SINO-EUROPE SYMPOSIUM ON TRADITIONAL CHINESE MEDICINE & HERBAL MEDICINE-MARKET OVERVIEW ®ULATION POLICY

Panel Discussion

Dr. Joseph Scheeren,Pharma Chair of DIA Board

Werner Knoess, Head of Division Licensing 4, Complementary and Alternative Medicines and Traditional Medicines, Germany

Diane Wilkinson, Acting Director, Business Improvement and Support Section Complementary and OTC Medicines Branch| Medicines Regulation Division, Health Products Regulation Group, Australia

Zhang Junhua, Head of Evidence-based Medicine, Tianjin University of Traditional Chinese Medicine, China Bernd Roether, Doctor, Head Division Drug Regulatory Affairs, BIONORICA SE, Germany

Zhang Shunnan, Research Professor, Vice General Manager, Tasly Pharmaceutical Group Co., Ltd., China Karin Schleisiek, Senior Regulatory and Scientific Affairs Manager, Global Strategy and Business Development Division, Dr. Willmar Schwabe GmbH & Co. KG, Germany

IMPACT OF BREXIT ON CHINESE COMPANIES'ACCESS TO THE EUROPEAN MARKET

Q: We have a product, which was approved in UK in 2017. Now we want to expand the market to the Europe. Do you have any suggestions about which country is easier to accept traditional Chinese medicine?

A: I don't know exactly what will happen, because there's no agreement between the EU and UK how the UK will be leaving the EU community. We can only guess what's going to happen, and I can give you 2 scenarios.The first is there's no deal. You are deadlocked. So you won't be able to use your approval in the UK to get your approval into other countries. The second one is you're lucky the deal is going to be made. And then there may be a traditional period to make this kind of recognition still possible. So your approval in the UK may turn out to be a black horse in order to get your approval in the Europe.

A: You are talking about the registration of traditional medicine, so you'd better make 参考文献 to the monographs of HMPC. The complexity of getting registered only in the UK is different from that in other countries. There are many laws indicating that registration in other member states must take these monographs into account. And I think the UK will probably not stay in the EU. Therefore if you want to enter the European market,you have to learn more about other member states and pay attention to their monographs.

A: Actually, there have been European member states play positive roles on traditional registration. So it's possible to find another positive road to the EU market for traditional Chinese product. If that's the case, I believe there is no legal base to get a Decentralized Procedure(DCP) for not-monograph traditional products, but anyhow, a lot of other member states do support European procedures. We have experiences for products which are not-monograph background. So it should be also possible.

Q: So, from my understanding, every country has its own monograph, right?

A: The monograph is issued by the Committee for Herbal Medicinal Products (HMPC) of European Medicines Agency (EMA).

REASONS AND POSITIVE OUTLOOK FOR THE RARE SUCCESS OFCHINESE MEDICINE REGISTRATION IN EUROPE

Q: I'm confused for a long time and I'd like to seek for help here. Because we have been registering medicines in Europe for more than a decade, thousands of medical herbs have been registered throughout Europe. And it's a pity for our Chinese companies that only 3 varieties have been registered. Please help me to analyze the reason. Are Chinese companies not willing to register in Europe? Is it too difficult to register in Europe? Or is it difficult to occupy the herbal market in Europe? If there is a new consideration that will allow more Chinese companies to actively participate in the registration of medical herbs in Europe?

A: I would just use a different word. You have already 3 successful examples. Because you should always keep in mind the legislation. In the EU, it was made to cover traditional products in the EU. It was not the idea to open a framework especially for TCM. And I think this is an approach to unite people, when you're looking at this traditional scheme in the EU. If you have someone who has experience in TCM and the management is wise, in the EU, it is hopeful to enter the traditional field, just as OTC area. So they are 2 different systems. If you now talk about modernization of TCM as, it's the right step to use modern technology to come to modern medicines. But some people being worried about this will ruin your tradition, because they are different medicines. So, there is definite a mixed land between both legislation and here. And I think it would depend on the strategy of the Chinese company of finding the best way. If you just want to go to the market to bring your traditional products into the market, and then you have to first look at the registration conditions. If you have other things in mind, and just want to look for strong indications,then you must be professional, you must be very into investment, and you must very into communication, so that it will be possible. This is the key element at the moment that Chinese companies must make their programs clear. They have to decide which market they want to target, and with which kind of product. And then we need to communicate the particular products. If you look for an example into the German market, we have the different taste with the other EU member states. So currently we have about 1700 products which had authorization, and 300 of them have such a traditional registration. So every product has its particular history, and also particular history is an evaluation of authority, and this would be the same for the products from China. So for each particular idea in mind, we have to check which lines are possible currently, and of course on the other hand, we have to check, what will be future change in the legislation. So, to inspiring Chinese companies, I just want to say that we already have 3 successful examples.

Q: Let us continue the question. There is a big difference that Professor Zhang just mentioned. Chinese medicine tries to be registered in Europe; we have to do many times of work, because there are 8-10 ingredients in it.When cooperating with foreign companies, their requirement is no more than 3 ingredients, so that it is not TCM. This is a little difference I want to know, what the legislation's point of view that how to consider TCM to get into the European market and benefit European people. And you say there are 3 of them are successful, yes. But the workload is double,triple and even tenfold. So this is quite different between foreign products getting into China and TCM getting into the Europe market. How to address this issue?

A: This is a substantial work need to be done. On the other way, the company representative from the EU, if they want to go to the Chinese market, it's the same vise versa. So they have to adjust to adapt to the Chinese pharmacopoeia as well as Chinese requirement. And we can also say it's the same that if you want to go to the United State. So the only chance is that we have more convergence on the requirements,and these can be done. But basically if you want to advance further you have to change the legislation and it's not to change one legislation. You have to change 5 different continents'legislation in the world. We all know it's time-consuming and very difficult. My favorite approach is that regulators and stakeholders communicate with each other and try to get some point where we share opinions and have a convergence on requirements. I know also this is very challenging,because time and money for regulatory authorities and everyone needs to contribute. And the market, it depends on the company that whether they want to enter European market. They have to make more efforts for companies. And if European medicines want to enter the Chinese market, they also have to make more efforts than usual.

A: That's a good answer. I think we need to talk about how we reach an agreement. Which kind of organization will be able to get to a kind of situation where TCM products will be recognized in the EU, while products from Europe will be recognized here in China.And this is the field need our efforts in my view.

DRAWING ON EUROPEAN MARKET EXPERIENCE

Q: A question I want to ask, especially considering into like a product without 15 years using in the Europe. This is related to the EU market. About 2 weeks ago, I visited a company using plant extracts, so we were introduced they are very interesting plants from South America and it's a kind of berry. And it's very beneficial to diabetes. However, they said they don't have 15 years' using experience, and it's quite new in Europe, also not listed in the monograph. Meanwhile they are trying to register in China and it's also challenging as well. So my question is, for example, like their herbs,is there any regulation suggestions from companies like in Europe or Germany? Who can share their experience for them? What do they need to do? Do they need to prepare a pilot study, or any clinical study for observation? Or do they need just to sell their healthy products in the stores or kind of things, so to prove they have 15 years' experience in Europe?

A: OK, you must understand I'm from the regulatory authority. You put forward an example you go to the Island called Saint Martin, an island of Netherlands. If you find the use in this island, the Netherlands, this would be accepted as a kind of European experience. Each star is different. If you're talking about diabetes and stepping into the EU, it's obligatory to go into a centralize procedure as European Medicine's Agency. So for Germany, if you step into the market with just claim related to diabetes is not enough.Inspectors will take you off the market, if you do not have marketing authorization. Each project is particular in its documentation, background, and legal obligations, so a lot of work can be done in this case. You can do a lot of work like clinical trails and you may spend tens of thousands of euros, and then you may find it can't realize at last. This is why we say you need scientific advice, you will save a lot of money, and you can shape your project. This was not very frequent in the past 5 years, but we gave scientific advice to companies from India, China, Japan, and from many parts in the world. As these are confidential, I cannot talk about any experience from the scientific advice. But I hope you can communicate with the regulators and get relevant advice.

Q: When it comes to medicine registration of crossing borders, I image that could ICH be an approach?Diane Wilkinson is from Australia, and their standards seem less restricted than EU or China. Could you share your experience with us?

A: The ICH is an organization whose target is developing guidance rather than legal or law issues as far as I know. And therefore I don't think this organization can change the law. What we can do is to establish a platform to get understanding and to organize the requirement to get the approval for the product. This is a prospect we can image. But from a legal perspective,I don't think it is an appropriate way. It probably needs inter-governmental discussions to get an agreement.

A: So, just now we have a national framework for medicine registration, medicines and poisons. Each state and its territory can choose whether or not to conform to a national framework, but there are generally some exceptions.

A: It could be interesting to see that activities for herbal medicines in ICH are rather limited. So we need to convergent people together. ICH is a network that belongs to WHO and since last year it became more formal. This is a good platform, which can appeal other associations to contribute. But it's not mandatory now, so it will be a very long process that there must be a bilateral agreement.There is a bilateral relationship between German and China. They cooperate on TCM, whose progress is also very slow, but indicating the cooperation between legislation field and scientific field. We have realized that legislation is out of step with scientific development, but we need to continue the communication with patience.

PROSPECTS FOR CLINICAL RESEARCH AND EVALUATION CRITERIA FOR TRADITIONAL MEDICINE

Q: I have a question for Professor Zhang from Tianjin University of Traditional Chinese Medicine,because you're very professional in evidence-based medicine and also clinical research. I always wondering on the traditional medicine, because we've already have thousands of years of clinical use on this, but it's very hard for TCM to get approval through clinical evaluation,based on western medicine double blind control. Can you give some advice on what will be the future on the clinical research for traditional medicine, especially the condition used on different ingredients all together?

A: It's a good question. In fact, no matter Chinese medicine, western medicine, or traditional medicine, under the Chinese regulatory system, it is necessary to complete clinical research. The formulas before the Qing Dynasty do not have to go through clinical trials. If it is not a classic one,for example, a new formula commonly used in the hospital,clinical trials are necessary. Traditional Chinese medicine has its curative effect and can be evaluated. However,sometimes our evaluation methods and treatment system may be different, but sometimes it is the same. Research on classical formulas and formulas for patterns, research needs and indicators may be different in different categories, but clinical trials must be done. When registering in Europe,although you don't have to do clinical research, they will record that you have no evidence of clinical research, so your market is hard to expand. As long as your product is effective, no matter it is effective in symptoms, patterns of TCM, or other indicators, it can certainly be evaluated. This process is really difficult and the cost is too high. But if a new variety wants to better occupy the market and let more people use it, it must go through the steps of clinical trials.Whether you register or not, if you can't provide evidence,it is difficult to be accepted widely. Because we have done a lot of such clinical research, in fact, we complete some highquality tasks every year. Therefore, in the future, we will have different regulatory requirements for different varieties.

A: In other words, is it possible to have any breakthrough changes that are different from western medicine in quantitative standard and evaluation criteria for clinical research of Chinese medicine or herbal medicine?

A: We may have some differences on medicines for patterns, because it is based on patterns to evaluate them. We use different evaluation systems for symptoms and diseases to conduct research on syndromes with characteristics of TCM syndromes. For example, Liuwei Dihuang Pill is a treatment for liver and kidney yin deficiency syndrome, and our medicine can promote blood circulation and phlegm, so its evaluation system is definitely different.

A: I'd like to add a little bit. In fact, the Chinese Medicines Administration Law is being revised. This is the business law for medicine supervision in China.With its revision, there will be a series of regulations.We also hope that there will be different evaluation methods for biochemical in traditional Chinese medicine.I will talk about it in PPT later, and its own research and development path is different. This may be reflected in the traditional botanicals in Europe, but there may be some differences in traditional Chinese medicine. Therefore, in this case, we are considering some different evaluation methods, and we hope to build an evaluation system that conforms to the characteristics of traditional Chinese medicine. As we adjust our technical standards, we need to further revise the regulations so that we can have better space in the evaluation of Chinese medicine.

A: I have a question on this. I just went to see a TCM doctor, and TCM doctor made a diagnosis. He took my pulse on my right hand and left hand. He looked at my tongue, and then he gave me a prescription. I went to a pharmacy to get some medicines. He told me that I have to drink it for 3 times a day, for one weekend, and after 8 months I would be back to health, because the prescription was very effective. But if you look at the way of the diagnosis, the methodology for his diagnosis needs to be validated. So if you have 50 patients and 20 different doctors, what will be the results of the diagnosis of these doctors on TCM perspective? Is that something which will be very similar, or there will be differences? If you don't have a good way to make diagnosis, you are not able to do a good clinical trial.

A: Firstly, the interesting thing is talking about the pattern diagnosis of TCM. And secondly, it's been used in TCM for 5000 years. So what has been discussed previously was that whether TCM diagnosis can be used in clinical trials? How the TCM diagnosis can be measured? So you have to identify the biological base of patterns, and then to correlate TCM diagnosis with western medical terms before people can understand really what you are talking about. Because when you use that in China, and that's fine you can get a Google that medicine base on TCM, and treatment and diagnosis and evaluation. However, you can't use the same piece of evidence in Europe, in Australia or in the US. Because people don't understand what is "yin deficiency" or something. So what I'm trying to say is that we use TCM diagnosis, pattern diagnosis for a small number of clinical trials. And use the western medicine as the main tool, and use TCM tools to evaluate the diagnosis.

A: Basically, we have a system of clinical trial and this is independent. And Dr. R told us an example of the authorization. A product with the combination of 5 different ingredients and it shows that it can work. And other examples in Germany, they are also for combination products which we can do clinical trial and come to an end. From a scientific perspective, scientists are always debating whether in the EU there are regulations focusing on the medical product or not. There are some treatment options around, so that you are not only using the medical product but maybe some physically activities as well.So this may be discussed on a scientific level to identify a better trail design, just like the question asked by our professor that whether the diagnosis can be validated or not. This could be discussed on the scientific level,because the guidelines on clinical trials, they give you at least some design base to adapt your clinical trail to the product you are looking at.

Q: Dr. Zhang, can you share with us how the evidence-based diagnosis approach is you are practicing?

A: The method is the same. Chinese medicine can cure diseases, and this "disease" is not the same as that in western medicine. Some methods are based on symptoms,such as headache, and others are based on special patterns in TCM. Just as some people said, by taking the pulse and looking at the tongue, we can judge whether you have a cold pattern or a heat pattern, a deficiency pattern or an excess pattern. According to this kind of pattern evaluation, and different functions of Chinese medicine,we can screen them. So the indicator system is different.In terms of methods, the key to our research design is to control bias, and our approach is different from the global one. We also use randomized double-blind and randomized control. Another point is we also hope to have our own diagnostic equipment suitable for the characteristics of TCM in the future. Western medicine has its own CT, nuclear magnetic and B-ultrasound, but we only have 3 fingers now, which is not enough. Our index system is different that when we look at the tongue,we know that this person suffers from a heat pattern.We are concerned about whether the indicator system is suitable for the characteristics of TCM. The most important thing in the study of TCM is the characteristics of it. There are usually 10 or 20 ingredients in a formula.As long as I know your formula, I probably know in which disease it can be effective, and its characteristics.We have a lot of experience in it, which, in turn, can be used to optimize our system, not just our scale.

OBSTACLES OF COMMERCIAL INTERCOURSE BETWEEN CHINESE AND EUROPEAN MEDICINES

A: Today, our core topic is how to sell Chinese products abroad, and at the same time introduce foreign products to China. First of all, we have to answer this question. Whether it is a foreign market or the local market, is there a lack of medicine? Second, is there a shortage of traditional medicine? I think that there is a shortage and I also think there are no shortages.Why? Because when treating diseases, there are certain medicines, but the medicines are not enough. There are no good medicines for some serious diseases; no matter it is Chinese medicine or western medicine. I think traditional medicine may be needed, but is it the one that is urgent? So in the second case, when entering your market or our market, we have to examine each other and set a threshold. The first threshold is the culture. There are difficulties in traditional medicine: research is difficult,treatment is difficult, and legal approval is difficult. So to set the threshold, the first is from a cultural perspective. I can't speak English very well, and you can't speak Chinese very well, so this is a big obstacle itself. The second is the interrelationship of traditional medical theories. It's very difficult to explain, which need a lot of work. Sometimes it's not just a scientific issue, but a cultural one. The third is probably a technical issue. Who is responsible for approving this matter at home and abroad? The fourth is the evaluation criteria, which are divided into two. One is the evaluation standard of the technical level. The second is the concept we developed. Are we going to develop the best medicine, or the medicine that is not available in the market, or some dispensable medicine for the market? Now the market is no longer the time of lacking medical care and medicines. How to improve? Fill in the blank. I think it is still necessary to dig out the value of clinical medicine.This is the fundamental problem of our entire discussion.As for the other rules, I think we can sit down and discuss and can solve them. So, many rules are essentially artificial problems. My understanding is, there are 4 differences between Chinese medicine and western medicine in the aspect of formulating standards. First, western medicine mostly uses a single indicator, while Chinese medicine applies multiple indicators. Second, Chinese medicine pays attention to the whole. Third, western medicine often pays attention to objective indicators, while Chinese medicine focuses on a combination of both objective indicators and subjective indicators. Fourth, western medicine keeps an eye on modern literature, publishes the latest literature and technology. Chinese medicine focuses on inheritance,which possesses nearly thousands of years of tradition.There are kinds of literature including modern ones as well as western medical ones with neurological evidence.Therefore, the 2 evaluation systems of modern medical science are considered to be very different. Since the evaluation systems are different, there may be obstacles in communication. I want to share this with you for your 参考文献.