Xiao Xiaohe (肖小河)

(Executive Member, Chinese Pharmaceutical Association, Director, ClinicalTraditional Chinese Medicine Professional Committee of Chinese Pharmaceutical Association, Director, Institute of Chinese Materia Medica, 302 Hospital of the People's Liberation Army, China)

My topic is the risk assessment of safety of Chinese materia medica. Next I will take drug-induced hepatic injury as an example. First of all, let us look back at what Chinese materia medica is. What are the real meanings of these 3 words? These 3 words Zi Hua Zi have been said more than BC 500. "TCM practitioners are for treatment and medicines," what do you mean? Treatment means to find the cause of the disease and to find the law, while medicine is to find ways and means to cure diseases.

Today, we talk about the exchange of Chinese medicines. I think the exchange of traditional Chinese medicines we are talking about, should be the international sharing of traditional medicine. Now every year there are many Middle East, African, some European, military delegations, visiting our hospital, especially those, who are interested in traditional medicine. Chinese medicine could treat many common diseases and frequentlyoccurring diseases.

About 5,000 years ago, people began to produce medicine, which has developed very well now. Why does China have so many people? A very important reason is that Chinese medicine has made a relatively important contribution. Thus now we are sharing the traditional medicine internationally. The first purpose of our sharing is to share Chinese materia medica technology, Chinese materia medica methods, Chinese materia medica with the world; the second one is to use some of our technical methods to help developing countries, especially African countries, to develop and explore their treasure-house of traditional medicines. The third one is to build the future people's health maintenance system, by creatively and constructively contributing to the wisdom and strength of Chinese medicine. Those are our purposes and missions.

IMPORTANCE OF RISK EVALUATION AND CONTROL

Chinese materia medica has indeed welcomed a very good opportunity. In particular, our party and state leaders attach great importance to it, including some very important achievements of Chinese materia medica, which have been internationally recognized and winning Nobel Prize. But at the same time, our safety accidents and security incidents have also appeared.

There is a very important thing that a toxic drug, which has not been clearly recorded in history. After the emergence of toxin of traditional non-toxic Chinese materia medica, serious adverse reactions often cause uproar. So it is easy to hide, and is difficult to prevent. The thing that is easy to hide is traditional poisonous Chinese materia medica. Once an adverse reaction occurs, everyone can understand it and it will not be a big surprise. Therefore, everyone attaches great importance to that. Why is it important? Because China is a major resource of Chinese materia medica, a major country of research and development, a major producer, a big consumer, and a big export country.

The safety of Chinese materia medica is not only a question of people's livelihood, but also a social, economic and even political issue, with the broadest community of destiny. Safety issues, is the head sculpture, publicizing our Chinese materia medica industry. Once it is damaged, it will have a major impact on the entire industry.

Thus, a well-known think tank of Chinese Academy of Engineering investigates the development frontiers of global medicines in 9 major areas. The investigation of safety in Chinese materia medica has been ranked fifth. The survey in China proves that everyone is concerned about this matter. At this point, there are more than 130 core papers, but the citation rates are very low. Each paper has more than 60 citations, indicating that really valuable and useful quotations are cited, and persuasiveness is not enough.

What do you think about the safety of Chinese materia medica? What I have said is not very serious. Actually, this is not the case. I told all friends that the safety situation of Chinese materia medica is generally stable, controllable and good. However, as soon as we see a lot of problems, we always expose them. We found the changes in 3 aspects.

First, we are more and more aware of the level of human drug safety, scientific level, technology levels, and regulatory systems, making us find more problems of Chinese materia medica quality and Chinese materia medica safety, than ever before. That shows that our regulatory system is improving, so is the level of governance.

Second, people's health needs have undergone fundamental changes. We are no longer in time of lacking treatment and medicine. Actually, some major diseases indeed do not have no good drugs, while common diseases and frequent diseases generally have already had.

Third, the administration of drugs has changes. We used traditional medicine, especially traditional Chinese drugs, mainly for 3 to 7 days. Now it is used for health preserving in many cases. The patient may possibly take it for 3 months or half a year. Our extract process has changed, so has the system undergone major changes. Our Chinese friends are very impressed that we did not have enough eat and wear 30 years ago, and our constitution was then debilitating. Now our material life has greatly improved. When we enter the era of prosperity, we are all high in blood fat, blood pressure, blood sugar, uric acid, and body weight. How to reduce them? We should use traditional medicines, whether it is treatment or health care. We should be aware of the 3 changes, which will cause problems, without realizing them.

There are still 3 things unchanged. Our concept has not changed. To say that Chinese materia medica is unsafe after a problem occurs, or to say that Chinese materia medica has no toxic side effects is wrong or prejudice. Additionally, the evaluation criteria are not suitable. To use traditional chemical drugs to evaluate Chinese materia medica is also inappropriate. Just like Compound Danshen Dropping Pills produced by Tasly, it is a very good medicine. Originally, it was an all-around champion, and it is not bad compared to other people's single champions. It has great courage and is very suitable. Whether we should stop this or not or destroy the whole medicine after the adverse reactions. For example, the aristolochic acid mentioned above is basically not used. If so, what shall we do if serious adverse reactions occur? Keeping pace with the time and strengthening the safety of Chinese materia medica construction is very important. We must also develop with the world.

HEPATIC INJURY AS THE CASE

With so many security issues, where shall we start? 302 Hospital of the Chinese People's Liberation Army is the world's largest hospital of liver disease. Nearly 2,000 beds are used to treat liver disease, and the treatment of drug-induced hepatic injury accounts for 10%. Here, liver is a very important organ.

Our vast Chinese herbal medicine and traditional drugs are used orally. After taking them orally, they are absorbed into the blood through the liver, which is the most important organ for detoxification and metabolism. We start from here. It is true that drug-induced hepatic injury is also the main cause of adverse drug reactions, missing or not being approved in the world. In China, adverse drug reactions in Chinese materia medica are mainly caused by target organs. If we say from the point of variety, it is mainly the injection, in which target organ exists. The national adverse reactions have repeatedly notified the safety of Chinese materia medica. The state attaches great importance to this issue and puts forward a good regulatory countermeasure.

It is found that some drugs are often caused by some traditional non-toxic Chinese materia medica. What are the reasons? We solve these problems by proposing a prevention and control plan of hepatic injury by Chinese herbal medicine, which is a three-step process, as follows: The first step is that standards should be established to avoid misunderstanding. The second step is that we should find out the degree of the drug-induced hepatic injury by Chinese herbal medicines, and the degree of the hepatic injury by chemical drugs. And they should be dynamically monitored. The third step is that we should have comprehensive prevention and control.

How to prevent and control this matter? There are no more than 10 kinds of drugs that actually cause severe hepatic injury, from the point of single-drug. However, there are many compound drugs causing hepatic injury. The purpose of the work is to reduce the "four-rate", misdiagnosis rate, incidence rate, adverse (end rate), and failure rate caused by hepatic injury of Chinese herbal medicines. I hope that adverse reactions represented by hepatic injury caused by our Chinese herbal medicines, mainly is from not clear to be basically clear. It is indeed regrettable that many of the adverse reactions of Chinese patent medicines are still unclear. Thus we should learn from modern chemical medicines, and the instructions of which contain detailed explanation of adverse reactions. During these years, we have some growth in the establishment of methods and some drugs.

Setting Standard - Guiding Principles for Clinical Evaluation of Drug-induced Hepatic Injury in Chinese Materia Medica

The first growth created such a guide, a standard methodology. There are many international standards for drug-induced hepatic injury, but these standards do not go into herbal medicine in traditional drugs. Traditional drugs are too complicated, so are the chemical medicines themselves. You can look at chemical medicines because drug-induced hepatic injury is all about rejection. It does not raise the standard, so the misdiagnosis rate can be as high as 50%. Chinese herbal medicine is complicated, and the varieties are too much. The problems of drug producing, safe medication, especially the combination medicine, are together with the chemical medicine. How to judge Chinese materia medica and enterprise products are very difficult? There are many factors here, so Chinese herbal hepatic injury is in a very low market. How to do this work? How to treat us with serious druginduced hepatic injury? Our Chinese materia medica is often traditional, passive, and beaten. There is no trick to deal with this matter. How to change the passive behavior into the subjective one? We made the first identification method and standard of objective fungi for drug-induced hepatic injury: Integrating evidence chain method (IEC) is used, which is based on the current hepatic injury, plus the elimination of western medicines. It is required to have traceability, and to strengthen the markers in vitro and in vivo to conform it. By that, we can avoid the current misdiagnosis and refractory phenomenon. Now this standard is also widely distributed at home and abroad. And this method can be very scientific. Drug-induced hepatic injury, liver has nothing to do with western medicines, and with Chinese materia medica. Then a 5-level standard was established, excluding suspiciousness, possibility, very likeliness, and affirmativeness. Such is the exclusion system. Objective evidence evaluation was compared. That method can indeed greatly reduce the rate of misdiagnosis of hepatic injury by Chinese herbal medicines, which can be doubled.

This method can also be applied to chemical drugs, in which exclusive method is used. As our method is better, China Association of Chinese Medicine, entrusted me to take the lead in making a clinical diagnosis guide related to hepatic injury caused by Chinese herbal medicines. The guideline later became an industry standard. After the issue of this standard, it has been highly evaluated by various parties. And it filled the gap and showed the open mind of Chinese medicine practitioners. Clinical practitioners can participate in the standard for fungal diagnosis, to detect whether it is a hepatic injury caused by Chinese herbal medicines.

Many people in China do not advocate that Chinese herbal medicines had hepatic injury, and they feel that they would lose face by admitting it. In fact, it is not a scientific follow-up, nor a serious attitude. Everyone knows that this medicine is a three-point toxic drug. We should face this correctly, whether we are government officials, or our old Chinese medicine practitioners, or general scientific and technical personnel.

As the guide is more useful, on that basis, National Food and Drug Administration entrusted us to conduct a review and supervise a guideline for the prevention and control of drug-induced hepatic injury. That guide is the beginning of the project. From prescriptions, it processed the varieties of medicine, discovering the risk, the risk of drug-induced hepatic injury. How to find it and evaluate it? How to prevent it to establish a complete system? After the system was promulgated, it was highly evaluated by the most qualified experts in the country, because this was a representative of the milestone of safety supervision of Chinese materia medica.

In our country, we have been highly appraised by various media because it is a very good thing. There should be evidences of hepatic injury in Chinese materia medica. If there is no evidence, we should not wrong a medicine. Meanwhile, we have widely promoted in many aspects at home and abroad, and have been highly praised by various parties. Nowadays, drug-induced hepatic injury requires 3 methods to evaluate. The relevance score of European program, integration evidence chain of Chinese program, the laboratory or a clinical pharmacy expert or a medical expert, together complete such a good job. Now WHO has let us make this guide to the prevention and control of hepatic injury by traditional drugs. Now it is completed and is ready to submit. Meanwhile, we are also very interested in the evidence chain. I hope that it will be reflected in it.

Drug-induced hepatic injury in China

We have method and standard here. How is our Chinese drug-induced hepatic injury? Is it serious or not? You can look at the epidemiological investigation we have done, in large areas, including National Center for Adverse Reactions and large hospitals. After the investigation, it was found that the hepatic injury by Chinese herbal medicines accounted for about 1% of the total adverse reactions, which was not so serious. The hepatic injury of Chinese herbal medicines have increased rapidly in recent years. It can also be found that the age-structured drug-induced hepatic injury is from 40 to 60 years old, and the standardization makes the most common people aged from 40 to 60. After standardization, the older the patient is, the greater the hepatic injury is. Especially today, when it comes to drug-induced hepatic injury, many people say that Chinese materia medica or health care products are the main reasons. Chemical medicines still account for 95% of the proportion, while Chinese herbal medicines account for about 5%.

In the adverse reaction center, our investigation results, after the issue of the paper some time ago, show that the percentage is 20% to 30%. The data is also correct. Why? It is a serious adverse reaction. Once go to the class-A hospital, China's best hospital, it means the patients have serious reactions. Hepatic injury does not seem to be very serious in general, but it is very scattered, with many varieties. Chinese patent medicines are like this. It is difficult to supervise the base station without hepatic injury. It is not difficult in itself, but it is difficult to control and prevent.

In the top 50 medicines in China, there is no Chinese materia medica and all of them are chemical drugs, especially antibiotics, anti-tumor drugs, and cardiovascular drugs. The anti-tuberculosis drugs are mainly in antibiotics. Actually Chinese materia medica is not very serious. Chinese materia medica is mainly for the treatment of rheumatoid bone disease, and they are in forms of injections.

In the past few years, Gynura segetum (Lour.) Merr in Chinese patent medicines have been developed very fast. Radix Notoginseng development is taken as an industry in China. Many people think that Gynura segetum (Lour.) Merr is Radix Notoginseng. Thus, they misuse it. What are the results? Radix Notoginseng contains pyrrolizidine. What will be the phenomenon? Why is it so serious? How can we divide it? Why do people say that Chinese medicines are the first? Actually the classification is wrong. It should be said that we should use the comparison method of three-level classification. Chinese medicine should not be the first. There are some problems in classification, which is created by us to avoid exaggerating the safety of hepatic injury by Chinese herbal medicines. We should not exaggerate the problems of hepatic injury, but it should not be underestimated. It is certainly not minor problems. You can tell everyone.

Comprehensive prevention and control

I have found out what the reasons of hepatic injury. As our drugs are all clinically produced in phase I and phrase II, how does hepatic injury happen? Additionally, our medicines have been used for 2 or 3 thousand years. Why does it still have the injury? In fact, the original evaluation of Chinese materia medica is often in a very narrow range of standardization. It has been limited to a few hundred years, or thousands of years of clinical practice. Additionally, Chinese materia medica is used in the different ways from the past, and the changes lead to the problem. What are the reasons? Hepatic injury, which is concealed, and unpredictable, is very difficult. Chemical drugs are like this, so are the Chinese medicines.

We have established a new method of toxicology, which has been refined from our ancestors. If you have the disease, you can take the medicine. You will be in trouble to take the medicine without the disease. That is an old saying of Chinese materia medica. We take medicine by our body. According to this model, we have systematically evaluated these drugs.

I am talking about Radix Polygoni Multiflori, which is a very famous medicine today and is a traditional complementary medicine in China. But there are many reports of its hepatic injury. It is caused by the hepatotoxicity, a millennium supplement medicine. Actually, our ancestors also know that Radix Polygoni Multiflori leads to hepatic injury. Yes, as we all know, serious adverse reactions dose not harm liver, which was recorded 200 to 300 years ago, or 300 to 400 years ago.

After the investigation, the hepatic injury of Radix Polygoni Multiflori is constitutional and is immunely constitutional. It has no obvious relationship with time, dose, and age. It is possibly that the ratio is rare, about one in ten thousand. By the previous complete chain of evidence, we follow a rule of exclusion. How can we exclude other diseases? You have white hair by taking Radix Polygoni Multiflori, without anything else. And you may have live injury and secondary hepatic injury by taking Radix Polygoni Multiflori. There are many cases, which show that hepatic injury is repeatly caused by accidentally taking Radix Polygoni Multiflori.

Meanwhile, we also excluded quality problems. The medicinal materials are qualified, and some metabolic components are detected in the body. We actually take it. Meanwhile, we follow this with other liver diseases, and distinguish between immune liver disease, alcohol liver and fatty liver. The most difficult thing is to find its hepatitis B gene, which is also a breakthrough. Now we have found the gene in hepatitis B group caused by Radix Polygoni Multiflori, which will increase by about 30 times. This document has been released immediately, in American Journal of Liver Diseases. To find this gene, you may follow the next step of control. We should think more whether the medicine is unsafe, or the person, or the administration of medicine?

Radix Polygoni Multiflori may cause hepatic injury, and toxin response. We must find what ingredients cause hepatic injury? Radix Polygoni Multiflori has good immune promotion and can synergistically increase this effect. By the inside, we find out what its regulatory system is, and we can find most of them. What are the reasons? We summed up a hypothesis of "3 reasons leading to toxicity", which are firewood, oil, and spark. The firewood is the disease that is activated by abnormal immune mechanisms, or autoimmune diseases are often prone to occur. Here, Radix Polygoni Multiflori, is very immune-promoting, which is called firewood. The spark is the hepatitis B substance of the hepatic injury. Just now I mentioned 2 ingredients. There is another hypothesis, which involves the ingredients in other medicines. And the ingredients are Chinese materia medica supplements and have the same principles. Radix Polygoni Multiflori can actually lead to hepatic injury, and it is the second specific substance, and the third immune specific substance. It is rare. General speaking, it is safe and it does have such problem.

Knowing its mechanism, we change from the drug control to population control. First, we should find the hepatitis B population, and the diseases. Then we find the symptoms of Chinese medicine, and the genes. Thus we distinguish them very well. Reasonable use of drugs is the tradition of Chinese materia medica, in which we have a variety of methods, such as processing detoxification, blowdown detoxification, compound detoxification etc., for reducing toxin. These methods can really reduce toxin.

OUR ACHIEVEMENTS

System establishment on quality evaluation and control

How to evaluate the quality? Now we can only test the individual components. Quality of control is really problematic. How to evaluate this matter? I think that a set of evaluation system, called the integrated evaluation method, has been established. If the composition is clear, we have established the composition index. If the chemical background is clear, we establish the effect component. If the chemical background is mature, the biological evaluation should be mainly adopted. If there is no chemical or biological method, the product specification is used to decide the kind of medicine. All medicines, no matter what medicine is, must meet the standard of Chinese Pharmacopoeia. As long as the quality of Chinese materia medica is controlled or the indicators is convincing, it is ok.

We made a guideline, which was issued nationwide. The core of quality control is to control the fingerprint, the contour spectrum. We can also introduce such a concept. We have established the safety of biological evaluation, and we are effective in guiding us to establish these methods. Some methods are original, and are in the world's Chinese materia medica bio-evaluation monograph, by which the application in some medicines, especially medicines with unclear effects, big compound medicine or Chinese materia medica injections, are common.

After this method came out, Zheng Yongqi, a Yale Professor, was very concerned about this. He evaluated this, combining tradition and modernity very well, and combining chemistry, pharmacy and biology very well. We have also won some awards for promotion. We have also promoted the quality of Chinese materia medica by our work, from biological to chemical change, including the American FDA guidelines, the previous doctor in Tasly mentioned. The professors have read materials related many times, because they have a wide range of knowledge and are very interested in writing this constitution. I think he is doing very well in biological evaluation and integration of controlling a model.

Providing reasonable advice on hepatic injury

Chinese herbal medicines can lead to hepatic injury, but now the main drugs for the treatment of druginduced hepatic injury are from Chinese materia medica or natural medicines. Heaven and man are united. Hepatic injury can be well treated by several medicines. We put forward a reasonable proposal for the adverse reactions after drug use, to provide for the national industry, from non-prescription drugs to prescription drugs. Production and sales of Radix Polygoni Multiflori, have not changed significantly. We have been entrusted by the state, for many times, to study the safety of Chinese materia medica, especially hepatic injury, and liver cancer. We have provided valuable reports to Food and Drug Administration, National Administration of Traditional Chinese Medicine, Ministry of Science and Technology, National Health Planning Commission, and even Central Health Bureau etc. for the first time, and they are all recognized by them. They write letter of thanks to us.

Establishment of database, league and system

We have established the world's largest database of drug-induced hepatic injury. Based on the database, we have established an international alliance for safe drug use, with the United States. And we are the chairman of the alliance for the use of drug safety regulatory research. Last year, the alliance was formed and we released the first declaration on traditional drug safety medication in Beijing. After the release, we established a evaluation system for risk assessment and risk control of drug-induced hepatic injury through a series of work. We have realized the safety risk management of Chinese materia medica from passive response to active prevention and control. Originally, we encountered sudden infectious diseases in China, especially SARS. In the past, we all avoided that matter. We did not take good measures after avoiding it. Some large officials were recalled. After that, the security risks have expanded, and the bad things have become good things. The risk system has been established. A good system has been established here for hepatic injury caused by Chinese herbal medicines.

As for the work we have done, I think we should be grateful to our ancestors, who are very concerned about the safety of drugs. From Shen Nong's Classic of the Materia Medica, I knew, at that time, the drug had a safety problem. Drugs were divided into upper, middle and low product, with large, small poison, no poison, which is a sense of safety. In this book, there were 18 flavors 800 years ago and 9 flavors more than 600 years ago. The interaction of drugs reduced efficacy or safety. There are fewer guiding contents in the book. Now the work that we do, can fill this gap, so they say it is a milestone, or an epoch-making issue.

By doing this, I believe that our Chinese medicine or Chinese dream will be realized. The purpose of the realization is to contribute to the construction of the future health system, and to jointly promote the development of the wisdom of traditional drugs, which is traditional Chinese medicine and western medicine to jointly develop this matter. As it is systematic project, many people have realized it. This is the end of my report, thank you.