(2002; 91 pages)
Herbal medicinal products in the European Union
Lecture presented at the 26th International Conference on Internal Medicine, Kyoto May 25-30, 2002, by Konstantin Keller, Federal Institute for Drugs and Medical Devices, Bonn, Germany, and Chair of the EMEA/CPMP Herbal Medicinal Products Working Party.
European pharmaceutical law classifes herbal products as “regular” medicinal products if they claim to treat or prevent ilness or if they are to be administered with a view to restoring, correcting or modifying physiological functions (1). Several decisions of the European Court of Justice confirm this status. There are examples where a herbal preparation, such as peppermint tea, could be either food or medicine, depending on the claim made for the product. In other cases, such as for senna extract, a product has to be declared a medicine (notwithstanding the labelled claim) by virtue of its pharmacological action: in this case that of a laxative stimulant. The characteristics of herbal medicinal products make regulatory assessment difficult and present a challenge to health agencies and national authorities.
For centuries, herbal medicinal products have been part of cultural heritage. This may be one reason why herbal medicinal products continue to be widely used in Germany. In a recent study, more than 70% of the German population declared that they used natural medicines, and for most of them herbal medicinal products were the first choice in the treatment of minor diseases or disorders (2). With 39% of the total European market, the German market holds the biggest share by value, followed by France (29%), Italy (7%), Poland (6%) and the United Kingdom (6%). It is important to stress that in Germany and some other European Union countries, herbal medicines are fully integrated into conventional therapies, especially by general practitioners. The share in the prescribed herbal medicines market is 73% in France, 43% in the United Kingdom and 38% in Germany. Herbal medicinal products are found among the top 200 of the 2000 most prescribed medicines that were reimbursed by state-supported health insurances in the year 2000 (3). As an example, a product composed of saccharomyces yeast used for the symptomatic treatment of diarrhoea holds rank 51 with 1.5 million prescriptions, whereas the most popular brand antidarrhoeal, loperamide, is placed at 145 with 851 000 prescriptions. By value, the most important herbals are ginkgo leaves, hypericum, ivy (Hedera helix), mistletoe, hawthorn, saw palmetto and horse chestnut.
These data show that herbal medicines are rightly classified as medicinal products because they are used as such. Another reason involves the risks that may be associated with these products. Some herbal medicines may present risks even when properly used. Such risks are mostly mild and can be avoided by appropriate labelling. However, in some cases, the withdrawal of products from the market has been necessary because serious reactions were identified.
An increasing problem is the potential interaction of herbal medicinal products with conventional medicines: the most prominent example here is hypericum. Such risks have to be carefully assessed, balanced against potential benefits and clearly labelled for consumers and health professionals in order to protect public health. Such an approach can be enforced if herbal medicines are subject to pharmaceutical legislation.
An additional aspect that makes herbal products a very special group is the particular character of the quality requirements. Herbal products are, even if they contain only one herb, very complex biological mixtures and in most cases it will not be possible to identify a certain chemical constituent responsible for the efficacy of the product in question. Consistent production parameters and process validation become increasingly important to achieve reproducible efficacy. Because of this complexity, strict quality control is a prerequisite for safety. There are plenty of examples where insufficient quality control has led to toxic effects, such as by contamination with heavy metals or adulteration with toxic plants.
Since many herbal products rely on traditional use, only very few new clinical studies are available. Industry is not motivated to perform such studies, because the results cannot be patented and protection of intellectual property is practically absent. Clinical trials with herbal medicinal products pose specific difficulties. For essential oils, blinded studies are not feasible because of their strong smell and taste. Recent studies with hypericum in major depression demonstrate that in studies with an active comparator, sertraline in the case of hypericum, the comparator was unblinded due to side effects (6). This makes the interpretation of results very difficult. Finally, anyone who has been involved in the design of clinical trials will agree that trials that are particularly important for herbal medicines (i.e. symptomatic treatment of minor conditions in an over-the-counter (OTC) environment) are most difficult to plan and perform.
These specific challenges were acknowledged at the Eighth International Conference of Drug Regulatory Authorities (ICDRA), in Bahrain in1996. WHO Member States were encouraged to establish groups of experts for herbal medicines in their own countries and regions and to update national legislation in order to allow registration of herbal medicinal products. This was reconfirmed at the Ninth ICDRA in Berlin in 1999.
In 1996, the European Parliament requested facilitated systems for marketing of herbal medicinal products; and in 1997 a specific Herbal Medicinal Products Working Party was created at the European Medicines Evaluation Agency (EMEA). A permanent working group is now composed of delegates from all member countries of the European Union, experts and observers from future new member countries, the European Commission, European Parliament and European Pharmacopoeia.
The main focus of the group is to facilitate mutual recognition of marketing authorizations within the European Union by preparing guidance for documentation and assessment of quality, safety and efficacy of herbal medicines. In addition to these tasks, the group may give advice on pharmaco-vigilance action and on future legislation. All documents prepared by the group are available from http://www.emea.eu.int. The work of the group is complemented by the European Pharmacopoeia that has established two working parties to prepare general and specific monographs on herbal drugs. These monographs are fully integrated into the official European Pharmacopoeia.
Quality assurance and control of herbal medicinal products has to start at a very early stage, i.e. at collection or agricultural production of a medicinal herb. A specific guideline addressing this aspect was published recently. Two other documents defining criteria on how to test quality and how to set appropriate specifications are available as well. One important part of both guidelines is the glossary that explains how the term “herbal medicinal product” is defined in the European Union. It should be understood that isolated constituents such as digoxin, taxol, or menthol are not classified as herbal drug preparations.
Safety and efficacy
The most controversial topic relates to assessment of the safety and efficacy of herbal medicines. The European Union facilitates the registration of well-established and traditional herbal medicinal products by permitting different types of applications for marketing authorization.
Herbal medicines may be authorized on the basis of new pre-clinical tests and new clinical trials. This type of full dossier application is mandatory for any new product, including herbals. The same type of dossier is required if a completely new indication is requested for a product that has already been marketed for a different use. However, if the product has “well-established medicinal use with recognized efficacy and an acceptable level of safety” an applicant may substitute new tests and trials by reference to bibliographic data.
The concept is based on the idea that long-term use in humans will probably have resulted in sufficient and even more reliable experience than animal experiments could ever provide. Factors that have to be taken into account are the time and extent of use, the amount and quality of bibliographic information and the consistency of that information. A minimum time frame of ten years of medicinal use within the EU is requested.
The European Herbal Medicinal Products Working Party has clarified the extent of pre-clinical data that are required for a bibliographic application for a herbal medicinal product: new studies should concentrate on effects that are difficult - or even impossible - to detect clinically. This includes data on mutagenicity/genotoxicity, toxicity on reproduction and carcinogenicity. If sufficient experience in humans can be extracted from the literature, tests such as single dose toxicity, repeated dose toxicity, immunotoxicity and local tolerance are not required. Due to the complex composition of herbal medicinal products, pharmacokinetic studies are not required unless there are safety concerns.
A specific guideline addresses the assessment of efficacy. The strategy is to follow the concept of evidence-based medicine and to require evidence that will relate to the type of claim, e.g. treatment of symptoms, cure or prophylaxis of disease, etc. and seriousness of diseases. For the treatment of symptoms in minor disorders, a lower level of evidence will be acceptable if experience with a particular herbal medicinal product is well documented and plausible on the basis of pharmacological data. However, such an approach can only be accepted if the product does not present any risk to the consumer/patient. For more serious conditions, or if the product may present any direct risk, a higher level of evidence must be provided and the therapeutic alternatives have to be carefully considered.
This concept is in line with WHO guidelines (5) published in 2001, and similar approaches in other countries, such as Australia. On the basis of this concept, agreement has been reached for a number of herbal drugs, and core data have been published. These core data give a summary of the herbal product characteristics, including indications, contra-indications, side effects, warnings, etc. An example would be isphagula husks, where different levels of evidence support three different indications.
Despite the fact that these two types of marketing authorization will be appropriate for a great number of herbal medicinal products, especially those covered by monographs published by the WHO (6) or the European Scientific Cooperative on Phyto-pharmaceuticals, ESCOP, (7) it is evident that there will be traditional herbal medicinal products that do not dispose of sufficient bibliographic evidence. As an example, the hop plant has been used as a mild sedative for centuries but experimental or clinical data are virtually absent. The question was raised whether such products should be classified as food or whether a third level should be introduced under pharmaceutical law.
The European Union has decided to introduce a new category of traditional medicines into pharmaceutical legislation and a proposed Directive is about to be discussed by the European Parliament (8). The benefit of this regulation will be that traditional medicines are classified, labelled and controlled as medicines. This will include strict quality control, compliance with good manufacturing practice (GMP), control of safety, and application of all rules and regulations related to pharmacovigilance.
Herbal medicinal products that have been used for at least 30 years, with a minimum of 15 years in the European Union, will be eligible for registration as a traditional medicinal product. In respect of quality-related data, such registration will be identical to full marketing authorization. The applicant has to submit bibliographic evidence that the product is safe. For the documentation of efficacy, the applicant must produce expert evidence of the traditional use that makes the claim of efficacy plausible - even though scientific evidence is not available. A new committee will be set up to publish European lists of traditional herbal substances and monographs on traditional and well-established herbal medicinal products. These lists and monographs will serve as the basis of any marketing authorization within the EU unless new evidence is submitted.
This threefold requirement for more complete evidence for new products and for treatment options in serious diseases, lesser evidence for minor claims, and allowing a “traditionally used” label for really traditional herbal medicinal products, will guarantee protection of consumers from fraudulent and unsafe herbal medicines while allowing access to well-founded and safe treatment options.
In summary, the European experience is that herbal medicines are rightly classified as medicinal products because they are used in the same way as any other medicine, they may have risks that must be identified, assessed and labelled as with any other medicine; they have clear pharmacological effects and need, probably more than many chemically defined pure substances, strict quality control and adherence to GMP.
To do this, specific experience and expertise is needed coupled with fair assessment of long-term experience; while marketing authorization procedures have to be adapted to this special group of medicines.
1. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001. Community Code relating to Medicinal Products for Human Use. Official Journal, Number L 311, 28 November 2001. http://pharmacos. eudra.org
2. Institut für Demoskopie Allensbach: Naturheilmittel (2002) www.ifd-allensbach.de
3. Schwabe, U., Paffrath, D. Arzneiverordnungsreport 2001, Springer-Verlag, Berlin, 2001.
4. Hypericum Depression Trial Study Group. Journal of the American Medical Association, 287: 1807-1814 (2002).
5. World Health Organization. General Guidelines for Methodologies on research and evaluation of traditional medicine. WHO/EDM/TRM/2001.1 (2001)
6. World Health Organization. WHO monographs on selected medicinal plants, Volume I (1999)
8. Commission of the European Communities. Proposal for a directive of the European Parliament and of the Council amending the Directive 2001/83/EC as regards traditional herbal medicinal products, January 17, 2002. http://pharmacos.eudra.org