by the PHARMACEUTICAL COMMITTEE of the EU-Commission (Health systems and products- Medicinal products – authorizations, European Medicines Agency) in relation to the Matrix-Report of 2012, referring to the Herbal aspect.
By Nora Laubstein (inspired by Dr. Mathias Schmidt and Dr. Hubert Schwabl)
The summary of comments about the Matrix report gives a fairly good overview about the regulatory difficulties of herbal medicinal products. But in the report a rather neutral position prevails.
An example - Looking back in German Herbal Medicines history:
Practically all of the registrations mentioned in the report for Germany are NOT new products or switches from food supplement to drug status; they are generally products that existed for many years as authorized herbal medicinal products.
The marketing authorization procedure stated in Germany back in 1972, when a notification for entry into the register of drug specialties of the governmental „Bundesgesundheitsamt“ was introduced. Before that date there was absolutely no control of marketed drugs – so there is not only a problem with dossier upgrading in Germany, but mostly with downgrading. As a result, the majority of herbal medicinal products have their first traceable mention in this specialty register, as can be confirmed through the AMIS database of the German BfArM. This notification was followed by a registration procedure, which then led to a marketing authorization scheme. When this happened, the owners of the registered products were asked to provide new dossiers (- these „ex ante“-dossiers had to be presented until the early 2000’s. The rule was, however, that these dossiers were never evaluated, as there was no pressure to do so with the fictitious marketing authorizations in place). After the installation of the new EU drug legislation and the introduction of the traditional registration scheme for herbal medicinal products, BfArM started picking up the marketing authorizations not yet officially decided (partly after 10 years!), and applying the latest rules of marketing authorizations relating to new entities. Of course the data provided by the manufacturers could not compete with that, so BfArM send out letters of withdrawal of marketing authorizations, at the same time offering the manufacturers to use the traditional registration scheme as a resort. The dossiers have to be re-written and downgraded to traditional use, which means that many indications are no longer acceptable, not being deemed fit for self-medication and trading in supermarkets without any supervision. The 30 year rule still applies, and in some cases this means that the product simply has to vanish.
The Herbal Medicinal Product Committee (HMPC) at the European Medicines Agency (EMA) tries its best to unify the different standpoints. The HMPC prepares monographs and guidelines for registration. Despite the good work within the HMPC, the member states are far from applying these guidelines in a coherent manner. As a result THMP registered in one country face difficulties when with the same data an application is filed in another MS. Even if the same HMPC guidelines are in place, the national competent authorities interpret them in sometimes complete different ways.
Since one year there is agreement that THMP could enter a Mutual Recognition Procedure (MRP) on a voluntary basis. Again one could think the set of HMPC guidelines would facilitate the mutual recognition. In fact the MRP procedure turns out to result in highly controversial outcomes, and is thus a difficult avenue for THMP. This shows clearly the lack of European integration in this field, as the MRP is one of the cornerstones of the European cooperation in the pharmaceutical field.
Result after ten years
The summary highlights the fact that despite a common regulatory framework for Traditional Herbal Medicinal Products (THMP) in Directive 2004/24/EC the approach of the Member States (MS) is rather inhomogeneous and scattered.
More than 10 years after inception of Directive 2004/24/EC, only a few THMP are registered in the EU. Added together only a few hundred THMP are registered in all the member states - the most THMP registered are Poland, United Kingdom, Germany and Austria. The majority of member states have only registered up to 10 THMP, some only one or even no product at all.
Bringing all these facts together, it can be stated Directive 2004/24/EC is not a success story.
Patients and Health Professionals
In the report European citizens as patients and as health professionals are not recognized adequately. Health professionals and patients need medicines to treat illnesses and health problems. The lack of availability of Herbal Medicines poses a challenge for the European citizens if they want to make choices about their treatment options. Some MS opt for a different option; they classify Herbal products as Food Supplements (FS), which are regulated by EFSA. By definition FS are intended to improve health and contribute to the normal function of the body. Following this definition FS cannot replace medicines. Especially France, Belgium and Italy favor the classification of herbal products as FS. Consequently the MS following this approach do not register THMP. The European Commission has so far not achieved to clarify this situation.As a consequence EFSA and the HPMC lack a coherent strategy how to give clear and definite guidance.
General conclusions about the current legislation
- The current limited interpretation of possible therapeutic indications permitted by the HMPC also needs broadening. The Directive 2004/24/EC states for THMP they “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 THMP 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.
- In addition, it is also recommended that less restrictive conditions for the manufacture of herbal medicinal products under GMP conditions should be adopted, e.g. by prospectively using GMP manufacturing protocols for quantities instead of sophisticated validated analytical methods retrospectively measured post-manufacture .
- The ‘Action plan for herbal medicines 2010-2011’ and ‘Work Program 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 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.
- Quality relates to the analytical determination of every single component of a combination, which can be extremely costly (I had cases where the registration was given up after the investment of more than 100.000 Euro), and in some cases simply impossible. The question is why a marker has to be quantified for every single herb when the marker has by definition no relation to the efficacy. There are more wuitable ways to uphold GMP standards.
- Safety related mainly to questions of carcinogenicity, a point not covered by the EU legislation and introduced through the backdoor. The demonstration of the absence of mutagenicity is frequently a challenge with herbs, not because they are mutagenic, but because they frequently kill the bacteria used for the testing at medium doses. Examples are peppermint oil or cinnamon. With such effects the manufacturer will have to switch to extremely costly in vivo models, to prove that peppermint does not cause cancer, when at the same time peppermint is used as a foodstuff in much higher quantities. It does not make sense, but can effectively kill an attempt to registration. Of course the previously existing marketing authorization will be gone at the same time.
- Further obstacles are created by artificial discussions of the effects of isolated constituents. E.g., the HMPC is currently discussing that peppermint oil should no longer be used in medicinal products because it contains the constituents Pulegone and Menthofurane, constituents that are part of the official definition of the oil according to the European Pharmacopoeia. These substances are thought to be hypothetically harmful, thus new factors for thresholds based on theoretical assumptions are created that cannot be fulfilled. Going over these thresholds automatically means rejection of the registration.
Annex: Options for legislation
Future Strategic Options for Directorate-General Health and Food Safety (DG SANTE):
DG SANTE should guide Members States to adopt a consistent application of the THMP- scheme. Within the EMA, the coordinating committee, the Herbal Medicinal Products Committee (HMPC), 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 implementation of the THMPD across the EU. For this reason, the HMPC needs support from DG SANTE to:
- strengthen its status and coordinating power with respect to the Member States
- extend and interpret the scope of traditional herbal registrations to enable a much more flexible TUR registration scheme
- speed up the registration process
- provide a harmonized 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 decisions taken by another Member States regarding a THMP registration, this remains the exception. Positive decisions on registering an 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 harmonized market, the recognition by all Member States of positive 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 THMP registration 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 general include more indications suitable for THMP (in line with other OTC indications).
- Implement a protocol for patent and data protection for THMP- applications. This is also a prerequisite to stimulate research efforts for THMPs.
- 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.