Herbal medicinal products
Directive for all pharmaceutical products
In 2001 the EU adopted the new Directive 2001/83/EC for all pharmaceutical products. This Directive required documented scientific evidence for the efficacy and safety of all pharmaceuticals, including herbal medicines. However, it soon became clear that applying such stringent demands for the quality, safety, and efficacy of herbal medicines with their characteristic complex chemical composition (in contrast to pharmaceutical drugs generally comprising a single chemical entity) would mean that the majority of herbal medicines could not fulfil these criteria and would consequently disappear from the European market.
Traditional herbal medicinal products (THMP)
To remedy the situation, in 2004 the EU Parliament and Council amended Directive 2001/83/EC by enacting Directive 2004/24/EC. This allows the registration of traditional herbal medicines under a Traditional Use Registration (TUR) scheme, whereby documentation demonstrating clinical efficacy (usually verified in clinical trials) is replaced with a documentation proving long-term traditional use as stipulated in Article 16c of the Directive: ‘…[If ] the medicinal product in question, or a corresponding product has been in medicinal use throughout a period of at least 30 years preceding the date of the application, including at least 15 years within the Community [EU-member states]’ then it can qualify as a ‘traditional herbal medicinal product’ (THMP).
The TUR provisions were intended to provide a framework under which herbal products demonstrating the required number of years of safe traditional use could enter the pharmaceutical regime of the EU. The requirement to demonstrate at least 15 years traditional medicinal use in EU Member States, all having established pharmacovigilance systems. This meant that the safety of the herbal medicine in question as well as its therapeutic indications based on traditional use was acceptable throughout the EU. Directive 2004/24/EC also established the Committee on Herbal Medicinal Products (HMPC) at the European Medicines Agency. To date the agency has published more than 100 official monographs (community herbal monographs) for herbal substances and preparations, specifically including information on the traditional use. The HMPC has also released key guidelines on quality requirements for herbal remedies.
Formulation of ingredients in THMPs
Directive 2004/24/EC restricts THMPs to formulations containing herbal materials and some specified mineral ingredients. Under this scheme minerals included in such preparations can only have an ancillary mode of action, and, of course, no potentially toxic ingredients are allowed. This excludes minerals or vitamins from registration (as these would no longer be considered ancillary), along with substances of animal or mineral origin such as pollen, propolis, or clarified butter (a typical constituent of Ayurvedic preparations) which have an established food use or medicinal clays and gypsum (also used in making soya been curd). It also excludes the use of isolated commonly used herbal substances such as thymol, cineol, menthol etc. The scope of the Directive needs to be enlarged to include these simple non-plant substances as has also been discussed by the Commission in its communication to the Council and European Parliament.
Formulations are based on traditional empirical knowledge without the need for biomedical-scientific research to support the rationale of composition. This creates a new route to market for herbal formulas based on traditional empirical use.
Herbal medicines may also occasionally be licensed via a full market authorisation either like conventional pharmaceuticals or under well-established use, but the required level of research to validate these market authorisations (e.g. clinical trials) is lacking for most herbal medicines and so the TUR scheme is currently the most favourable route to market for traditional herbal medicinal products.
Undermining the success of the TUR
The following paragraphs highlight factors that currently undermine the success of the TUR scheme. The final part of this section suggests practical ways in which the European Commission and Parliament can improve the Traditional Herbal Products Directive to ensure an unrestricted but safe supply of herbal products onto the European market thereby making a valuable and affordable contribution to 21st century healthcare.
Slow uptake of granted TUR in only a few Member States
The success of the TUR scheme can be measured by the numbers of granted registrations. Since the new legislation for TUR was enacted in 2004, just over 1,000 THMPs have been registered throughout the EU. Although at first sight this may appear a satisfactory number of registrations, this figure is less than impressive when one takes into account that this is the total number of registrations achieved in a decade by all 28 Member States together. Moreover, the same single herbal product has often received registration in more than one Member State and is therefore counted several times.
The registration figures also demonstrate that the chances of successful registration depend on in which Member State the application is made. Four Member States (UK, Poland, Germany and Austria) have granted the majority of all registrations. In contrast, during the last 10 years the majority of Member States have registered only a few THMPs - often less than ten products. For example, France received 160 applications but has granted only 7 registrations.
Although Germany is one of the leading Member States in respect of total registrations, it nevertheless has granted only 154 registrations out of 426 applications. At the time of the EMA report in 2012, 149 applications were still under assessment whilst 123 applications had failed or been withdrawn. Whilst the 1,000 or so applications recorded by the Commission relate to a total of 134 different plants in mono-preparations; the majority of registrations represent only 21 commonly used medicinal plants.
Registration fees vary considerably between Member States. For example in Italy the registration of a traditional herbal medicinal product is currently invoiced at approximately €50.000 but the same registration is considerably less expensive in other Member States. Consequently, in Italy only 5 TUR applications have been successfully granted in a 10 year period.
Number of THMPs insufficient for the needs of EU citizens
The majority of Member States have only registered a handful of TUR, the current total number of THMPs is manifestly insufficient for the needs of EU citizens. Moreover, given that the number of newly registered THMPs is increasing only slowly and the process of registration can take years to complete, it is evident that the THMPD registration scheme is far from being harmonised and that the TUR is limiting rather than enabling the availability of herbal products. Because of TUR’s shortcomings, herbal medicine in Europe is losing its unique range and diversity as well as being inhibited from developing its significant potential to help meet the health needs of EU citizens.
Overly restrictive focus of some member states
Other problems arise from the overly restrictive focus of some Member States on hypothetical risks. For example, this overcautious approach currently prevents any herb containing furocoumarins (e.g. those from the genus Angelica) from being registered, regardless of the fact that the genus Angelica constitutes one of the most important medicinal plant families with over 60 species of medicinal plants used on a worldwide basis. Similar problems are caused by the requirement for genotoxicity. Directive 2004/24/EC does not imply extensive genotoxicity data for the TUR scheme as safety is provided by evidence of longstanding use. Nevertheless, some Member States require expensive and extensive genotoxicity studies despite the guidance of the HMPC which simplifies the process.
In addition, the stipulation requiring 15 years use within the EU restricts the registration of herbal medicines from non-European medical traditions. In reforming TUR, means must be found to recognise traditional medicines from outside the EU, in accordance with the spirit of the THMPD (2004/24/EC) that states:
‘The long tradition of the medicinal product makes it possible to reduce the need for clinical trials, in so far as the efficacy of the medicinal product is plausible on the basis of long-standing use and experience. Pre-clinical tests do not seem necessary, where the medicinal product on the basis of the information on its traditional use proves not to be harmful in specified conditions of use. However, even a long tradition does not exclude the possibility that there may be concerns with regard to the product's safety, and therefore the competent authorities should be entitled to ask for all data necessary for assessing the safety.’
Member States evidently need encouragement from the Directorate General for Health and Food Safety (DG SANTE) to harmonise the TUR scheme. The number of TUR granted by Member States and the number of herbal species included in the TUR should be closely monitored. Member States should be encouraged to increase the number of products granted TUR.
Limited scope of current traditional use registration scheme
The limitations of the THMPD are made worse because the THMPD Directive 2004/24/EC currently makes no provision for Asian traditional systems of medicine, such as Ayurveda (from the Indian subcontinent) or traditional Chinese medicine (TCM). This serious omission has been openly acknowledged by the Commission in its 2008 communication to the Council and the European Parliament.
‘Medical traditions such as those mentioned above (i.e. anthroposophic, Ayurvedic, Chinese, Kampo, Korean, Mongolian, Thai, Tibetan, Unani, or Vietnamese medicine) are based on a holistic approach, and the set of requirements for the simplified registration procedure under Directive 2004/24/EC is not appropriate for a global regulation of such medical practices. The regulation of such traditions would demand a different approach from that introduced by Directive 2004/24/EC. Therefore, the Commission does not envisage extending the scope of the simplified registration procedure to cover traditional medical systems as such. Nevertheless, independently of this report, the suitability of a separate legal framework for products of certain traditions should be assessed.’
A separate extended regulatory framework
Unfortunately, the Commission’s call for a separate extended regulatory framework for these traditional medicine systems has not had any practical response to date and few herbal products from these traditions have gained TUR registration. For example, at the time of writing, only one traditional Chinese medicine herbal product has been registered as a THMP. Consequently, the use of such herbal medicines remains a grey area in many Member States.
The current limited interpretation of possible therapeutic indications permitted by the HMPC also needs broadening. 2004/24/EC Art 16a.1(a) states that THMPs
“have indications exclusively appropriate to traditional herbal medicinal products which, by virtue of their composition and purpose, are intended and designed for use without the supervision of a medical practitioner for diagnostic purposes or for prescription or monitoring of treatment.”
It is recommended that the scope of indications displayed on THMPs should be extended to enable the marketing of traditional formulations for use ‘after being diagnosed by a physician or health practitioner’. Such wording is already in use in some Member States. For CAM practitioners, THMPs have an unrealised potential to play an important role in providing an effective and safe range of treatment. The current rather low number of THMPs is insufficient for the effective treatment of different disease modalities: CAM doctors and practitioners need a significantly expanded range and scope of herbal medicinal products to practise effectively. However, under the current arrangements, the TUR scheme is designed to register herbal medicinal products for sale over-the-counter direct to public without any professional intervention. Consequently its scope is limited to products designed to treat mild and self-limiting conditions and this does not allow for herbal medicinal products that are suitable for practitioner use.
Herbal medicines versus food supplements
The Directorate-General for Health and Food Safety (DG SANTE) coordinates both the regulation of food supplements and pharmaceutical products including herbal medicinal products. It oversees the regulation of the former with the European Food Safety Agency (EFSA) and the latter with the European Medicines Agency (EMA). Unfortunately the borderline between these two categories is not clearly defined which leaves consumers, health professionals and the herbal industry confused about the status of herbal products.
In some Member States these remedies are classed as foods whilst in others they are considered medicines. European law is increasingly confusing about this classification as evidenced by a recent EFSA ruling which declared that Transitech®, a food supplement containing 6 herbs including rhubarb root (Rheum officinale) which contains anthraquinones known to have a laxative effect, can be considered a food and marketed as such with health claims.
Currently Belgium, France and Italy are creating the “BELFRIT” list of botanical food supplements with accepted health claims, as a response to the restrictive approach of the EFSA in the process of health claim assessments for botanicals. For example, France has recently decided to adopt of a 600-strong, positive list of botanical foods based on the BELFRIT list. This will undoubtedly add to the confusion and lack of harmonisation with respect to herbal products throughout the EU.
For the most part, food supplements have neither the required potency nor the controlled quality (e.g. defined designated active constituents) to treat disease. They are normally marketed for the purposes of health maintenance.
The only way to discourage a black/grey market, which has already started to emerge for these kinds of products, is to adopt a clear strategy that implements a consistent regulatory registration scheme for herbal medicinal products across the EU. The potential of the TUR scheme can only be achieved if DG SANTE strengthens the standing of THMPs and clarifies the therapeutic scope and differences as well as the borderline between herbs marketed as food supplements and herbal medicines.
Any regulatory scheme for these traditional medicine systems should take into account the fact that traditional formulations often comprise up to a dozen or more plant medicines in combination. The difficulty in providing the required quality assurance data (e.g. assessing marker phytochemicals in the end products) should not be underestimated in assaying herbal products comprising multiple plant components and, as discussed below, the expense involved can effectively mean production costs make these registrations financially impracticable. Quality assurance schemes adopted wholesale from processing conventional marketing authorisations are mainly designed to deal with a single chemical entity. These requirements are ill suited to assess the orchestra of chemicals present in a combination of several plant medicines in a single product.
Current registrations fees vary considerably between Member States. In Germany the registration of a traditional herbal medicinal product is currently invoiced at approximately €15,700 but the same registration is considerably less expensive in other Member States. The registration fee is only part of the total cost of achieving a traditional registration under the THMPD. The main costs occur with the development of validated analytical procedures and stability testing. Typically, the development of suitable methods of validation for quantitative assay costs around €10,000 to €15,000 in a GMP/GLP certified lab. Stability testing costs a further €40,000 to €60,000 for a single-herb preparation and, as mentioned, more for combination products. Registration costs for single-herbal products can easily run to €150,000 and beyond whilst the registration of new multi-herbal products under the THMPD costs at least €100,000 per product, depending on the amount of expert work to be performed. The cost of registration also depends on the availability of Community Herbal Monographs on traditional use and/or on the existence of relevant monographs in the European Pharmacopeia. There are still only relatively few published Community Monographs for herbs from non-European traditions. Where no monographs exist, the required data must be developed, which significantly adds to the costs of registration. Many herbal medicine suppliers/manufacturers are small and medium enterprises (SMEs) producing numerous herbal products in small volumes and many of these consist of multi-herbal mixtures. These SMEs simply do not have the financial resources to fund multiple THMP licence applications and are consequently being driven out of business.
Future Strategic Options for DG SANTE
• DG SANTE should guide Members States to adopt a consistent application of the TUR scheme. Within the EMA, the coordinating committee, the Herbal Medicinal Products Committee, also needs guidance from DG SANTE as the HMPC has to work on the basis of majority voting. This voting process currently permits Member States with a poor record of THMP-registrations to slow down further the TUR implementation of the THMPD across the EU. For this reason, the HMPC needs support from DG SANTE to:
i. strengthen its status and coordinating power with respect to the Member States
ii. extend and interpret the scope of traditional herbal registrations to enable a much more flexible TUR registration scheme.
iii. speed up the registration process
iv. provide a harmonised approach in Europe for all CAM medicinal and food status products.
• Although the THMPD 2004/14/EC provides that Member States should take ‘due account’ of positive TUR decisions taken by other Member States regarding a THMP registration, this remains the exception. Positive decisions on registering a herbal product taken by one Member State are more often than not ignored by other Member States for no apparent reason. In order to achieve a harmonised market, the recognition by all Member States of positive TUR decisions taken with regard to a THMP by a single Member State should be the rule rather than the exception. The process of mutual recognition procedure (MRP) has just started for THMPs. MRP progress has to be monitored and further encouraged by DG SANTE.
• The potential of the TUR scheme can only be achieved if DG SANTE clarifies the therapeutic scope and differences as well as the borderline between herbs marketed as food supplements and herbal medicines.
Legislative Options for European Parliament
To facilitate the use of herbal medicinal products the European Parliament should extend the scope of the existing Directive 2004/24/EC to:
• Include other medical traditions, which have proof of a longstanding medical tradition, but cannot qualify under the 15/30 year regime of traditional use.
• Broaden the scope of indications applicable to THMPs to include more indications suitable for THMPs.
• Extend the registration scheme for products intended exclusively for the use of statutorily regulated healthcare professionals.
• Ingredients of THMPs can be herbal substances, herbal preparations and minerals. The scope of this regulation is interpreted and applied differently by Member States. In order to compete with food supplements, common foods such as honey, butter fat (ghee) or minerals, which are used in traditional systems of medicine should be allowed in THMPs.
• The ‘Action plan for herbal medicines 2010-2011’ and ‘Work Programme for 2012-2015’ of the Committee on Herbal Medicinal Products (HMPC) at the European Medicines Agency mark some progress in improving the scope and application of the THMPD. However it is evident that the THMPD (Directive 2004/24/EC) requires thorough reassessment to ensure that there is a workable regulatory framework for traditional herbal medicinal systems in the EU.
• Such a revision along the lines suggested above will act to discourage a black/grey market assuring the supply of high quality medicinal herbal products and supporting the development of traditional medicine systems and herbal medicine/phytotherapy in the interests of EU citizens.