Professor Dr. Fritz H. Kemper
Chairman of ESCOP, President of the German Society
for Phytotherapy

Welcome adress

Ladies and Gentlemen, 
Welcome in Bonn,  until recently the capital of Germany, now with good right a beutiful city of science and health administration (Letter Simon). Professionals came together to discuss and solve problems to meet the necessities which were proposed and asked for. I regard ESCOP as a professional scientific association or cooperative but in the sense of an institution getting scientific advice if it is wanted or needed and this since more than a decade. During the beginning in establishing was in 1988 and the formal beginning of ESCOP took place later in 1989 in Cologne. ESCOP works as an association of independant national scientific societies - you may recall ESCOP has no personal members- and this concept has proven excellent and especially looking back over the past 12 years ESCOP was highly effective in the field of herbal medicinal products and their scientific background. With the contributions of the ESCOP monographs -SPC in the administratve sense-  which were established with the appreciated and gratefully acknoledged generous assistance of the European Commission who awarded ESCOP a three years grant. But also I take the opportunity to renew my sincere thanks to all scientists working voluntarily and without any renumeration within ESCOPs Scientific Committees. All this voluntary and honorary work ESCOP inserted to the benefit of herbal medicinals with the goal to support the expectations of both health administrators and as well as the public, that means the citizens of Europe. From my point of view this is also fundamental in regaining the nearly lost trust for the scientific community and regulators respectively. 

So the aims of ESCOP is to advance the scientific status of phytomedicines and to assist the harmonisation of their regulatory status at the European level. The objectives to reach this aims is or are to develope a coordinated scientific framework to assess phytomedicines, to promote the acceptance of phytomedicines, especially within general medical practice, to support and initiate clinical and experimental research in phytotherapy and to improve and extend the imperious accumulation of scientific attractively knowledge in the field of phytotherapy but also to support all appropriate measures that will secure optimum protection for those who use phytomedicines, the consumers not only in Europe and to produce reference monographs on the therapeutic use of plant drugs, last but not least to further cooperation among national societies on phytotherapy to advance these aims and objectives. 

At the time of unpresedented scientific and public interest in phytomedicines, research papers on herbal medicinal products and their ingredients are being published in a continual growing scene and number. The term harmonisation rules the scene and indeed we do need harmonisation. We need also a special kind of modernisation and this is not only coming along with the internet and different links. At present ESCOP is preparing the revised edition of 60 or more monographs, the mentioned SPCs (Summary of Product Characteristics). ESCOP acknoledges all as already mentioned in this respect the great input of the members of the scientific committee as well as those of the research committee. 

The present legal situation and consequently the status of herbal medicinal products differs within the member states of the European Union. I imagine and agree that it may be difficult to find the common denominator for the ones who had to slip a level over those who had to attain a higher level. But we will have to solve this problem within soon. 

ESCOP is highly indebted to Dr. Paul Weissenberg Director, Single market, Regulatory Environment, Industries under vertical legislation of the DG Enterprise of the European Comission for accepting our invitation to give the key lecture of the 6^th scientific symposium of ESCOP on Herbal Medicinal Products -Scientific strategies in Europe. This item directly aims to my previous remarks. 

Also we thank Professor Dr. Konstantin Keller from our host country Germany, member and head of the department for HMP of the Federal Institute for Drugs and Medicinal Products, but also chairman of the Working group on HMP of the European Agency for the Evaluation of Medicinal Products - Human Medicines Evaluation Unit (EMEA) in London. We are indebted for accepting our invitation as contribution in this 6h ESCOP Scientific Symposium.

Allow me already in my welcoming address to thank all other speakers listed in your programme for coming to Bonn and give all of us insight views on their items and special questions.

In my welcoming adress I may also want to express my deep concern about the market situation and the position of HMPs not only in Europe but also elsewhere in the world. Beside the urgent and strong demand on better and more extensive efforts in direction to basic investigations in phytochemistry and phytopharmacology as well in clinical trials we have to realize the fact of a dependency between science and the drug market, in our case HMPs. 

If their is no turnover in HMPs in the market there will be lesser money or even no budget for scientific work. As an urgent consequence a harmonization of the legal background but also of regulatory toxicology in this field is mandatory. It can not be that selfnominated "expert-groups" claim to be watchdogs (of their own interests). 

As one who knows about the subject matter either as a specialist in internal medicine and clinical pharmacology, or as an acknoledged expert in affairs round about Herbal Medicinal Products, I have strongly to protest that e.g. an admission of clinical studies take place before these had been submitted to the Drug  Agency of the European Union or to Swiss Authorities.

Let me add that at present, at least in Germany the realibility of clinical studies is based on the acknoledged rules of GCP (Good Clincal Practice). Clinical studies are valid and can be used as such if they fulfill in a critical appraisal the criteria layed down in these rules and not until they have been acknowledged or even their admission is "permitted". 

ESCOP welcomes the European deliberation in the context of amending the EC Directive 65/65 on new definitions and consequnetly new regulatory backgrounds on HMPs in the sense of well established use as "well-established use" and "traditional use". These terms and their application indeed could be the right key to the right lock.

The last point I want to adress is the - from my point of view - indistinct situation or better borderline in the field of Dietary Supplements, Functional Foods, Dietary Integrators and others. What is the difference at least in a number of instances between nutritive actions and physiological ones? But besides these differences which will have to be definded in a regulatory sense, I trust already today to the future work of EFA, the European Food Authority, and above all I hope for a good cooperation between EMEA in London and EFA. 

It will be a task for the European Community and especially between the General Directory Enterprise and DG SANPO to prevent in these respects an unallowed and possibly harmful widening of the spectrum at present in the respective Directive on Dietary Supplements, that means within a regulation preferably of Vitamins and Minerals (Trace Elements). This can not be in the sense of the work which has been done during the last 20 years excessively and this can not be in answering the expectations of the consumers. Also in this scenario ESCOP should be good advised to offer our expertise in an application of the principle in question especially in dosage regimens for children and elder people.

ESCOP also agrees and supports the ideas of Dr. Thomas Lönngren, the new Director of EMEA to establish a "lifely  net work" between EMEA and the new member states. ESCOP welcomes in this context the institutionalised position of the Committee for HMPs, chaired by Dr. Keller. Despite ESCOP is not responsible but indirectly engaged in regulatory affairs with scientific advise. We welcome all this as symptoms an European harmonisation. Alcide De Caspari, Robert Schuman and Konrad Adenauer may look on Europe today as they did some fifty years ago from the nearby Petersberg establishing the European Union. Hopefully they would be satisfied with the EU of today. Lets go to work: The 6^th European International Scientific Symposium on Phytotherapy "Strategies in Phytotherapy in Europe" is opened.

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Professor Dr. Konstantin Keller, member and head of the Department for Herbal Medicinal Products of the Federal Institute for Drugs and Medicinal Devices and chairman of the Working Group on Herbal Medicinal Products of the European Agency for the Evaluation of Medicinal Products, Human Medicines, Evaluation Unit in London (EMEA)

Welcome adress 

Professor Kemper, dear cooleagues, Ladies and Gentlemen. 

It is a pleasure for me to welcome you in Bonn on behalf of the President  of the Federal Institute for Drugs and Medical Devices, Professor Schweim.

ESCOP was founded in 1989 in Cologne and another international ESCOP meeting took place there in 1996. Scientific boards of ESCOP held many meetings in Bonn, which shows that ESCOP seems to find the Rhine valley an attractive area - and it really is, isn't it. My colleagues from the Federal Institute for Drugs and Medical Devices, BfArM, having completed the move from Berlin to Bonn quite recently, are just beginning to discover this attractiveness. Residence has been taken up in the first section of the new BfArM building at Robert-Schumann-Platz.

The BfArM was founded in Berlin as an independaent Superior Federal Authority within the portfolio of the Federal Ministry of Health on the 1^st of July 1994 and its seat was transferred to Bonn in the course of the Government's move to the new capital, Berlin.

Now approximately 950 BfArM employees - including physicians, pharmacists, chemists, biologists, technical assistants and administrative staff - work in the Federal City on the river Rhine. They are concerned with the prevention of health risks by continuous improvement of the safety of medicinal products and by risk monitoring of medical devices as well as by controlling the market of narcotic drugs and precursors.

Granting marketing authorisation for finished medicinal products is a central task of our Institute. The review of the so-called "old products", i.e. products already on the market before the German Medicines Act (AMG) came into force, is another priority. We are confident that the review process will be finalised within the next few years. The BfArM records all reports of adverse drug reactions in the Federal Republic of Germany and decides on pharmacovigilance actions where necessary.

In all these activities herbal medicinal products play an important role. It is a particularity of the German health system that herbal medicinal products are widely prescribed by medicinal doctors. Many of these prescribed medicines are reimbursed by the state supported health insurance companies and rank among the 100 most prescribed and reimbursed medicinal products. Looked at it from this angle, phytotherapy is part of main-stream medicine in Germany, at present, and only to a lesser extent complementary or alternative medicine. In the organisation of our Institute, this particular role of phytotherapy is reflected by a "Particular Therapies" department with two seperate units, one for the pharmaceutical and one for the clinical assessment of herbal medicinal products. More than 30 physicians, pharmacistsm chemists and technical/administrative assistants are involved in the assessment of applications for marketing authorisation and in the review of herbal medicinal products with the aim to protect consumers and to guarantee availability.

We are fully aware that this particular position of herbal medicinal products in our health system requires improvement and continuous update of the scientific basis of phytotherapy. This cannot be achieved without taking into account the European Union's framework for pharmaceuticals. We think, however, that the assessment of herbal medicinal products needs specific expertise and adjustment of certain technical requirements. For this reason we fully support the efforts of the European Commission and the EMEA to create an adequate regulatory framework.

The political and regulatory efforts must be completed by scientific efforts to document and to complete the evidence of saety and efficacy of herbal medicinal products. ESCOP continues to contribute to these efforts. The important role of ESCOP monographs was acknowledged by the European Commission and laid down in the note to Applicants. Without the bibliography provided by ESCOP the discussion of core.SPCs in the Herbal Medicinal Products Working Party at the EMEA would have been impossible.

The current, sixth international ESCOP symposium is addressing, again, key questions related to the future of herbal medicines. These are:

• the developement of a regulatory framework,

• the safety of herbal drugs and possible interactions with other medicines and

• how to set up appropriate levels of evidence for efficacy.

The meeting will help to improve the understanding of the particularities of herbal medicinal products. I hope that it will contribute to the European harmonisation in this area.

Finally, I think it would be a good idea if you could spare some time to enjoy the charming centre of Bonn or the beautiful surroundings along the banks of the river Rhine, I wish you all a successful conference.                            

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Dr. Paul Weissenberg, Director, Single Market, Regulatory Environment, DG Enterprise, European Commission, Brussels: 

"Developements in the regulation of medical products"

In his overview of the present status and the further prospects for the regulation of herbal medicinal products Dr. Weissenberg said: "Whenever we legislate in the European Union,  bear in mind  we are not as good and as sufficient as member states. What does it mean? A member state is able to legislate, lets say in 12 months time including national parliament. I am unfortunately not in this position. I am bound by treaties of Amsterdam, Maastricht, Nice and these European treaties are complicated. Complicated in the sense, that I need much more than twelf months before our European law comes in force. To give you an idea,  the average is between four and five years before I am on the market with the European law. I say this becauseif I draw now a directive proposing it on traditionals, this directive will not come in force before between 2004 and 2005. We have to realize, that if we have a certain ambition in the European Union we still want to live a certain time with such a directive in face. In other words whatever we are proposing now, has to be able to rule, to govern the modern society of the European Union, lets say up to 2010. And if we talk about 2010 it is easily conceivable what we are facing. In 2010 we have a European constitution, in 2010 we only have a single European currency, in 2010 we have at least 20 member states. So in 2010 the European landscape will have changed dramatically and this is a challenge, it is an opportunity. Whatever we are doing in the pharmaceutical field, in legislation and in none-legislation has to bear in mind this objective politically, which we are bound by our democratic institutions. So in other words: pharmaceutical legislation is part of pharmaceutical policy, but pharmaceutical policy is only one piece of policy in the overall picture for the years to come. And when people ask me what I did proposing the pharmaceutical legislation I have to tell them as a lawyer concerning my objectives  in very short are relatively simple but important. The first objective for my pharmaceutical review is, that I have to guarantee a very high level of health protection for the European citizens. I have to make sure, that  products are safe, innovative and  available for the patients as quick as possible. This has changed because according to different treaties recently the importance of health has dramatically changed. The second objective is:  we have to improve the surveillance of the market, in particular by threngthening the pharmacvovigilance procedures on the European level. Our third objective is: the internal market has to be completed. The pharmaceutical products are far from being in such a position that we can say there is an really single market of pharmaceutical products. And finally, that is our biggest political challenge,  whatever we are proposing as Commission now, has to be able to cope on the challenge of the years to come. To legislate for 15 member states is already difficult enough, but to legislate for 25 or for 27  is a tremendous task. So we have to try to find an optimum equilibrium between these objectives. And immediately the question raises: what is the role of the European Union in ten years time and what is the role of the member states in ten years time? And to be honest, I don't know. Who knows, what is in 2010 the landscape in the European Union? But we have to draw and to draft now a legislation which has a certain vision and has to draw a certain borderline because what has to be done in London, in our European Agency and what has to be done in National Agencies. And when we meet regularly heads of national agencies I always tell my colleagues that we have to find an optimal complementarity between what remains to be done nationally and what must be done on an European level. This brings me to the first point of my review: the review is only legally speaking concentrated on the centralised and the decentralised procedure. So we are legally not obliged to go further but I think it would be politically a mistake, not to use this chance to cover the whole range of the pharmaceutical world. So concerning the centralised procedure our first problem is: what is the role of the Agency in London in ten years time? What is the scope of products we want to go to London and what is the scope of products that we meant to be treated nationally? You know for the time being we had Biotech exclusively authorized by the Agency in London, there is a certain feeling in the Union that we should use more and more our expertise we have gained so far, to give a little bit more to the Agency in London. So when our survey be made, people told us, since London was a success for the Europeans it would be a mistake not to build on the experience we have gained in London.

The second point is, what are we doing with generics? You know we have for the time being a principle in the European Union saying, simplified, "the son follows the father". In five years time we will have a first products in the Union which have originally a European authorisation. The question is, do we maintain the principle " the son follows the father" or is there the possiblitiy that the generic for those products originating from London may be authorized on a national level. So this is an open question, we will discuss this in a couple of weeks with  member states.

Finally the centralised procedure called mutual recognition.When I took over this file one year ago I was astonished, to be honest with you, because I didn't see why you could call something mutual recognition when as a matter of fact it is not a mutual recognition.Member states have difficulties to accept, that in one member state he product is authorized, this product can circulate freely in all  member states of the European Union. Referring to this, I think again if we reason in terms of ten years time, can you imagine that each member state is opposing the authorisation of another member state in saying "no there are health risks"?. Whatever the Germans are doing, the French may say "cannot be accepted for a French citizen or the other way round. For me being payed by European tax payer I must admit is difficult to accept that this is the situation in 2010. That is why we have a ceertain ambition in the European Commision. This ambition is, I apologise for the word- to force more and more member states to accept the first authorization. There should be a certain proinciple in the European Union, "what is good for a French is as well good for a German and the other way round. However, and here member states are right, the Court of Justice told us clearly, for health reasons you can always propose a national market authorisation. So we play with the idea to identify some criteria which enable ex ante to define some serious health objections that  member states may continue to introduce.

And finally we play with the idea if member states continue to disagree - and for the time being unfortunately member states continue to disagree heavily on a lot of files - we should be enough European to have the courage to settle this issue on a European level. In other words given a certain time they can dispute the file, they can discuss the file, everybody is involved. But if after a couple of days or weeks there is no agreement with the member states we should use the expertise we have on an European level in the Ageny in London to settle the issue. It is a little bit our idea to put a little bit more steam in what we call the decentralised procedure and mutual recognition. And I think having studied a little bit a file, my impression is, it is primarily a question of confidence between institutions and individual persons being involved. That is why we try to set up a system, in which upstream before decisions are taken nationally we bring more and more people together and national agencies for increasing the understanding between them. This may enable us, to detect a problem earlier then after the first market authorisation be given.

Traditional Herbal Products: If you legislate in a modern society, you should legislate according to the needs of the society. What is a need of the society, in this case of the European Union? Because if you talk about herbals, traditionals etc. the perception for this sort of problem is different when I am in Germany and in Austria or when I go to Spain or to other countries. That means behind a perception is a culture,which is positive in itsself. So we have a problem in the sense that if we have a clash of culture on such a file we have a clash of the single market. That is why I have come to the conclusion that we should do something about it, not only because there is a problem of  the single market, as well there is a need of a modern society. Looking the figures of Germany it is evident, that 30% of all OTC products sold were herbal medicinal products. 65% of the whole German population use herbal medicinal products. These figures for me are relatively high. Even if these figures are much lower in Spain or other member states of the European Union this shows there is a bottom. And so I think, we have to realize, that we should tackle some of the issues regarding the herbal medicinal products. And if you allow me Mr. Chairman in a bracket, when I assisted some of these meetings between scientists I always had the impression, that you have fight not between culture only, like Indian tribes; you have this herbal people, the traditional people and then you have these biotech people. And the biotech people consider themselves as the most modern of the world. This was my perception coming from outside and privately people confirm, that my perception is not so wrong. That is the real problem that we have different schools of thinking regarding such a file and this has an implication on market authoisation.  We have already a legislation in place which does cover a lot of the problems. So there is no specific pharmaceutical legislation so far for these sort of products and a lot of these products  succeed to pass this hurden important enough, because some of the colleagues tell me: pay attention that with the creation of a new specific directive you are throwing everything in one basket. Our aim is that if a product is able to cope to the normal legislation which is in phase so far this product should continue to pass this herbal via the normal piece of legislation. With our German friends we had a lot of debates on the so-called "Nachzulassung" which is unknown outside Germany. This "Nachzulassung" for the none-Germans was something which they considered with sympathy but as well sometimes in saying 'well, the Germans they are not so good as they should be. We selttled this issue in a pragmatic way and I wanted to thank you very much ESCOP, because you have done a lot of working on these monographs. These monographs are a very valuable contribution in a pragmatic way to settle a couple of these issues. The second point beyond the normal legislation was our idea to set up a Working Group on Herbal Medicinal Products in the Agency. This was not so easy, because Mr. Keller is not covered by legislation, and if you are not covered by legislation in the European Union, you have to explain at least three times, why it is necessary that he has to sit in the Agency with his Working Group. So that was a success in itsself and I think this is partly due to the predecessor of  Thomas. Lönngren Fernand Sauer who realized that the need of society had to be reflected on the European level, and so he invented this idea "Working Party". Then in 1999 we proposed this directive "well-established use", laying down this common understanding on the conditions for bibliographical applications. If you would try to make a benchmark if this directive was a success, I think it was not a success foray, because member states continue to refer on this directive. One reason more for me to propose to the college a draft directive on traditional herbal medicinal products. And this is the latest piece we have in the pipe line.

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Professor Dr. Konstantin Keller

The European Union CD 1999/83/EC on "well-established use":
Application to herbal medicinal products

The CD 1999/83/EC of 8 September 1999 amends the Annex to the CD 75/318 EEC on the approximation of the laws of the Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of medicinal products. Whereas it is in particular necessary to clarify that bibliographic reference to other sources of evidence (postmarketing sudies, epidemiological studies, studies conducted with similar products, etc.) and just tests and trials may serve as a valid proof of safety and efficacy of a product if an applicant explains and justifies the use of these sources of information satisfactory. A new section I in Part 3 and 4 to Directive 75/318/EEC refers to the term "Well-established medicinal use". It reads: For the purpose of demonstrating pursuant to article  4(8)(a)(ii) of the directive 65/65/EEC that the consituents of a medicinal product have a well established use with an acceptable level of safety the following  specific rules shall apply.

Factors which have to be taken into account: 

• the time over which  a substance has been used
• quantitative aspects of the use of the substance
• the degree of scientific interest in the use of the substance reflected in the published scientific lieterature
• the coherence of scientific assessment.

Different periods of time may be necessary for establishing "well established use" of different substances minimum of one decade from the first systematic and documented use of that substance as a medicinal product in the EU.

The documentation submitted should cover all aspects of the safety and efficacy assessment and must include or refer to a review of the relevant literature, taking into account pre- and postmarketing studies and published scientific literature concerning experience in the form of epidemiological studies and in particular of comparative epidemiological studies. All documentation, both favourable and unfavourable, should be communicated.

Paticular attention must be paid to any missing information und justification must be given why demonstration of an acceptable level of safety/efficacy can be supported although some studies are lacking.

At the 49th Meeting of the Pharmaceutical Committee, March 2000 ist was stated, that bibliographic dossiers must always be "full dossiers". Whenever information on specific points are missing, justification must be given why demonstration of an acceptable level of safety and efficacy can be supported, although some studies are missing.

Well-established use always refers to the use of a specific substance for specific therapeutic use. If well-known substances are used for entirely new therapeutic indications, it is not possible to refer to "well-established use".

An interpretive Guidance on the application of Directive 99/93 will be given both in the Commission (through the updated NTA) and the CPMP through Guidance documents on the safety and efficacy of "old" substances.

Expert report: The expert report must explain the relevance of any data submitted which concern a product different from the product intended for marketing. A judgement must be made wether the product studied can be considered as similar to the product which will be granted a marketing authorisation in spite of the existing differences.

Points to consider on the evidence of safety and efficacy required for well-established herbal medicinal products in bibliographic applications: Concerning "well-established use" the question arises, if published literature on one herbal product can be used in the assessment of another herbal medicinal product. Indeed complex biological mixtures produced by different manufacturers are never identical. They are sufficiently identical if the specification is the same and no relevant differences in the manufacturing process exists. This is particularly important for highly purified extracts or a new method of preparation of an extract.

In the case of "classical" herbal preparations such as tinctures and extracts descibed in pharmacopoeias and used for long time, a "comprehensive" specification will not be available from published literature in most cases. For these preparations the starting material and the extraction solvent must be identical. If there are reasons to expect a different pharmacological or toxicological profile, additional data and an update of the specification and/or appropriate data on bioavailability may be necessary.

Post-marketing experience with other products containing the same constituents is of particular importance and applicants should put a special emphasis on this issue.

Toxicological and pharmacological tests:

The toxicological and pharmacological tests must show:

•  the potential toxicity....and any dangerous or undesirable toxic effects that may occur under the proposed conditions of use in human beings
• the pharmacological properties of the product, in both qualitative and quantitative relationship to the proposed use.

Effects that are difficult even impossible to detect clinically:

• Toxicity to reproduction
• Genotoxicity
• Carcinogenicity

The Expert-Report points out the necessity or not of new studies.

It is appropriate to assess genotoxicity initially in a bacterialreverse mutation test using a test batterry of different bacterial strains and metabolic activation (s. CPMP/ICH and OECD Guidelines). This test has been shown to detect relevant genetic chamges and the majority of genotoxic rodent carcinogens. If positive results can not be clearly attributed to specific constituents with a well-established safety-profile (e.g. Quercetin) additional in vitro and, if necessary, in vivo studies should be performed.

A cooperative approach is encouraged to investigate herbal drug preparations with the same specification.

Clinical Documentation:

Evaluation of the application for marketing authorisation shall be based on clinical trials including clinical pharmacological trials designed to determine the efficacy and safety of a product under normal conditions of use having regard to the therapeutic indications for use in human beings. Therapeutic advantages must outweight potential risks.

General requirements: The clinical particulars to be provided pursuant to point 8 of Article 4(2) of Directive 65/65 EEC must enable a sufficiently well-founded and scientfically valid opinion  to be formed as to wether the medicinal product satisfies the criteria governing the granting of marketing authorisation An essential requirement is that the results of all clinical trials should be communicated, both favourable and unfavourable.

Clinical Efficacy and Safety: In general clinical trials shall be done as "controlled clinical trials" and if possible, randomised: any other design shall be justified. At last as possible, and particularly in trials where the effect of the products cannot be objectively measured steps shall be taken to avoid bias.

A critical assessment of relative safety, taking into account adverse reactions, shall be made in relation to:

• the disease to be treated,
• other therapeutic approaches,
• particular characteristics in sub-groups of patients,
• preclinical data on toxicology and pharmacology.

Recognised efficacy: The requirements for the documentation required to support the indicated claims should depend on the nature  and the level of the medication(s). For treatment of minor disorders a lower level of evidence may be adequate when the extent of long-term use, the experience with that particular herbal medicinal product and supportive pharmacological data are taken into account. The level of evidence and the grading of recommendations must correspond to the nature of the disease that is to be treated. The therapeutic alternatives available, the risks of a delayed or insufficient treatment and the risks of the herbal drug preparation have to be taken into account.

Grading of Recommendations:

Grading is divided in 4 parts:

• Grade A: Evidene Ia, Ib: It requires at least one randomised controlled trial as part of the body of literature of overall good and consistency addressing the specific recommendation.
• Grade B: Evidence IIa, IIb, III: It requires availability of well-conducted clinical studies but no randomised clinical trials in the topic if recommendation.
• Grade C: Evidence IV: It requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities and indicates absence of directly applicable studies of good quality.

As an example for an recommendation of a herbal medicinal product, the core-SPC for Isphagula Husk is presented. It was drafted in January 1999, finalised and submitetd to the CPMP in March 2000.

Therapeutic indications: Herbal medicinal product for :
a) the treatment of habitual constipation, conditions in which easy defecation with soft stools is desirable, e.g. in cases of painful defecation aer rectal or anal surgery, (II-III).
b) adjuvant symptomatic therapy in cases of diarrhoea from various causes (III-IV, Decision by majority).
c) conditions which need an increased fibre intake, e.g. irritable bowel syndrome (IIb-III, Decision by Majority).

Concerning scientific monographs the Notice to Applicants, Chapter I 'Marketing Authorisations', Section 4 - 'Stand Alone Application for a Marketing Authorisation' reads:

Scientific monographs 8e.g. those drifted by the European Scientific Cooperative on Phytotherapy (ESCOP) and the World Health Organisation (WHO) for Herbal Drugs) offer a valuable and updeated overview on published scientific literature, which together may be used in support of the safety and efficacy of a medicinal product in a bibliographic application .

These monographs help to avoid duplication of work and bring about gradual harmonisation in the evaluation if medicinal products, e.g. herbal medicinal products. Therefore the Commission and member states recommended that both applicants and competent authorities should make use of these monographs.

The role of "core-SPCs"

The so-called core-SPCs (e.g. those elaborated by the Herbal Working Group of the EMEA) are legally not binding.  The value of these core-SPCs is based on their "persuasive power", underpinned by the fact that technical experts of all EU competent authorities have considered and agreed upon them. 

The Joint Meeting of the Human and Veterinary Pharmaceutical Committees, November 2000 stated that "the intention is progressivly harmonising generic medicinal products by agreeing up core-SPCs" was in general supported by the Member States.

Perspectives

• Herbal Medicinal Products are a reality in the European market.
• Public Health concerns related to uncontrolled herbal medicinal products and starting material are a reality in the European market.
• Lack of Interest in the Industry?
• Mutual recognition of herbal meicinal products not feasable?

Concerning the phase of consolidation the following activities have to be mentioned:

• European legislation updates procedures.
• There is an improvement of the current MR (mutual recognition) procedure.
• Expertise is implemented.
• Scientific standards are implemented.
• Information is exchanged and criteria are made transparent.
• A constant update of standards in the light of experiences gathered by competent authorities and applicants is performed.
• A harmonisation of the EU market is going on by help of the core-SPCs.

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Richard Woodfield, Medicines Control Agency (MCA), London

The "traditional use" - Directive - where are we now?

The UK-Approach - Is a Herbal Product a Medicine?

The classification of herbal medicines is based on the definition of medicine in European law and depends on ingredients and presentation. The updated classification referring to the MCA Guidance Note 8 contain new arrangements that give companies formal right to make representations. Herbals are classified on the same basis as other products. There are two regulatory routes:

1. Licensed herbal medicines which have to prove safety, quality and efficacy,

2. Unlicensed herbal remedies, which must be herbal inly, must not have brand names and no indications.

Public Health issues with unlicensed herbal remedies

These products have a variable quality and safety (lack of consistency in products, substitution, contamination, adulteration: example Aristolochia). Some unlicensed remedies have been made to good standards, but it is difficult for the public to distinguish the different products. Here is a lack of systematic requirements for information with the product, e.g. interactions, side effects etc.

Why does the UK want a Traditional Medicines Directive?

The regulatory arrangements for herbal medicines are weak concerning  (a) public health problems, (b) issues of legal stability and clarity, (c) incentives issues for companies. In other Member states the schemes are alo problematic (cf. AESCP-Report). At last parts of existing European law not will have suited to some of these products.

MCA Objectives:  The public should have access to a wide range of safe, high quality herbal remedies with appropriate information about the use of the product. For licensed herbal medicines there exists protection, but there is not enough choice, while for unlicensed remedies here is choice but not enough protection or information.

The UK is interested in an early progress on the Traditional Medicines Directive. Public health issues with the current regime. There is domestic pressure for a new national scheme "without waiting for Europe" - as some other Member States have put in place. The MCA position is, that herbal remedies should be appropriately regulated as medicines. Hence the MCA agreed to be rapporteur for the Pharmaceutical Committee Expert Group on Traditional Medicines.

Main features of the 2nd draft

The second draft of the TMD may apply beyond herbals ("blank annex"). It doesn't apply to products which can be authorized under 65/65 EEC. There must be evidence of 30 years traditional use, taking into account of 15 years none-EU use. Bibliographic data on safety with expert report are necessary. Sources for the assessment are the European Scientific Committee - monographs and guidelines. Further a quality dossier is required in compliance with the EP-monographs. Concerning cerrtain categories e.g. teas, a simplified quality dossier is planned. Positive list(s) are discussed. A refusal can be expressed if pharmacological effects or efficacy are not plausible. If efficacy is not proven, this can be set forth in respective labelling. Member States can require labels to state the nature of tradition. Relevant provisions from other directives, e.g. pharmacovigilance are possible. There will be a 5 year transitional period once the directive is in force.

Concerning the none-EU-traditions there will be a strong view in recognizing and respecting culture and traditions of ethnic groups. Medicines may be 1000 years old and it seems to be artificial to reject these remedies because they don't exactly satisfy EU definition or tradition. Safety and quality of ethnic medicines are crucial. The risk that the none-EU-Traditional Medicines are pushed onto the grey market has to be considered.

A positive list of the EU would encourage harmonisation and share resources. There should also be scope for a national positive list. Such a list should cover substances rather than products.

No traditional registration should occur where 65/65 is possible and essentially similar products are run in that Member State under 65/65.

Beyond herbals? Disparate views of Member States reflect varied traditions and differences in how products are classified. The recognition of a case of the UK for going beyond herbals may need national reflexibility if no early consensus emerges.

Definition of Traditional Use:

A rolling period (30 years) is favoured. There is no cut off date fixed. It is not clear how 15 years use in none-EU States relates to 30 years traditional use. Agreement exists for traditional combinations.

Safety and Quality:

Provision is supported which allows regulators to require safety data where concerns necessary backup for less familiar medicines. Simplified dossiers e.g. for essential oils and plant juices should be included (?). Material for assessment of quality and safety may be EP-monographes or pharmacopoeias of Member States.

"Plausibility" of pharmacological effects or efficacy:

Plausibility is a very vague criterium and it is not clear, if applicants should be asked to demonstrate plausibility. There is a risk of complicating issue of amount and type of evidence needed to demonstrate traditional use. 

It needs further classification of the role of the European Committee e.g. on 99/83 as there are differences in Member States' view on well-established use. Further with respect to advertising the length of wording needs consideration.

Questions and Issues:

• How can the essence of "tradition" be captured in a regulatory scheme?
• To what extent is EU harmonisation realistic given different visions on: "Is a product a medicine?" and if so: "Is it 'traditional' or 'well-established'".
• How far are traditional medicines directive and rapid product innovation compatible?

Further open questions and/or problems are: linkages with Food Supplements Directive and possible extension to herbal supplements and a continuing  pressur from parts of the industry for "mid and match" approach to traditional ingredients.

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Dr. Bernd Eberwein, Director German Medicine Manufacturers, Bonn

The new regulatory landscape in Europe for herbal medicinal products - what does this mean for the industry?

The market situation at present is characterised by the fact that every national market has developed its own individualities. Examples for this situation are given in table 1

Table 1

For the future of HMP the question arises if national individualities will be upheld or will here exist a melting-pot towards one harmonised regulation, fitting the needs of all countries.

During the last years several attempts for harmonisation were started by the European Union 
(see table 2).

Table 2: EU-Attempts for Harmonisation

Directive 65/65 and the "explanation" for well-established use
Purpose of this directive is to provide an instrument for harmonisation of the European pharmaceutical market. Up to now the following experiences have been made:

• Concerning licensing of HMPs as medicines there are different experiences due to the inhomogenous interpretations of the directive 65/65.

• Many products could not meet the requirements of the directive.

• The creation of the Working Group HMP at the EMEA was helpful (AESGP)

• The ESCOP-monographs provide a basis for well-established use.

• The acceptance of ESCOP-monographs in the Commission HMP (WGHMP) is unclear yet.

Directive on Traditional Medicines 2000/2001
As many well-established medicinal products with long tradition can not meet the requirements of the Directive 65/65 the Directive on Traditional Medicines with a "low profile" would be a possibility for HMPs taking into account the long product experience. There is still no experience with this directive, as it is still in draft. 

Up to now the following  criteria have been worked out: a proof of efficacy is not needed, but there are high requirements for quality.

 Directive on Food Supplements 1990/2000/2001
Purpose is to create a new directive for harmonisation of the EU food supplemets market. The first draft was done in 2000 concerning vitamins and minerals, but the EU-Parliament in 2001 extended the definition for food supplements from only nutritional purpose also to products with physiological function: e.g. herbals like garlic and artichoke will be included. This new directive will influence the area of HMP. Open questions are: Is there a transition period or are there any claims.

New Definition for Food? 2001
At present a new draft of a new directive for the establishment of a European Food Agency and other food related regulations is being prepared. According to  COM(2000)716 and 2001/C96 E/17 there is a proposal for a regulation of the European Parliament and of the Council laying down the general pronciples and requiremens of food law, establishing the European Food Authority, and laying down procedures in matters of food safety.

Conclusion
From this the follwing cnclusions can be drawn: In general: The regulatory is changing national and inernational. In detail: There are two levels if medicines: 1. 65/65 inclusive "well-established" and 2. traditional medicines. Additionally we will have herbals in the food supplements area.

Consequences for the Industry
1. 65/65 and "well-established use"

     There will be higher requirements for proof of efficacy.
     Key will be a good scientific documentation.
     Maintenance of registrations will become more expensive.
     There will be a concentration on only few registrations per company.
     There will be a concentration on only few medicinal plants.
     There will be a competition with chemical drugs.
     Reimbursement and selfmedication will be possible.

2. Traditional Medicines

     There ia a low level of indication.
     Requirements for quality and safety will be comparably to 1.
     Monographs will have to be established by the CHMP.
     Safety problems and the consequences thereoff have to be considered.
     There will be a competition with food supplements (esp. claims).

3. Food Supplements

     Is there an "easy way" for the creation of health products?
     There will be lower requirements for quality compared to 1. and 2.
     Details will have to be regulated by the SCF e.g. by a positive/negative list for ingredients.
     There will come new players in the game /competition in the food area?

     Open questions are the health claims of food supplements.

Concerning the consumer/patient, will there be a continuing acceptance of herbal products, independent of he legal product status??

What does the Industry want?

• pragmatic lincensing of HMP

• a clear system of 2 levels of HMP: 65/65 including well-established-use and traditional medicines

• ESCOP monographs to be considered as part of 65/65

• pragmatic consideration of indications also for traditional medicine.

What does the Industry not want? 

• lincensing requirements which cannot be fulfilled

• a food supplements directive with the extension on "physiological functions" which will cover all herbal products in future times.

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Jeff Kaufman , Yarra SA, Paris

Complying with the law - applying for marketing authorisations in a changing landscape.

Regulations and Procedures:

Ther are two different regulations/procedures, one concerning supra-national and one concerning national MA applications. The supra-national procedures in the EU are decentralised, rarely used by self.medication, and even nore rarely used for herbal medicines. Standards are monographs such as the pharmacopoeias of ECOP and WHO.

National MA applications:

Pharmaceutical (NTA + Guidelines):
Plant and drug: The development of analytical methods includes consideration of the characterisation and stability at each step. Impurities have to be taken into consideration.
Finished product: Criteria include KH-stability and organoleptic characteristics.

Pharmacology and Toxicology: 
Data from literature studies have to be up to date and comprehensive. Toxicological investigations have to include acute testing (rat) and 4-weeks-testing (rat). For topicals extra tests are necessary.

Clinic: 
As in the case of pharmacological and toxicological investigations data from literature have to be up to date and comprehensive. Clinical trials have to be performed vs. placebo and vs. a reference product

European Harmonisation:
Legislation has to differentiate between well-established use and traditional use. Monographs used for the assessment of Herbal Medicinal Products are pharmacopoeias and that of ESCOP and WHO. The result of European harmonisation should be an common technical document. The main question concerning harmonisation is: Is every one pulling in the same direction? Problems arise from the fact that decisions have to be made concerning food supplements, foods and structure-function claims. There are confusions concerning regulation and the position of consumers/patients and a further problem arises from the fact, that harmaonisation is done by means of tighter or looser regulation. 

There is an European Free Market for goods and services. Industry wants to get a faster and cheaper access to claims; the market has to decide success. Concerning innovation there arise dangers from standardisation of drugs and indications. Innovations are stifled, regulatory framework is ignored.

Agriculture: More stringent pharmaceutical regulations are demanded. There is a trend towards mono-cultures, industrial farming and globalisation.

Market - Consumers + Patients:  Demands of the consumer/patient are lower costs, better perceived quality and reassurance on safety concerning side effects and contamination. Herbal medicinal products are looked at by the consumer/patient as natural, gentle and less drastic than "chemicals".

Political: The EU is enlarging, there will be a common agricultural policy. MRP will be modified to faciliate "bibliographis application". "Traditional use" is a supra-national law for a national procedure (OTC only).

Conclusions 

• There is no European harmonisation at present.
• Products are developed according to the national requirements.
• It is difficult o take products cross-border by whatever procedure.
• The future is unclear
  

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Interactions

C. Ionnaides Xenobiotics - the impact on the body of secondary plant metabolites

The human body is continuously exposed to a variety of structural diverse chemicals, most of them naturally occuring and derived from the diet, which are recognised as foreign, and potentially detrimental. The first line of defense against these substances is to faciliate their elimination by means of a number of enzyme systems adept at converting them metabolically to more extractable water-soluble metabolites. Undoubtedly the cytochromes P450, an ubiquitous enzyme system, are by far the most important contributors to xenobiotic metabolism.

They are also responsible for the metabolism of anthropogenic chemicals such as medicinal drugs, leading to termination of their pharmacological activity. Further cytochromes P450 are capable of metabolising chemicals to generate reactive intermediates that can interact covalently with cellular macromelecules thus developing toxic and cancerogenic effects. The cytochromes P450 are characterised by a broad substrate specifity, which it achieves by existing as a superfamily of enzyme proteins, each enzyme displaying its own substrate specifity.

Any factor that modulates cytochromes P450, wether elevating or suppressing their activity also influences the metabolism of drugs to either low plasma levels and consequent loss of pharmacological activity, or high plasma levels and appearance of toxicity. As has been shown recently dietary components such as furanocoumarins, indoles, caffeine, isothiocyanates, flavonoids etc. perturb cytochrome P450 activity and thus influence the metabolism of drugs, altering their pharmacological activity. During the last year it has become evident, that herbal remedies, such as St. John's wort, contain chemicals capable of modulating the cytochrome P450-dependent metabolism of medicinal drugs with fatal consequences.

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Bernhard Uehleke: Hypericum interactions - an update

During the last years interactions of a high-dose hyperforin-rich extract of St. John's wort with various drugs such as theophylline, cyclosporine, warfarine, ethinylestradiol/desogestrel, and amitryptiline have been reported. Each of these drugs is metabolised by hepatic CYP microsomal oxidase enzymes. In relation to the wide-spread use of St. John's wort as a mild antidepressant the spontaneous reports of interactions are very rare: 16 spontaneous ADRs have been reported to shorten bleeding time in patients under therapy with phenprocoumon and Jarsinâ, which is estimated 2 reports per Million treatments with Jarsinâ. Spontaneous reports indicating interactions with ovulation inhibitors and with cyclosporin A are estimated 1 per Million treatments (Schulz 2000)

Despite the fact, that the use of St. John's wort is a high level since more than one decade, the known ADRs had been reported within the recent year. The dosage of St. John's wort with respect to the plant extract itsself as well as the concentrations of hypericin and in the last year also to that of hyperforin was increasing: concentrations of hyperforin in plants and formulations are today higher due to the late harvest.

But there are also reports  on transplant rejections (Ruschitzka eet al. 2000); the situation is still confuse, also because St. John's wort preparations are in Germany in the legal status of a registered drug and in other EC-countries and in the US they are used as health foods.

Also by recent clinical studies a reduced bioavailability of digoxin, phenprocoumon, indinavir and ovulation- inhibitors after continuous  administration or coadministration of hyperforin-rich St. John's wort extract (Jarsinâ) has been demonstrated (see table). 

An activation of P-glycoprotein (gGP) has been suggested to explain the results of the first digoxin-interaction study, in which the c_max showed a decrease whereas the elimination showed not much change (Johne et al. 1999); this was confirmed by experiemental studies, in which hyperforin was shown to be the relevant constituent as a potent activator of the pregnane X receptor in liver cells and in carcinoma cells (Wentworth et al 2000).

In in-vitro models (rat) as well as in healthy volunteers after administration of hyperforin rich extract for 14 days an induction of CYP3A4 was observed (Durr et al. 2000; Roby ett al 2000). On the contrary, no significant effect on CYP3A4 or 2D6 activity was seen in healthy volunteers comedicated with alprazolam or dextromethorphan (Markowitz et al 2000). On the other hand, the inhibition of CYP3A4 in vitro enzyme-assay (Budzinski et al. 2000) and in micosomes (Obach 2000) could be misleading and might refelct an unspecific effect of surface-active ingredients of the plant.

An unpublished study with the hyperforin-free hypericum.extract Ze117 could not demonstrate a significant effect on the serum levels of ethinylestradiol and 3-ketodesogestrol. Available St. John's wort formulations in Germany show a wide variety in respect to total daily dosage and amount of their constituents. There are various extracts differing in concentrations, solution fluids and dosages, but there are also administrations with plant powder, fatty oil extracts , herbal teas and fresh plant juices.

Therefore we evaluated the interaction of digoxin and different formulations and/or doses of St. John's wort in a randomised, double-blind, placebo-controlled parallel group trial in 97 healthy test persons in three study parts. The relative changes of digitoxin trough levels and the digoxin concentration area under the curve after 14 days of comedication with St. John's wort were compared to the corresponding values obtained after application of placebo. Comedication of digoxin with high-dose methanolic St. John's wort extract (LI160) and high dose encapsulated plant powder (4 g daily dose) resulted in a similar reduction of digoxin trough level by 19% and of digoxin AUC by 25% and 27% respectively compared to placebo (p < 0.05) Comedication with 2g of encapsulated plant powder daily reduced digoxin trough level by 13% and digoxin AUC by 18% less pronounced; these changes seem not to be of clinical relevance.

By comedication with encapsulated plant powder containing the same concentration of hypericin but almost no hyperforin no interaction occured. Lower daily doses of 1g and 0.5 g of encapsuled plant powder, fatty oil formulation, tea or fresh plant juice did not show any interaction.

From the results it can be concluded that interaction of St. John's wort with digoxin is dose-dependent and that interaction is most likely related to hyperforin, Low-dosed preparations used in selfmedication are not likely to produce relevant interactions. Furth er studies are planned with cyclosporin A to confirm

  the results.

Literature:
Budinski JW, Foster BC, Vandenhock S, Arnason JT (2000) An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 7: 273-282

Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, Theodore W (2000) Lack of effect of St. John's wort on carbamazepine pharmacokinelics in healthy volunteers. Clin Pharmacol Ther 68: 605-612

Donath F, Johne A, Maurer A, Bauer S, Hübner WD, Roots 1 (2000) The influence of St. John's wort extraet (LI 160) on the pharmacokinetics of cimetidine and carbamazepine.

VII World Conference for Clinical Pharmacology and Therapeutics & 4 th Congress of the European Association for Clinical Pharmacology and Therapeutics, Florence, Eds Velo G, Perucca E, Br J Clin Pharmacol 127

Drewe J, Gutmann H, Török M, Eschenmoser M, Käufeler R, Schaffner W, Beglinger C (2000) Mechanismen der Interaktionen mit Johanniskrautextrakten. In: Phytopharmaka VI, ed. N. Rietbrock, Darmstadt

Durr D, Stieger B, Kullak-Ublick GY, Rentsch KM, Steinert HC, Meier PJ, Fattinger K (2000) St. John's wort induces intestinal P-glycoprotein/MDRI and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 68: 598-604

Gewertz N, Ereshefsky B, Lam YWF, Bonavides R, Ereshefsky L (1999) Determination of the differential effects of St. John's wort on the CYP 1 A2 and NAT2 metabolic pathways using caffeine probe methodology. Poster 131, 39. Annual Meeting of the New Clinical Drug Evaluation Unit, Boca Raton, Florida, June 1-4

Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots 1 (1999) Pharmacokinelic interaction of digoxin with an herbal extract from St. John's wort (Hypericum perforatum). Clin Pharmacol Ther 66: 338-345

Markowitz JS, De Vane CL, Boulton DW, Carson SW, Nahas Z, Risch SC (2000) Effect of St. John's wort (Hypercium perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci 66: PL3-139

Maurer A, Johne A, Bauer S, Brockmüller J, Donath F, Roots I, Langheinrich M, Hübner WD (1999) Interaction of St. John's wort extract with phenprocoumon (abstrct). Eur. J Clin Res 55: A22

Moore LB, Goodwin B. Jones SA, Wisely GB, Srebjit-Singh CJ, Wilson TM, Collins JLm Kliewer SA (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. PNAS 97: 7500-2

Obach RS (2000) Inhibition of human cytochrome P 450 enzymes by constituents of St. John's wort, an herbal preparation used in the treatment of depression. Pharmacol and Exp Ther 294: 88-95

Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Fallon J (2000) Indinavir concentrations and St. John's wort. Lancet 355: 547-548

Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH (2000) St. John's wort: effect on CYP3A4 activity. Clin Pharmacol Ther 67: 451-457

Roots I, Johne A, Schmider J, Brockmöller J, Maurer A, Störmer E, Donath F (2000) Interaction of a herbal extract from St. John's wort with amitriplyline and its metabolites. Clin Pharmacol Ther 67: 159

Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G (2000) Acute heart transplant rejection due to Saint John's wort. The lancet 355: 548-9

Schulz V (2000) Häufigkeit und klinische Relevanz der Interaktionen und Nebenwirkungen von Hypericum-Präparaten. Perfusion 13: 486-494

Wentworth JM, Agostini M, Love J, Schwabe JW, Chatterjee VKK (2000) St. John's wort, a herbal antidepressant, activates the steroid X receptor. J endocrinol 166: RI 1- 16

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E.M. Williamson: Synergy - Interactions within herbal medicines

Synergistic interactions between the components of individual or mixtures of herbs are considered to be a vital part of their therapeutic efficacy. Proving such effects is a very difficult task since to do so would necessitate the testing of each individual constituent and comparing the activity with the same dose in the mixture. Measurement of synergy can be complicated, as it is difficult to differentiate between normal additive effects in mixtures and true synergy.

In vitro evidence: The most conclusive data of pharmacological tests have been those obtained with Ginkgo biloba. Wagner et al. have demonstrated the synergistic interaction between ginkgolides A and B. Other documented reports of interactions within a single herb include that of Cannabis sativa (elevation of levels of tetrahydrocannabinol in the brain by cannabidiol), and Piper methysticum (anticonvulsant activity of an mixture of kavalactones is superior to that of individual constituents). Glycyrrhiza glabra exhibits both: synergy between its own constituents as well as with other herbs. Blood levels of glycyrrhizin due to reduced absorption are lower if it is taken as part of an extract rather than as an isolated compound. Further the crude extract of liquorice inhibits angiogenesis, granuloma formation and fluid exsudation in a mouse model of inflammation, as does isoliquiritin and related compounds, whereas glycyrrhizin and glycyrrhetinic acid tend to promote angiogenesis. Synergy between different herbs in a formulation is shown pharmacologically by a combination of Urtica dioica and the bark of Pygeum africanum (a remedy used for benign hyperplasia of the prostate (combination of both herbs inhibits 5-a -reductase and aromatase significantly more than the sum of either alone).

Clinical evidence: Until recently evidence of synergistic interactions has been mainly anecdotal or by interference but there are a few clinical trials which demonstrate the phenomenon fairly well. Thus a combination of Piper methysticum and Valeriana officinalis appears to be superior in the treatment of stress-induced insomnia than either herb alone, and a product containing Panax ginseng with Ginkgo biloba was demonstrated to be more effective in improving cognitive function, as measured by the performance of normal volenteers in arithmetic tasks.

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Desmond Corrigan Adverse reports - some first principles

Main principle of evaluating herbal medicinal products is objectivity and precision. Those who provide advice to patients and their practitioners that such medicines should not be used because they are ineffective, of poor quality or unsafe should indicate clearly whether this advice or opinion is based on reliable scientific grounds or not. If it is based on scientific grounds then it must be clearly established that the herbal drug facing condemnation is in fact the herbal drug in question and not some other plant. To avoid fatal confusions only the scientific based latin name of a medicinal plants has to be used and not the common one. A number or authorities have observed that "many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations " to quote one recent example. Subsequent citations of these reports for Drug Information purposes often ignore that essential caveat thus reducing the scientific credibility of the information. It is also difficult to accept as authoritative, information from papers which refer to products such as chromium, vitamin E and proteases as herbal medicinals. Many reviews mention the risks of herbal drugs without any counterbalancing statement of the possible medicinal benefits, leading to concerns about objectivity of the reviews. It must also be strongly emphasised that the continued appearance on the market of products containing the wrong plant, the wrong chemovar, other more toxic plants, environmental contaminants, or plants with levels of the requisite phytochemicals below the minimum for pharmacological effectiveness is simply unacceptable and inexcusable given the ready availability of quality control techniques for herbal medicinal products. Many of the reported adverse reactions and interactions involving these products could be eliminated or their extent significantly reduced if adequate attention was paid to the Guidelines on Quality Control, GMP and GAP for herbal medicinal products prepared by the Working Party of the EMEA and by EUROPAM  respectively.

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Levels of Evidence

K. Überla: Assessing claims for efficacy by applying EBM and Meta-analyses

The evaluation of what is true in medicine and how patients should be treated has always been controversial. The state of art concerning assessing claims for efficacy during the last decades has focussed on randomised clinical trials (RCTs). But for ordinary outpatients the results of RTCs are not valid. Besides efficacy the risk-benefit ratio is a decisive criterion for most modern drug laws. Assessment of claims for efficacy is presently undergoing revolutionary scientific and organisational changes. Doctors no longer decide on how patients should be treated, but also the patients decide how to be treated and what type and extent of risk they are willing to take.

Old scientific principles today are replaced by evidence based medicine (EBM), meta-analyses, decision-analyses and health technology assessment (HTA). Further life time costs and cost efficiency are criteria for optimising medicine. Concerning the organisational changes public opinion gets more impact.

The European Commission changes national laws by introducing more centralised and unified admission procedures. Globalisation changes the processes of drug development and drug licensing tending towards a single worldwide market.

Evidence based medicine (EBM): EBM is the contentious, explicit, and reasonable use of the best available scientific evidence for decisions in the management of individual patients [Sacket DL, Richardson WS, Rodenberg W, Hayne RB: Evidence Bases Medicine - How to practise and teach EBM. Churchill Livingstone, New York 1997]. EBM is focussed on the individual patient and on problem orientated learning of medical doctors. EBM also aims at an evidence-based supply of medical care for the population. EBM is supported by the international acting Cochrane Collaboration and is represented in Germany by "Deutsches Cochrane Zentrum in Freiburg [Antes G: Evidence-Based Medicine. Der Internist 39 (1998), 899-908); Antes G, Bassler D, Galandi D: Systematische Übersichtsarbeiten. Deutsches Ärzteblatt 96 (1999), Heft 10, A616-A622; http://www.cochrane.de

EBM acknowleges only objectively proven therapies. It requires that only drugs or therapeutic procedures with proven efficacy should be paid by sickness funds or health insurances. However only one third of the procedures and cures in medicine have been investigated according to the state of art.

The goal of EBM is to dominate medicine and it has been developed toward a philosophy of rational clinical decisions. EBM requires that the rational decision process in practical medicine follows its criteria and rules. EBM is a paradigm requiring the dominance in the management of patients. It requires to apply and to implement medical research according to its principles.

Meta-analyses(MA): Meta-analyses are only partly connected to EBM. They summarise and condense several studies to one statement. By using the combined information and larger numbers MA increase the chance for relevant results. MA have to adhere to strict requirements and must follow a study plan. They start with a careful literature research. The trials enclosed must be randomised, must have the same inclusion/exclusion criteria and must use the same outcome variables.

Meta-analyses are a well established, well accepted methodology, which is recently even recommended by regulatory agencies. Meta-analyses are cheaper than new studies, they allow hypothesis testing, provided they are done according to the state of art and RCTs of high quality are available. They can provide new hints in efficacy, side effects and indications besides hypothesis testing and so give an input for the direction of further research and for the scope of licensing. Sensitivity analyses can show wether and how much the results vary depending for instance on quality of studies or time of publication.

Meta-analyses end with one of 5 Levels of evidence (see. table).

Phytotherapy in mild to moderate benign hyperplasia of the prostate (BPH) might serve as an example for the fact that the efficacy of a plant extract can be proven by meta-analyses. A well known study was published in JAMA (Witt TJ, Ishani A, Stark G, MacDonald R, Lau J, Mulrow C: Saw Palmetto Extracts for Treatment of Benign Prostatic Hyperplasia. JAMA 1998]. The objectives were to conduct meta-analyses regarding the therapeutic efficacy and safety of Serenoa repens (Dwarf palm) in men with symptomatic BPH. 18 RCTs involving 2939 men were selected. Treatment was 30 days. As compared to placebo Serenoa repens decreased urinary tract symptom scores (IPSS), decreased nocturia and improved peak and mean urinary flow rates and residual urinary volume. As compared to finasterid Serenoa repens decreased IPSS and improved urinary flow. The results were significant at least at the 5% level.

Frequent objections against the results of meta-analyses of herbal medicinal products are:

• The content of the preparations is different and varies highly.

• The causative mechanisms are not known exactly and are different.

• There is doubt about the clinical relevance.

Indeed there are many examples with unproperly performed meta-analyses and misleading results, however there are also examples in phytomedicine with water-proof results.

Results and Conclusions
Claims for herbal medicinal products are justified by general reasons (generally lower rate of adverse effects; improvement if quality of life; better acceptance of HMPs by patients and doctors contrary to more aggressive regimens; more aggressive regimens can be shifted for some time; HMPs play an important role in selfmedication; HMPs are generally cheaper than other regimens; because of the lower potential risks of HMPs; the requirement for proof of effectiveness and market access can be less rigid).

The positive evidence from available meta-analyses and EBM proves the efficacy and large population effectiveness of herbal medicinal products according level 1.

There are also negative evidence from available meta-analyses and EBM. As the long term reduction of symptoms and the longterm evaluation of complications is open, the consequence should be only the short term use.

The overall costs for the use of herbal medicinal products are generally higher, since patients pay on their own and the overall budget for drugs is rising. Treatment of  all patients with diabetes, hypertension and severe risk of myocardial infarction according to the best available evidence following the principles of EBM would approximately double the present drug budget. Neither governments nor health insureances nor sickness funds are able to pay the population costs for the broad implementation of EBM without rationing. Rationing is on the other hand not accepted by he voters and the population. A substantial increase or a doubling of the percentage for health care costs is alo unlikely. During the next decade a complete change of the health care systems in Europe or muddling through are the options. This is not an optimistic outlook, but it opens chances for phytomedicine and HMPs.

Meta-analyses are an interesting option for companies in the health care field to carry through their goals. They are a well established and acccepted methodology to get evidence on effectiveness, they are cheaper than new studies and they can provide meaningful hints for possible directions for registraton and research.

Meta-analyses are useful for getting herbal medicinal products on "positive lists" and getting them out of  "negative lists", for proving therapeutic benefits and for supporting "well established use" and "traditional use" according to new proposals which are discussed in the EU.

Therfore health policy in Europe should acknowledge meta-analyses for these purposes and should not talk so much about EBM, the costs of which are unsustainable for the population and for the total drug market.

The will of patients and consumers not to use classical therapy and to accept some risk in using herbal medicinal products must be respected. Drug companies should investigate the preferences of their consumers and use the results for changing health policy in their countries, Governments and the European Union have to place the will of the people at their highest priority. They should therefore change the procedures and laws in favour of herbal medicinal products.

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Dr. Karin Kraft: What is "traditional use" evidence

Theprocess of product-licensing in the EU is determined by product-specific evidence of quality, safety and efficacy. This also applies to herbal medicinal products, which however rather often cannot rely in product-specific randomised clinical trials. In the CD 1999/83/EEC additionally other sources of evidence such as post-marketing studies and epidemiological studies with similar products (bibliographic application ) are allowed as a valid proof of safety and efficacy, i.e. "well-established use". In terms of evidence based medicine well-established use means evidence levels I-III (s. Überla)

In contrast, the precise definition of traditional drugs and products and especially of the traditional use evidence are still intensely discussed. Due to the intense scientific effort in the last 15 years many herbal drugs/products have been upgraded with regard to their evidence level. For example, peppermint oil as a retarded preparation for the treatment of irritable bowel syndrome has reached level 1b (at least one ranomised clinical trial), St. John's wort (hyperici herba) even has reaches level 1a (meta-analysis including several randomised clinical trials). Many other drugs e.g. herb and root of dandelion (taraxi radix cum herba) or lesser galangal root (Galangae rhizoma), both used for treatment of dyspeptic syndrome, or herb of white dead nettle (Lamii albi herba), which traditionally is applied for respiratory problems, remained at evidence level IV.

Items determining levels of traditional use: Tha type of documentation of traditional use clearly is very important: Generally monographs are accepted to be superior to results of consensus conferences, recommendations in textbooks, expert opinions or historical sources, the evidence level supposedly declining in the order of mentioning. Monographs should only considered to be part of eveidence level IV when they are not based on adequate clinical trials. A typical example is the German drug monograph for peels of bitter orange (Aurantii pericarpum). This drug and its use is also mentioned in modern textbooks on phytotherapy and in several historical sources. In the German monograph, the drug is recommended for the indications: anorexia and dyspeptic syndrom, in historical sources the drug is also used as an appetizer and digestant. This remarkable consistency within the historical and present day use also is a strong inhibitor of a high level of traditional use.

The geographical distribution of the use of herbal medicinal drugs can be a further item to determine ists traditional use evidence. If the use is documented world-wide, this means a higher classification than a use within a continent, in several countries, in one country only or regionally. Of course additionally one has to consider the geographic availability of the drug.

Temporal aspects also can be used for the classification of traditional use evidence. Some HMPs such as onion (allii cepae bulbus) are documented since the Egyptain times, the laxative and diuretic effects of figs (caricae fructus) have been described by Dioskurides in 77, cloves (caryophylli flos) are known to mitigate toothache since the description by Ibn al Baitar, who died about 1250. These examples illustrate that the temporal aspect of the traditional use of a drug is by no means sufficient for the classification, as the knowledge of the healing potential of drugs derived from non-European plants is very often much older, at least in the respective countries of their origin.

This leads to the next item, the type of documentation. For millennia, copying of manuscripts has been the only possibility besides oral tradition to preserve previous knowledge for the following generations. many famous ancient books were copied literally in the early and medieval Christian monasteries, thereby preserving knowledge from the antiquity. The Materia medica by Dioskurides was a main source of the phytotherapeutic knowledge in Europe until 1800. In terms of classification of a traditionally used drug a documentation in many independent sources seems to be superior to only few independent documents, even less valuable are many documents which rely on few sources, or many documents or even only one document which rely on one source. There may be sometimes documents without any sources, this of course should raise some suspicion.

Traditional herbal drugs are often applied in a traditional form of application such as a tea, tincture, juice or syrup.Modern forms include rather often rather precisely defined extracts in e.g. pills or capsules. Only a stable form of application since at least 3 decades, perhaps including minor alterations seems to be compatibel with traditional use.

####the indications for the traditional use of a medicinal herbal drug arer sometimes very stable, sometimes they change during the course of time. A stable indication may be used since ancient times, since a millennium, since centuries, decades, or only since some years. Indications may have been adapted according to new findings in medicine or even completely changed, if an indication had become irrational. for example one of the indications for caraway in the Materia medica by Dioskurides has been the improvement of digestion, and even nowadays it is used for it. On the other hand, in china the fruit of the ginkgo tree (Ginkgo biloba) traditionally was used in asthma bronchiale, nowadays the indications for the extract from ginkgo leaves are vertigo, tinnitus, intermittant claudication, and ementia. This also is a nice example for the complete change of the use of a medicinal plant.

There are rather often problems with regard to the consistence in the desription, the name or the species of a medicinal plant or a medicinal herbal drug. This can be due to various reasons such as a wrong translation form a foreign language or a dialect, or wrong copying from old manuscripts. Examples are camomile (matricariae flos), which cannot be precisely identified in the Materia medica, but has been described by Hieronymus Bock (1489-1554). A possible classification may be a persistence with regard to description, name and/or species for at least three decades, minor or major alterations or a complete change in the decades or centuries before. Changes in the recent three decades should result to a loss of the traditional status.

This scshme can be applied very simply to a drug and/or its preparations used: Nor change for at least 3 decades, minor or major alterations or a complete change in the decades or centuries before. This may raise some problems in herbal medicinal products. For example, in response to the requirements of the changes of the German drug law, the number of constituents of herbal medicinal products often was reduced in the last ten years. Therefore the rules for the claim to be traditional may differ between herbal medicinal drugs and their products.
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Dr. Ary van der Kuy: Guidelines for the assessment of efficacy of phytomedicines in the Netherlands - The guidelines developed by the Dutch Committee for the Assessment of Phytotherapeutics (CTF), for the assessment of the efficacy of Herbal Medicines.

The CTF, the Dutch Committee for the Assessment of Phytotherapeutics, is an independent foundation of civil law, founded by a joint initiative of the organisation of the pharmaceutical industries NEHOMA and the Scientific Association for Phytotherapie. The assignment of the Committee. is to make proposals for a future registration of Phytotherapeutics, to start with the assessment of phytotherapeutics and to support by education everybody who is involved in Herbal Medicines, professionals and industrials, to make them accustomed to the fact that in the future registration of herbal medicines is inevitable. The effectuation of the task of the CTF is made possible by financial support by the Dutch Ministry of Health.

There are three major starting points.

1) Each Medicinal Herbal Product has to be considered as a single product.

2) Herbal products are only identical when:

• they are prepared from the same parts of the same plant species,
• the products are preparate with exact the same procedure,
• the fingerprints of the products are identical,
• the standardisation of components is identical,
• the way of administration and the preseribed dosage are identical.

The Dutch Comitee for Assessment of Phytotherapeutics has put the case that safety of Medicinal Herbal Products prevails over efficacy. In general the Registration Commitees will weight the efficacy of a medicine versus its adverse effects. As a general rule the Dutch Committee has stated that the use of Medicinal Herbal Products with an incidence of  "serious adverse effects" (as defined by the CPMP) greater than 1:2000 should be allocated as unsafe and should not be used.

The Assessment of the efficacy of Medicinal Herbal Products

For the assessment of phytotherapeutics the Dutch Committee uses three categories: A, B, and C. This classification is totally dependent on the strength of the evidence of the efficacy of the medicinal herbal product and corresponds with the definitions of the types of evidence and the grading of recommendation set out in the table from the US Ageney for Heath Care Policy and Research (AHCPR) and WHO.

Simon Y. Mills: Evidence for the clinician - a pragmatie framework for phytotherapy

Proposals for a new Directive on Traditional Medicinal Products have highlighted the obvious point that a history of usage has often substituted for new evidence of efficacy in the use of herbal remedies. Such evidence is generally considered inferior to rigorous controlled studies and the new legislation will clearly set a lower status for products registered on this basis.

Normann Boblitz: Levels of evidence: Black Cohosh

Extracts from the rootstock of Black Cohosh (Cimicifugae racemosae rhizoma) have been known as herbal remedy for centuries. They have been used for a wide range of indications comprising among other things rheumatology and neurologic complaints, but already gynecological disorders as well. Reports on standardised extracts were published in the middle of the 20th century putting the main emphasis on neurovegetative and psychic complaints. At the beginning of the 80ies open, controlled and randomized studies were carried out verifying the efficacy and tolerability of Black Cohosh rootstock extracts. This is expressed in positive monographs (Commission E, 1989; ESCOP and WHO monographs in preparation). Based on the quality of clinical studies Cimicifuga racemosa can be classified as "evidence level 1 b" ("evidence obtained from at least one randomized controlled trial").

Günter Meng: Levels of Evidence in Clinical Research with Herbal Medicinal Products. For Example: Hawthorn.

The concept of levels of evidence is widely accepted. It is based on the perception that any evidence available should be considered when the medical potential of a therapeutic intervention is assessed. This is even more important if the intervention is the application of a herbal medicinal product many of which have been applied for a long time. The concept of levels of evidence also points out that well-known and wellestablished therapies must be evaluated according to the developing medical state-of-the-art in an ongoing process. This work is increasingly expensive. lt is therefore very important to offer sufficient protection for every batch of new data submitted to the authorities for licencing purposes. This would not only be important for keeping ready well-established therapies for future medical use. lt is the only way, too, to make the scientific evaluation of herbal substances used in all the different countries around the world possible, for which other kinds of protection in many cases are not achievable. By this way not only the range of herbal therapies will be enriched but also the scientific acceptance of herbal medicinal products as a whole will be enhanced. A typical example of that situation is the one of hawthom, which has been in medical use for chronic heart failure for centuries lt has undergone elaborated medical research for the last decades and now end-point data is urgently needed.

Up to now a total of 882 trials using crataegus preparations have been published.Prior to 1970, animal or human pharmacological investigations resulted in thedesciption of the indications of hawthorn as: mild circulatory problems in the coronary arteries and heart failure not yet requiring digitalis treatment. However, the substance has been subject to criticism in classical circles, where it was pointed out, correctly, that this field of application was not clearly defined in view of the scientific paradigms.

In 1994, on re-evaluation of the scientific material a new indication was defined: Congestive heart failure classes I and II according to NYHA. However a number of syntehtic substances, which show a clear positive effect on mortality rates in chronic cardiac insufficiency patients have been developed in the meantime. The findings were collated into guidelines for therapy as well as for the execution of clinical trials for CHF registration. As a consequence, the manufacturers of hawthorn preparations werde faced with either carrying out corresponding studies or losing their registration status in the medium term, owing to inadequate documentation.

One of the smanufacturers, Schwabe, decided to undertake these clinical trials for their special extract WS® 1442. At present 1830 patients with chronic heart failure are enrolled in the placebo-controlled, double-blind SPICE study [Holubarsch CJF, Colucci WS, Meinertz T, Gauss W, Tendera M: Survival and Prognosis: Investigation if Crataegus Extract WS 1442 in Congestive Heart Failure. SPICE. Rationale, Study Design and Study Protocol. Eur. J. Heart Fail 2 (4): 431-437, 2000], which was started in 1999. The main inclusion criteria are symptomatic chronic cardiac insufficiency (congestive heart faile - CHF) of NYHA classes II to III and left ventricle fraction of 35% or less. The individual patient will each be observed for 2 years with regard to the occurence of the end points cardiac mortality, non-fatal myocardial infarction, hospitalisation owing to chronic heart failure.

Results are being expected in the year 2005, however, as 2500 patients are to be randomised in the 120 centres in 10 countries. By the way, this study, with an expected total cost of over 12 million EURO, is a good example of the necessity to protect research data in known substances, as mentioned previously.

What will the findings of this study signify ? If the findings are positive one could say that the indication "congestive heart failure" is an appropriate description for the field of application, at least for the product tested, and that not only is the indication correct, but it should also be extended to include NYHA class III. But if the findings are negative: Does this mean that hawthorn is without medical benefit and that the traditional use of the products is based in a misconception? Probably not. It is more likely to mean that the test model used in compliance with teh respective guidelines on clinical trials in chronic heart failure was not able to reflect the efficacy profile of the substance in a suitable manner. And that means: carrying on to work out what the correct place for hawthorn is.

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A report on the 6th International ESCOP-symposium in german language will be published in the next edition of "Zeitschrift für Phytotherapie"