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Pharmaceutical innovation capability is an important part of the country's comprehensive strength and an indispensable factor
for strengthening the country.
Traditional Chinese medicine is deeply involved in the whole process of fighting the new crown pneumonia epidemic, and has shown its unique value and contribution
in the global fight against the epidemic.
In the past 40 years, with the introduction of clinical epidemiology, evidence-based medicine and other disciplines, the quality and level of clinical research of traditional Chinese medicine in China have been significantly improved, and many high-quality and high-level clinical research of traditional Chinese medicine (including clinical trials of new drugs for the purpose of registration) have been carried out one after another, and a number of traditional Chinese medicines have been successfully registered and listed at home and abroad, which has promoted the development of the traditional Chinese medicine industry and the internationalization
process of traditional Chinese medicine 。
The pace of "going to sea" of traditional Chinese medicine has accelerated
According to the statistics of the World Health Organization, Chinese medicine has been recognized in the form of government legislation in 29 countries and regions such as Australia, Canada, Austria, Singapore, and Vietnam, and 18 countries and regions have included traditional Chinese medicine in medical insurance, and many Chinese medicine varieties have been registered in the European Union, Russia, Singapore, Cuba, Vietnam and other countries and regions, and the number of traditional Chinese medicine enterprises involved in the international market has gradually increased
。
In 2004, the European Union promulgated its current Directive 2004/24/EC on Traditional Herbal Medicines (THMP), which simplifies the registration of THMP with long-term traditional applications but lacks evidence of modern research, exempts the "non-clinical" and "clinical" research parts in the application materials of the product general technical file (CTD), and only needs to use literature, expert evidence and safety reviews and reports to prove that the product has sufficient traditional application and safety to be registered and listed, greatly reducing the difficulty of registration
。 The Decree gives THMPs, including TCM compound products, access to EU market access for
medicines.
At present, Chengdu Diao Pharmaceutical's Diao Xinxuekang capsules, Tasly's danshen capsules, Tongrentang's Yufeng Ningxin tablets, Xiangxue Cambridge's Banlangen granules and other varieties have been approved for registration and marketing
in the EU.
Chinese medicines can apply for natural drug registration
in Canada through the "traditional application" route.
The premise of this application route is that the composition, preparation process and indication of the variety must have more than 50 years of application time
.
In the preparation of application documents, the requirements for the declaration materials in terms of the efficacy of varieties are relatively flexible, but great attention is paid to the safety and quality
of varieties.
In July 2008, Tasly's application for compound danshen pills and chaihu drops pills as traditional medicines passed the full review process
of Health Canada.
In 2016, Hutchison Pharmaceutical's Cholin tablets obtained marketing authorization
from Health Canada's Natural Medicines and Over-the-Counter Pharmacy.
In addition, Xiangxue Pharmaceutical's orange red sputum cough liquid and antiviral oral liquid were approved for registration in Canada in 2012 and 2016 respectively
.
The "Huatuo Reconstructed Pill" produced by Qixing Pharmaceutical is one of the confidential varieties in China, which has entered 27 countries and regions such as Russia, Canada, Australia and Vietnam, and has also entered Vietnam's medical insurance catalogue and Russia's basic drug catalogue, and obtained the Russian drug permanent registration certificate
in 2010.
In May 2012, Qixing Pharmaceutical and the Belarus National Center for Scientific and Practice of Cardiology signed a clinical research agreement on evidence-based medicine in the treatment of stroke with Huatuo Reconstructive Pills, and jointly launched the evidence-based medical clinical research
of "Huatuo Reconstructed Pills".
In 2005, Peking University Wearnes' Blood Lipid Health was successfully registered as a prescription drug in Singapore; In 2006, the results of the clinical study of Lipid Health were published in Norway; In 2011, the clinical research results of Lipid Health entered the European Guidelines for the Management of Blood Lipids
.
Conlet injection has been undergoing clinical trials in Russia since 2001, obtained the drug registration certificate issued by the Russian Ministry of Health in 2003, and was launched
in Russia in 2005.
Yiling Pharmaceutical's Lianhua Qingwen capsules have been registered as "proprietary Chinese medicine", "medicine", "botanical medicine", "natural health product", "food supplement", "modern botanical medicine" and "natural medicine" in more than 20 countries and regions including Brazil, Indonesia, Canada, Thailand, Singapore, the Philippines and Russia, and have obtained marketing authorization
.
Xiangxue Pharmaceutical's orange red sputum cough liquid was approved for registration in Kenya in 2013, and Pediatric Oral Liquid was approved by the Health Sciences Authority of Singapore in 2017
.
Unlike other countries and regions, according to the "Botanical Product Guidelines" issued by the US Food and Drug Administration (FDA) in 2004, if traditional Chinese medicines want to be marketed in the United States as drugs, they can only be approved for marketing
through the New Drug Application (NDA) route.
In recent years, about 10 varieties have submitted new drug clinical trial applications (INDs)
to the US FDA.
Among them, three traditional Chinese medicine preparations, including Tasly's compound danshen drop pills, Xingling Technology's Xingling granules and HMPL-004 of HMP Whampoa
, were approved to enter phase III.
clinical trials.
Progress of international multi-center clinical research of traditional Chinese medicine
In recent years, the international multi-center research on traditional Chinese medicine has shown a trend of increasing year by year, but the total number is still small
.
A search using "Chinese herbal medicine" as the keyword found a total of 212 traditional Chinese medicine clinical trial projects carried out in Europe and the United States (as of April 12, 2022).
Among them, 156 clinical trial projects are from East Asia, 22 are from North America, and the rest are from Southeast Asia, Europe and other places
.
Unfortunately, most of these projects are researched in a single country, and it is difficult to see a true international multi-center clinical trial
.
In addition, in terms of study status, 67 studies have ended normally (31.
60%), 39 studies are recruiting participants (18.
40%), 24 studies have not yet started recruiting participants (11.
32%), 3 studies are ongoing (1.
42%), and the remaining studies were stopped
early for various reasons.
From the trial stage, 86 studies (40.
57%) were phase II clinical trials, 34 studies (16.
04%) were phase III clinical trials, 21 studies (9.
91%) were phase I clinical trials, and the rest were phase IV clinical trials or early exploratory trials
.
The number of published SCI literature in multi-center clinical trials of traditional Chinese medicines has also shown a year-on-year growth trend, mainly concentrated in the past 10 years, and has decreased significantly
in the past two years due to the impact of the new crown pneumonia epidemic.
A search of "herbal medicine AND Randomized control AND multicenter" on the NewPubmed literature analysis system yielded 326 articles (as of April 12, 2022).
Among them, from 1989 to 2000, there were 4 articles, accounting for 1.
2%; From 2001 to 2010, there were 47 articles, accounting for 14.
4%; From 2011 to April 12, 2022, there were 275 articles, accounting for 84.
4%.
The largest number of publications was published in 2020, reaching 59, which dropped to 21 in 2021 and only 6 in
the first 4 months of 2022.
China is the country that has carried out multi-center clinical trials of traditional Chinese medicines and published the most related SCI literature, with a total of 263 SCI literature, accounting for 84.
4%; It was followed by Japan, the United States, South Korea, Pakistan, etc.
, accounting for 5.
2%, 2.
8%, 2.
5% and 2.
1% respectively
.
Beijing, Shanghai, Guangzhou, Tianjin and Chengdu in China, Tokyo, Fukuoka, Kyoto, Chiba and Karachi in Pakistan are the cities
with more participation in multi-center clinical trials of traditional Chinese medicine at home and abroad.
The research mainly involves tumor, cardiovascular, respiratory, digestive and other system diseases
.
Nearly 70% of the multi-center clinical trials of Chinese medicines carried out overseas focused on classic Chinese medicine formulas and proprietary Chinese medicines, while the remaining 30% focused on dietary supplements and plant extracts
。 For example, Wulingshan in Japan treats tongue pain and prevents the recurrence of chronic subdural hematomas; rhubarb peony decoction for acute diverticulitis; Six gentlemen's decoction for cervical cancer or uterine body cancer; Dajian Zhong decoction for the treatment of paralytic intestinal obstruction after liver transplantation, colon cancer and pancreatic cancer resection; Banxia laxin decoction for colorectal cancer; Windproof treatment of obesity-type hypertension; Jin Kui Kidney Qi Pills for the treatment of chemotherapy-induced peripheral neuropathy (neurotoxicity); Evodia soup for headaches, etc
.
In addition, there are Wuwei pills plus and minus treatment for food allergies carried out in the United States, palm pills for chronic low back pain in South Korea, and Wuji Sanshan and angelica four reverse soup for cold allergies in hands and
feet.
International multi-center clinical trial prospect of traditional Chinese medicine
The "human experience" of traditional Chinese medicine has attracted international attention, and effective use of historical "human experience" is an important way to
revitalize the stock of original scientific and technological resources of traditional Chinese medicine.
In recent years, focusing on the supervision of the field of traditional botanical medicine, some countries and regions have issued new drug research and development policies and regulations
for human experience 。 For example, in December 2016, the US FDA issued the Botanical Drug Development Guidance for Industry, which provides guidance on the pre-market approval of botanical drugs, requiring human experience data when filing phase I and phase II clinical trials in order to put forward regulatory requirements for preclinical and clinical studies; The European Union, Japan, South Korea and other countries and regions also have special reviews around the prescriptions of traditional botanical medicines, Chinese medicines and classical medical booksBatch regulatory policies
.
"Human experience" is based on the long-term clinical practice of Chinese medicine and the formation of a certain regular, repeatable summary of the experience of diagnosis and treatment of Chinese medicine, historical experience of Chinese medicine is mainly contained in ancient medical cases, today's application experience of Chinese medicine prescription mainly comes from medical institutions preparations and famous old Chinese medicine and other expert experience
.
It is not difficult to see that adhering to the clinical value-oriented construction of a Chinese medicine evaluation evidence system that combines Chinese medicine theory, human experience and clinical trial will become an important innovation path
for Chinese medicine to move towards high-quality and international development in the new era.
How to summarize scientific laws and tap scientific value around the "human experience" of thousands of years of history of Chinese medicine, which is of far-reaching strategic significance and important practical significance
for improving the quality and efficiency of Chinese medicine and promoting the internationalization process of Chinese medicine.
Carrying out high-quality multi-center clinical trials is still the only way
for Chinese medicine to enter the international mainstream pharmaceutical market.
Chinese medicine products that are in line with international standards and supported by high-quality clinical research evidence can go further
.
Since the implementation of the Good Clinical Practice (GCP), the overall quality of new drug clinical trials in China has been significantly improved, but there are still some shortcomings
.
The "14th Five-Year Plan" for the development of the pharmaceutical industry mentions that domestic clinical research institutions should be supported to actively participate in and organize international multi-center clinical research to improve the internationalization level of
clinical research.
Therefore, under the premise of following China's current GCP and the International Technical Coordination Committee for Registration of Drugs for Human Use (ICH) GCP, it is of great strategic significance to formulate targeted quality control measures for the characteristics of multi-center clinical trials of traditional Chinese medicines, which is of great strategic significance
to promote the research and development of new traditional Chinese medicines in China and enter the international mainstream pharmaceutical market.
It is important to further innovate clinical evaluation technologies and methods that conform to
international norms and the characteristics of traditional Chinese medicine.
In recent years, new technologies and methods of international drug clinical trials have been gradually applied to
clinical trials of new Chinese medicines.
For example, it breaks through the adaptive design of frequency statistical methods that are usually used in the design and analysis of clinical trials for a long time; In order to improve the accuracy of the population included in the clinical trial, the enrichment strategy that occurs to reduce the occurrence of confounding factors; In order to improve the efficiency of clinical trials, shorten the time of clinical trials, and reduce the cost of clinical trials, efficient clinical trial design strategies such as the main protocol, as well as basket design, umbrella design, etc
.
are used.
In 2019, China officially implemented ICH "E17: General Principles of Multi-regional Clinical Trial Planning and Design"
.
Finding clinical positioning that conforms to the characteristics of traditional Chinese medicine in the drug treatment of diseases and can bring obvious clinical value and benefits to patients, and finding, researching, establishing and formulating scientific and consensus clinical efficacy evaluation tools and evaluation methods for such research purposes and clinical positioning will become an important research direction
in the field of clinical evaluation methodology of new traditional Chinese medicines.
In recent years, the relevant laws and regulations issued by the state have attached great importance to the clinical value
of traditional Chinese medicine.
What is the characteristic clinical value of traditional Chinese medicine and how to express it scientifically is one of
the "lifeline" issues related to the high-quality development of the traditional Chinese medicine industry.
The ageing of the population, health problems caused by chronic noncommunicable diseases, and the threat of infectious diseases such as the new crown pneumonia have all put new demands
on Chinese medicine.
However, in contrast to the popularity of traditional Chinese medicine, the development speed of the traditional Chinese medicine industry has declined in recent years, and one of the important reasons is that its characteristic clinical value has not been clearly
stated.
Among them, clarifying and expressing the clinical efficacy is the focus, rather than clarifying the material basis and mechanism
of action.
For example, Tu Youyou won the Nobel Prize in Physiology or Medicine for her discovery of artemisininin, a treatment for malaria, but the mechanism of action of artemisinin is still being studied
.
Of course, the scientific evidence of clinical efficacy can be diverse, and the expression of the clinical value of traditional Chinese medicine should not only be the results of randomized controlled trials, but also have more materials, such as medical cases, classic works, clinical experience records, etc
.
Even Gordon Guyatt, the head of evidence-based medicine, has said that any empirical observation can constitute potential evidence, whether collected systematically or not
.
The focus of the reform of the new review and approval system for new Chinese medicines is on the "three combinations" of clinical trials and human experience plus the interpretation of Chinese medicine theory, that is, to systematically excavate and scientifically evaluate multiple evidence
pointing to the same research conclusion.
In recent years, the state's investment in traditional Chinese medicine has further increased, and under the impetus of factors such as the construction of the "One Belt, One Road" and the acceleration of overseas layout of leading enterprises of traditional Chinese medicine, the internationalization of traditional Chinese medicine has ushered in an all-round, three-dimensional and multi-level development situation
.
Although facing many challenges such as standard convergence, policy barriers, and intellectual property protection, there is a long way to go, but the future can be expected
.
(Authors: China Science and Technology Development Center of Traditional Chinese Medicine, Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Institute of Traditional Chinese Medicine, Tianjin University of Chinese Medicine)
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