefore, there is an urgent need for TCM injections to further prove that they are safe and effective.