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

Overview of Herbal Regulatory Environment in the EU

Werner Knoess

(Head of Division Licensing 4, Complementary and Alternative Medicines and Traditional Medicines, Germany)

Ladies and gentlemen, it is a great pleasure for me to be here to thank DIA and also CPA for inviting me and having this very interesting workshop with many people around the world, who are especially from EU and China,and are experts on herbal and traditional medicines. And all I am going to do is just using 30 minutes to give you an overview on the regulatory framework existing in the European Union.

Looking around, there are many Yale classmates and colleagues, DIA staff members, and personnel from United States. There are also some people who work on herbal study, maybe 40 or 50 people in this room work on herbal regulatory framework, but I think there is some substantial interest in this kind of presentation.

As introduced, I am from BfArM in Germany,which has a long standing traditional in dealing with herbal complementary medicines and also traditional medicines. Any kind of population is the very key in using this product. On the other hand, we are a public European Union and so the regulatory framework in Germany is also the European framework. I will just focus mainly on the framework in the European Union. And even more,we are talking about global market.

Some years ago, for example, I had been to Chengdu where I paid a visit to the TCM market which was a fascinating world of TCM. But it is just part of the world people using herbals and traditional medicines,and it is just regional development linking to different cultures. So we develop regulatory frameworks to regulate it, and it is a challenge. Because for every part of the world, we develop different frameworks in the EU. We have traditional herbal medicine products and traditional medicine products in China, which includes

traditional Chinese medicine and herbal medicines.

In the United States, there are botanicals and also food supplements. There are different categories of drugs around the world, which is a challenge for regulators and also for companies to control herbal market.

So, here is the outline of my report.

First, I would like to give a brief introduction of the EU network and also the legislations to show the backbone out of system we are dealing with. Then, I will give you an example of European regulatory agency and all the committees, which is the core of the harmonized standard used in EU.

We aim to harmonize national regulatory framework throughout the world. Moreover, I will just introduce some basic concepts and standards and then look into the future.

Look at this network within the EU. This is very complicate and it will need 20 minutes to go to every detail for this slide. The upper is the European committee and parliament, whose responsibility is to make a legislation framework, which is the basic for all EU states. The national authorities are doing a major part of passing assessment and also European procedures.

The European pharmacopeia gives quality standards.And finally, the European national agency is trying to coordinate all the frameworks and is also responsible for the centralized procedures.

When we look at the basic legislation, we have found that pharmaceutical legislation is binding for all the member states.

This is the so called community 2001/83, which defines basics and other dialectics that supplement this basic pharmaceutical legislation. And the approach is quite similar to all over the world. We have quality, safety and efficacy before having access to the market. And of course, we also have time for maintenance and time for pharmaceutical vigilance.

The life cycle is regarded as the most important element of a medicinal product, and this setting is general for all regulatory products. Within our legal framework, there is a particular space for herbal medicine products. So we have a set of the definitions which is dedicated to herbal medicinal products, herbal substances and herbal preparations.

We are going to focus on the definitions, but I just would like to guide you especially to have a look at this definition for herbal medicinal products. So this is the outline. Due to the complication of herbal medicines, the definition of a herbal medicinal product basically contains one or more active ingredients, or herbal substances or herbal preparations or maybe the combination of them.

And finally it is important to be aware that we are talking about multiple components. In the world where chemical defines products, you have only one component which is active. Here we are talking about multiple components, which may have different actions and different targets, making it complicated. It is also complicated to evaluate its quality, safety and efficacy.

Behind this, we define the quality by the whole process, from its beginning to end, as well as the field for growing. If the whole process is good and herbs are well collected, you will have a herbal substance or herbal drug.Then, by the manufacture process, it becomes a herbal preparation, which will be finished as a product. This must sound complicated, which is a challenge to provide all the data. But quality must be seen as a starting point of any development.

This guideline was prepared by the European Medicines Agency (EMA). And I recommend it to anyone who wants to step into this business, because it is a guideline on the use of CTD format document, which includes more than 100,000 pages. On the quality part,you may see a flow chart on processing, which offers the information instrument to the EU industry and industries from all over the world to get an idea of what is the expectation of the authorities in the European Union.

If you are looking on how standards are harmonized in the EU, you may be aware that there are different parts playing different roles on the standards.

As for herbal medicinal products, for example, from EMA, HMPC monographs mainly focus on safety and efficacy. Another part of standard is released by European pharmacopeia and later we will have another lecture on its details.

As for the quality standard, if you are familiar with Chinese pharmacopeia, you maybe also aware there are other numerous guidelines addressing different aspects of the quality, safety and efficacy on herbal medicinal products. The particular system of multiple organizations just shows a picture with different cultures and different regulatory requirements. But its end will be fortunately harmonized by EMA.

You can get all the information of monographs together with assessment report from description literature. Comments given by the public statements are also fully transparent. Here is a list of the monographs and you can decide which one you want to see, and the, just look at the internet. For example, there is a monograph from HMPC addressing the name of a product, its qualitative and quantitative conditions, its pharmaceutical form and clinical particulars. This is likely the regulation of EU member states.

Now we are looking a little bit more of the standards behind the system and I prepare only a few slides on this topic.

Basically we have 3 different approaches to marketing authorization for herbal and traditional medicinal products. Of course, for a new product, we need to try its efficacy, safety and quality. And the requirements are the same.

We have another option, which is based on the 10-year use in Europe, and in the EU. It is more useful within the EU. For example, you are coming with this product from Asia. This is a particular history part.

Everything which is going through marketing authorization underlining safety and efficacy must be available in public scientific literature. The EU implemented a new law in 2004, which also has a line for traditional medicinal product. If you really treat traditional medicine slide chemically, you find this will be a problem to fulfill all the requirements. In order to give traditional products the option to stay on the market and to have an change within the EU, there is a kind of procedure where the efficacy is not on clinical trials, but on traditional use,for there may be some new data in the safety area. And you can see, for quality, there is no compromise. In CMP,the same requirement is available for this product.

In the process, there are different categories of procedures. We can see that this product was authorized by a centralized procedure, which is run by the European Medicine Agency and also up with authorization by European Commission. And all the 28 member states of EU can make use of it. Another option is the so called decentralized procedure. We have 2 examples for it, extracts of green tea and cannabis. Some member states of EU may run a decentralized procedure of marketing authorization and there was a legal member state. And other member states rely on the assessment on the member state.

So you can see all the elements in the use of chemical products are also to be used by herbal medicinal products. Within the concepts, these particular medicinal products maybe sound very interesting on the first sight.Looking at the detailed introduction of herbal medicinal products, you need at least 30 years of tradition. Maybe there is a chance if 15-year tradition in the EU and 15-year tradition outside the EU. But it has restrictions: only for oral, external and inhaled administration; only allowed for minor diseases; can be taken by oneself.

No monitoring by medical doctor should be obligated. No mention of animal origin to be used and so no supervision. If you are talking about cancers, stroke,you can use traditional Chinese medicine. But this is not allowed within the framework on traditional medicines within the EU. There have already been some successful applications for traditional herbal products of Chinese origin in the EU, like the Netherlands and the United Kingdom. In Germany we have had the authorization of a product, which is a combination product.

Look at these traditional medicines registered in the EU. The light blue ones are combination products,while the dark blue ones are single-drug products. So the EU regulatory framework is really fixed in these kinds of products and the most important application is mainly for cough and cold as well as mental disorders, covering about the 3/4 of all the registrations. Traditional Chinese medicine is existing in the EU. In Germany we have hundreds of pharmacies offering Chinese medicines.

They are also available in some herbal shops and hospitals. In EMA there is a question-answer document of the framework, which needs to be translated for non-European countries and companies. If you want to bring a product to the European market, visit these options in this question-answer document.

MPC is doing a monograph or a trail project on herbal drugs of traditional Chinese medicine, for example,to provide scientific data of salvia and subprostrate sophora for HMPC assessment. I cannot tell about the result of this project, but at least we bring more experience dealing with this kind of herbal drugs. Sometimes we are just facing the situation that there are a lot of data and scientific literature,but it is a problem to translate them into the European regulatory framework. Here are some recommendations.Those who want to go to the European Union market,for herbal and traditional medicinal products, need very tough planning and development. You must think about the classification of the product and the right pass way - new or traditional. You must decide about the procedure in one of the EU states - a decentralized approach or a centralized approach. And you must have a rational indication, which must be either traditional or must to be proved by clinical trials. The main recommendation is to look for an early scientific advise whether to be national or from EMA.This is the most important step, and you should do very early planning. Everything is confidential but there will be no problem with it. You need quality data, clinical data,professional approaches and a lot of money. Otherwise, it is hard to realize.

So, coming to the final part: what about the future?We'll have new methods in pharmaceutical experiments:fingerprint NMR, classification or clustering methods, as well as other scientific methods to conduct component verification and analysis.

If you look at the regulatory framework besides science, you'll have the same ideas about regulatory framework, quality, security law, pharmacopeias,monographs, pharmacovigilance and enforcement. But if you are discussing on the international level, we also face challenges due to different frameworks. There are problems for regulators and also for the industry.And the next slide may summarize at least the idea that there is a chance for convergence, which was a headline missing a year.

So if you look at the laws, pharmacopeias and monographs, it's not easy to change the laws of EU,China, United States and Australia to have a harmonized view. This will be needed sometimes, of course. But in other fields, there are scientific networks for exchange among the pharmaceutical peers. So that there are ongoing projects and monographs, where the NBC is also in contact with big Chinese companies, which are contributing to the scientific laws. There are other ongoing projects with observers in, for example, in EMA. And there are other international projects around the world.WHO has just begun a multinational pharmaceutical research project, so we have a lot of regiment. That will be a convergence over time. Also for quality, ICH has built a good standard and we have to see how the different approaches can be matched, because no approach is the best one that different approaches have different advantages and disadvantages, safety and efficacy. Here is a very good example for Chinese medicine. There are terminologies and indications about it, which cannot be one by one translated into some EU languages. Then we need to consider the translation problem to ensure the close communication between doctors from different countries. In conclusion, in the EU, we try to have harmonized standards in the project for assessment before the marketing. We have been doing this in the last 50 years, and the framework also offers options for herbal medicinal products from non-European countries. But this has to be developed step by step. We have different procedures in the national or even European level, so that pharmaceutical companies can well choose what the best option to go ahead is. Finally, I personally convince that communication and dialogue are very important among regulators, stakeholders, the scientific community, and so on. This is why we are so much enjoying being here. And if the scientific community joins us, we'll find the base place forward to the convergence that requires to have a same field. But this is nothing we can reach in 2 or 3 months. We need to set goals and we have to follow these goals what is the development of next decades. So thank you for your attention.