Regulations applicable to plant food supplements and related products in the European Union

Abstract

This paper deals with the current regulatory and legal settings of traditional plant food supplements and herbal medicinal products in the European Union (EU). Marketing of botanicals in foods and food supplements in the EU is subject to several provisions of food law, which cover aspects of safety, production, labelling and product composition, including the use of additives and maximum levels of contaminants and residues. However, due to limited harmonization at the EU level, specific national regulations adopted at a Member State level also apply and mutual recognition is the mechanism through which such products can be marketed in EU countries other than those of origin. Unlike food supplements, marketing of traditional herbal medicinal products is regulated by an ad hoc Directive (i.e. Directive 2004/24/EC) covering in detail all the relevant aspects of these products, including a facilitated registration procedure at national level. However, by distinguishing traditional herbal medicinal products from plant food supplements and establishing selective marketing modalities for these two product categories, the EU has been confronted with implementation difficulties for traditional herbal medicinal products and a lack of homogeneity in the regulatory approaches adopted in different EU Member States. In fact, currently the nature of the commercial botanical products made available to consumers as traditional medicinal products or food supplements, depends largely on the EU Member State under consideration as a consequence of how competent National Authorities and manufacturing companies interpret and apply current regulations rather than on the intrinsic properties of the botanical products and their constituents. When the EU approach is compared with approaches adopted in some non-European countries to regulate these product categories, major differences become evident.

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1. Introduction

It is well known that botanicals and botanical preparations contain many different biologically-active substances. It is, therefore, not surprising that as much as 40% of current mono-molecular medicines derive directly (i.e. by extraction and purification) or indirectly (i.e. by chemical synthesis of naturally-occurring substances) from botanicals species and their preparations.

Many active substances with largely different therapeutic activities (e.g.amino acids, alkaloids, cardiac glycosides, mono-, di-, tri- and sesquiterpens, phenolic compounds, antrachinons, coumarins and enzymes) have been, during recent decades, identified in (and isolated from) a large number of common botanical species and parts thereof, to which human beings have been exposed in different geographical areas for long periods of time.

In addition to the above-mentioned therapeutic substances, a number of other biologically-active substances are known to be present in botanicals and botanical preparations, including vitamins, minerals, other nutrients and many other less known, but still biologically-active, substances with a physiological effects in humans.

Such a situation explains why highly heterogeneous preparations from many different botanical species and parts are currently used with the objective of:

a. Correcting altered physiological processes in the case of diseases or preventing their occurrence (i.e. traditional herbal medicinal products and well established medicinal products);

b. Helping the body in maintaining homeostasis, that is the normal functioning of physiological processes in human beings (i.e. traditional and non traditional plant food supplements).

Due to the heterogeneity of botanical preparations being used as traditional plant food supplements (TPFS) or traditional herbal medicinal products (THMP), it is quite rare to be able to fully identify and characterize the nature of the components exerting homeostatic effects or relieving symptoms of a disease. Further research to this end would be very helpful.

For a long time botanicals and botanical preparations have been used in TPFS and/or THMP and/or other products (e.g. teas and infusions) in the European Union and worldwide. Traditional use of botanicals and botanical preparations in a specific country has been the main basis for accepting the use of one or another category of products. Therefore, uses of botanical products have developed differently in different European countries and worldwide, depending on specific cultures, current medical and nutritional practices, availability of particular botanical species in the agricultural setting and main policies of established companies on the territory, not to mention national governmental regulatory and administrative approaches facilitating directly or indirectly the marketing of traditional botanical products as food supplements and as medicinal products or vice versa.

Therefore, markets for both botanical traditional food supplements and medicinal products (see Definitions) have developed over time and continue to be segmented both within the European Union and worldwide.

Definitions

Herbal substances or botanicals. All mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried, form, but sometimes fresh. Certain exudates that have not been subjected to a specific treatment are also considered to be herbal substances. Herbal substances are precisely defined by the plant part used and the botanical name according to the binomial system (genus, species, variety and author).

Herbal or botanical preparations. Preparations obtained by subjecting herbal substances to treatments, such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.

Botanical or Plant Food Supplements. Plant Food Supplements means foodstuffs intended to supplement the normal diet containing botanical preparations. Plant Food Supplements are taken alone or in combination and marketed in dose form, namely forms such as capsules, pastilles, tablets, pills and other similar forms, sachets of powder, ampoules of liquids, drop dispensing bottles, and other similar forms of liquids and powders designed to be taken in measured small unit quantities.

Herbal medicinal products. Any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.

Traditional herbal medicinal product. A herbal medicinal product that fulfils the conditions laid down in Article 16a(1); of Directive 2004/24/EC.

2. Plant food supplements in the European Union

TPFS (already present to a significant degree on the EU market before 15 May 1997) and novel PFS (not present at a significant degree on the EU market before 15 May 1997) are regulated in the European Union under Directive 2002/46/EC.¹ This Directive was appealed by a number of different parties before the Court of Justice of the European Union (CJEU) in Luxembourg with the main motivation that its legal basis (i.e. Art. 95 of the EU Treaty) was not considered suitable for harmonizing national regulations on food supplements for public health reasons. Other arguments for the appeal were that Directive 2002/46/EC violated the principle of free circulation of goods, the principle of proportionality and equal treatment as well as the right of property and of freedom of economic activities. However, in its judgement of 12 July 2005 in the combined Court cases C/154/04 and C/155/04, the CJEU confirmed the validity of the Directive.²

Novel plant food supplements (not present on the EU market to a significant degree before 15 May 1997) are also subject to the Novel Food Regulation (Regulation (EC) 258/1997).³

As far as voluntary nutritional and health claims are concerned, food supplements are subject to Regulation (EC) 1924/2006 and subsequent modifications and integrations.⁴

2.1. Directive 2002/46/EC on the approximation of the laws of member states relating to food supplements¹

Food Supplements are legally defined as foodstuffs, the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect, alone or in combination, marketed in dose form, namely forms such as capsules, pastilles, tablets, pills and other similar forms, sachets of powder, ampoules of liquids, drop dispensing bottles, and other similar forms of liquids and powders designed to be taken in measured small unit quantities.

Directive 2002/46/EC only provides for a partial harmonization of food supplements that covers, in addition to presentation, labelling and advertisement of food supplements, modalities for use of vitamins and minerals. In particular, only vitamins and minerals listed in Annex I and II of the above-mentioned Directive can be marketed as food supplements in the EU, at minimum and maximum levels to be established by the Standing Committee on Food Chain and Animal Health procedure.

However, Directive 2002/46/EC does not provide much clarification of what is covered in the term ‘other substance with a nutritional or physiological effect’ although it is generally understood that this could include substances such as amino acids, enzymes, pre- and probiotics, essential fatty acids, and botanicals and botanical extracts. However, for all these substances, no specific rules exist at the EU level and existing legislation in EU Member States is quite heterogeneous.

Also the term “nutritional and physiological effect” is not defined in Directive 2002/46/EC and neither does it clarify the botanical species and varieties that can be utilized in TPFS. Therefore, decisions concerning safety and efficacy (and effectiveness) of TPFS continue to depend mainly on national legislation and manufacturer's practices. Member States competent Authorities supervise the market according to their own criteria, which have not been harmonised at EU level. Conclusions on the use of TPFS at national level in the EU, as reflected by negative and/or positive national lists, are different and sometimes even contradictory or conflicting, thus causing fragmentation of the European market. In fact, national competent authorities tend to evaluate TPFS based on their long term experiences, reflecting common practices in the different countries.

It is not surprising, therefore, that, based on information officially published by the competent Authorities in 20 EU Member States plus Croatia and Switzerland, out of about 1900 herbal species, several hundred botanical species are:⁵

– Prohibited from use in some Member States and allowed for use in other Member States;

– Prohibited in some Member States and not regulated in other Member States;

– Allowed for use in some Member States and not regulated in other Member States.

To help Member States' Competent Authorities and interested companies, a guidance document for the safety assessment of botanicals and botanical preparations has been recently been published by EFSA.⁶ This guidance includes:

– Data requirements for the assessment;

– A science-based framework for the assessment;

– Criteria for priority setting.

Moreover, EFSA also developed a Compendium listing substances of concern so far identified in many botanical species, which is currently under further development. The Compendium lists the botanicals reported to contain toxic, addictive, psychotropic, or other substances of possible concern. More than 1200 genus, species and varieties have been listed so far and the work is expected to be completed by the end of 2011.⁷ While the Compendium is very effective in flagging plants or parts of plants or compounds naturally present in the listed botanicals of possible concern for human health, the presence of a substance of concern in a given botanical does not mean that this substance will also be present in the botanical preparation. This depends largely on the plant part used, as well as the preparation method. Therefore, the Compendium implies no judgment on whether listed botanicals are suitable or not suitable for food applications in Europe.

It is currently difficult to know whether and to what extent this EFSA guidance document, that could be seen as a harmonized approach to safety evaluation at EU level, is being used by Member States at national level to systematically review the safety of the botanical food supplements available on their markets.

The classification of food supplements as food implies automatically that manufacturing has to be carried out under Hygiene Regulations (Regulation (EC) 852/2004) and that these products must comply with Regulation (EC) 1881/2006 on maximum levels of nitrates, aflatoxins, heavy metals and dioxins.^8,9 Furthermore, the requirements for food safety, traceability, recall and notification included in the General Food Law Regulation (EC) 178/2002 and general food labelling (Directive 2003/13/EC) also apply.^10,11 Finally, the food fortification legislation (Regulation(EC) 1925/2006) contains a procedure to cover situations where safety issues would arise with food components, including botanical ingredients. It enables the European Commission to take measures, based on a scientific risk assessment by EFSA, and prohibit or submit the use of the food component to conditions of use.¹²

2.2. Regulation (EC) 258/97 on novel foods and novel food ingredients³

Regulation (EC) 258/97 on novel foods and novel food ingredients concerns the placing on the market, among others, of foods and food ingredients, including plant food supplements, which have not been used for human consumption to a significant degree within the EU before 15 May 1997 and which fall under the following categories:

– Foods and food ingredients consisting or isolated from plants, except those obtained by traditional propagating or breeding practises and having a history of safe use;

– Foods and food ingredients to which has been applied a production process not currently used, where that process gives rise to significant changes on the composition or structure of the foods or food ingredients, which affects their nutritional value, metabolism or level of undesirable substances.

According to Regulation (EC) 258/97, novel foods and food ingredients must not:

– Present a danger for the consumer;

– Mislead the consumer; and

– Differ from foods or food ingredients that they are intended to replace to such an extent that their normal consumption would be nutritionally disadvantageous for the consumer.

To ensure such conditions, the placing on the market of novel food and novel food ingredients is subject to an authorization procedure. To this end, the applicant shall submit a request to the competent Authority of the Member State in which the product is to be placed on the market for the first time. A copy of such request shall also be forwarded to European Commission. An initial assessment is carried out by the national Competent Authority and shared, through the European Commission, with all the national Competent Authorities of the EU Member States. In case there are no objections within 60 days from the circulation of the initial assessment, the novel food or food ingredient can be marketed without any further delay. However, if objections are raised by a Member State, an EFSA opinion is required and a final decision will have to be taken by the ad hoc Standing Committee. A revision of this Regulation was recently rejected by the Council and the European Parliament, mainly because these two Institutions failed to agree on how cloning would be regulated.

2.3. Regulation (EC) 1924/2006 on nutritional and health claims⁴

According to Regulation (EC) 1924/2006, voluntary claims applicable to foods, including food supplements, can be nutritional (Art. 8) or health-related (Art. 13 and 14). Health-related claims can be functional of a generic nature (Art. 13.1), functional of specific nature with proprietary data available (Art. 13.5) or dealing with disease risk factor reduction (Art. 14.a) or children’s development (Art. 14.b).The use of a health claim requires an authorisation by the European Commission through the Standing Committee for Food Safety and Animal Health and after a scientific assessment by EFSA (NDA Panel) to ensure that they are based on “generally- accepted scientific evidence, taking into account the totality of the available scientific data, and by weighing the evidence”. Whether the evidence available on each claim is sufficient to represent generally accepted scientific evidence to substantiate the claim is a scientific judgement of EFSA.

EFSA has provided scientific and technical guidance for the preparation and presentation of the applications for authorisation of a health claim and has conducted several consultations:

– A public consultation and a meeting with stakeholders (June, 2007);

– 2 public consultations and meetings with stakeholders on the scientific principles (June, 2009 & June, 2010).

A briefing document for stakeholders on the evaluation of Article 13.1, 13.5 and 14 health claims has recently been finalised and published.¹³ The scientific requirements for substantiation of specific health claims are being established progressively – as claims are evaluated. The main elements to be verified include:

– Whether a cause and effect relationship is established between consumption of the food/constituent (that should be well characterized) and the claimed effect for the target group under the proposed conditions of use (all of the evidence from pertinent studies weighed – overall strength, consistency and biological plausibility);

– Human data (interventional or observational), preferably on healthy people, of adequate design and quality, which are central for substantiation;

– Studies in animals or in vitro that may provide supportive evidence.

No pre-established formula (number/type of studies needed) has been defined.

So far EFSA opinions on more than 100 applications (requested according to Art. 13.5/14) have been adopted and published.

The claims requested under the Art. 13.1 procedure, including most of the claims on TPFS, however, have been a real challenge for EFSA due to their large number (over 4500), the lack of pre-established guidance and the poor quality of information provided for many claims. A progressive adoption/publication of EFSA's opinions under the Art. 13.1 procedure is taking place and more than 2000 claims have been assessed to date by EFSA. This work is expected to be completed by mid 2011 except for claims relating to botanicals. In fact, all the functional health claims concerning botanicals examined so far (several hundred) have received a negative evaluation by EFSA due to absence or poor quality of available data and the fact that traditional use is not accepted as an evaluation criterion. Currently, following a request by the European Commission, the evaluations of the remaining claims concerning botanicals are “on hold”.

Therefore, the result of this Regulation has been that, according to the criteria adopted by EFSA in strict compliance with the legal formulation of Regulation 1924/2006 (“based on generally accepted scientific data”), no general functional claim for botanicals examined so far has been considered to be acceptable by the competent EFSA's NDA Panel. Although in general, the absence of voluntary health claims does not prevent TPFS marketing, it may remain more difficult for consumers to fully understand, in the absence of health claims, the benefits, if any, associated with the consumption of the product.

2.4. National regulations in EU Member States applicable to traditional botanical food supplements

In view of the limited harmonization ensured by Directive 46/2002/EC in the case of botanical products, it is not surprising that major differences exist among the rules for marketing of TPFS implemented in the different EU Member States.^14,15 As an example. Table 1 illustrates the different approaches applied in the Member States on a few selected botanicals marketed asTPFS.¹⁴

Table 1 Examples of different national approaches for the use of selected botanicals in food supplements in the Member States of the EU³⁶

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3. Traditional herbal medicinal products

The European Institutions have started their actions for harmonizing applicable regulations and scientific criteria to traditional herbal medicinal products (THMP) only recently. A Directive for traditional medicinal products (Directive 2004/24/EC) was adopted in 2003 and published in 2004.¹⁶ Therefore, phyto-therapeutic products, able to modify, correct and restore human organic functions fall under the legislation of medicinal products.

When, in the second half of 2003, the EU Council Pharmaceutical Working Group started its work on the draft proposal on traditional herbal medicinal products, it was very clear that no traditional medicinal product could have ever been authorized under any of the European Directives and Regulations on medicinal products existing at the time, mainly due to limitations of available data on efficacy. For this reason, according to Directive 2004/24/EC, it has to be demonstrated that the product is “not harmful under the specific conditions of use and the pharmacological effects and efficacy are plausible on the basis of long term use and of available experience”, thus accepting openly the concept that efficacy requirements for traditional herbal medicinal products are lower than for the other categories of medicinal products.

An ad hoc “facilitated authorization” (so-called “registration”), released at national level, only for oral, external or inhalation administration for non-prescription medicinal products, is necessary for marketing traditional medicinal products, including ad hoc indications and contra-indications. Vitamins and minerals can be present in the medicinal products as long as their action is “ancillary” to that of active substances present.

A marketing authorization as THMP according to Directive 2004/24/EC can be granted, in general, only for products present on the market for at least 30 years, of which 15 years is in a European Union Member State. To this end, any products containing the same active substances, regardless of excipients, with same or similar indications, dosage and posology equivalent and identical administration routes are considered equivalent. The requirements of 30 years of presence on the market is satisfied even if the product has been marketed without a specific authorization and even if the number and amount of active substances has been reduced over time.

The application for the registration of a traditional herbal medicinal product requires, as for other medicinal products, a complete dossier including, among others, composition, manufacturing methodology, indications and contra-indications, adverse reactions, posology and administration route, storage and control methodologies. Other key elements to be included in the application dossier are:

– (i) Information on possible authorizations in other EU Member States or third countries;

– (ii) Documentation to prove the 30 years of marketing, 15 of which were within the EU; and

– (iii) A bibliographic review of all data concerning safety.

These data can be omitted in case the product is included by the Community List of substances, preparations and their combinations for the use in THMP, prepared and systematically adjourned by the ad hoc Committee for THMP established in the European Medicines Agency (EMA).

The mutual recognition procedure applies to registrations of herbal traditional medicinal products released from an EU Member State, based on Community Monographs prepared by the above-mentioned Committee or on the previously-mentioned Community List. The EMA has been assigned, through the HTMP Committee, important tasks intended to facilitate the release of national registrations for these products. The label and information leaflet of THMP have to specify that:

– The product is a THMP to be used only for specific indications based on the practice from long term use;

– The user has to consult a physician or a qualified health operator in case symptoms persist or adverse reactions not specified in the information leaflet appear.

Table 2 shows that Directive 2004/24/EC has been slowly implemented and only in some countries; in fact, after almost 7 years from adoption, this Directive has not been used to any significant extent in as many as about 2/3 of the EU Member States.

Table 2 Number of registrations of traditional herbal medicinal products after the adoption of Directive 2004/24/CE and its implementation in different European Member States (status in 2010)^a

a TOTAL: 171 in 16 different countries.
AT: 27	BE: 2	BG: 1	DE: 13	EE: 1	ES: 9	FI: 1
GR: 2	HU: 7	LV: 1	NL: 12	PT: 1	SE: 24	SK: 2
SI: 5	UK: 63

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The situation of the market with regard to THMP is likely to become more clear after the expiring, on 30 April 2011, of the transitional period foreseen by Directive 2004/24/EC for continuing the marketing of medicinal products already on the market. In fact, after 30 April 2011, all products covered by Directive 2004/24/EC need a prior marketing authorization or a certificate of traditional use registration to remain on the market. However, an ad hoc review of the market will be needed in due time to understand the impact, if any, of the expiring of this transitional period, although it is quite unlikely to show any major changes.

4. The borderline between food supplements and medicinal products: Overview of CJEU case law

While Food Supplements are expected to exert nutritional or physiological effects (Directive 2002/46/EC, article 2), THMP should exert a pharmacological, immunological or metabolic action (Directive 2001/83/EC, Article 1, 2b and Directive 2004/24/EC). The terms used in these definitions are not univocally defined and, therefore, are a matter of discussion and controversy. From the analysis in the present paper, it is clear that the current regulatory and legal situation in the EU is not adequate to lead to a harmonization that would make it possible for all European citizens to benefit from traditional botanical food supplements and medicinal products under, if not identical, at least comparable conditions. Therefore, it is not surprising that the Court of Justice of the European Union has already been called upon several times to sort out specific contentious issues (Table 3).

Table 3 Overview of CJEU court cases relating to the borderline between medicinal and other products

– Case 227/82: Criminal proceedings against Leendert van Bennekom. European Court Reports 1983.²⁶

– Case C-369/88: Criminal proceedings against Jean-Marie Delattre. European Court Reports 1991.²⁷

– Case C-60/89: Criminal proceedings against Jean Monteil and Daniel Samanni, March 1991.²⁸

– Case C-112/89: Upjohn Company and Upjohn NV v Farzoo Inc. and J. Kortmann, April 1991.²⁹

– Case C-290/90: Commission of the European Communities v Federal Republic of Germany, May 1992.³⁰

– Case C-219/91: Criminal proceedings against Johannes Stephanus Wilhelmus Ter Voort, October 1992.³¹

– Joined Cases C-211/03, C-299/03 and C-316/03 to C-318/03: References for a preliminary ruling from the Oberverwaltungsgericht fur das Land Nordrhein-Westfalen: HLH Warenvertriebs GmbH, Orthica BC v Federal Republic of Germany, June 2005.³²

– Case C-319/05: Action brought on 19 August 2005 by the Commission of the European Communities against the Federal Republic of Germany, November 2007.³³

– Case C-140/07: Hecht-Pharma GmbH v Staatliches Gewerbeaufsichtsamt Lüneburg, January 2009.³⁴

– Case C-27/08: BIOS Naturprodukte GmbH v Saarland, April 2009.³⁵

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A main issue is the difficulty of differentiating clearly the use of botanical ingredients in food supplements and medicinal products in spite of the rather sophisticate and careful wordings used by the relevant regulations.^1,16,17 The CJEU has elaborated clear limitations for Member States to consider certain products as medicinal.

A more simple case is the definition of medicinal product “by presentation” as it specifies that: “Any substance or combination of substances presented as having properties for treating or preventing disease in human beings” is to be considered as a medicinal product.¹⁸ This means that food supplements must not be presented with therapeutic properties for specific diseases, although the attribution of claims concerning the reduction of a risk factor for a specific disease is permitted following authorization by the European Commission under the Nutrition and Health Claims Regulation (EC) 1924/2006.⁴

A more difficult case is the definition of a medicinal product “by function” as it states that “Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis” is to fall under the scope of medicinal law. It is this provision that often gives rise to diverging views as it offers the potential to consider many foods and food ingredients with an effect on human physiology to be covered under medicinal law. Some Member States have also considered a number of botanicals as medicinal under this definition and prevented their use in foods.

The main principles established by the CJEU in its various judgments can be summarized as follows:

– It is the responsibility of the national authorities to determine, subject to review by the Courts, whether or not a product is to be considered as a medicinal product, having regard to all of its characteristics (composition, pharmacological properties as they may be ascertained in the current state of scientific knowledge, the way in which it is used, the extent to which it is sold, its familiarity to the consumer and the risks that its use might entail).

– The borderline between food use and medicinal use is often established based on national habits and a particular interpretation of definitions and legal provisions. This means that it is possible in the current state of European law for a national authority to judge a specific product as a medicinal product on its territory, even when such a product is lawfully marketed as a food supplement in another Member State. But it cannot do so in a general way or based solely on the definition of a medicinal product. It needs to perform a case by case assessment of each individual product and consider all the relevant aspects.

– This principle is confirmed by Article 2.2 of Directive 2004/27/EC, which states that in cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a “medicinal product” and within the definition of a product covered by other Community legislation, the provisions of this Directive shall apply. As the CJEU has clearly ruled, the scope of this possibility is firmly limited to “cases of doubt” and individual products.

– An essential element is the fact that the product must have a medicinal purpose or therapeutic activity. Products which have an effect on the human body but do not significantly affect the metabolism and thus do not modify the way in which it functions cannot be considered as medicinal. It is noted that certain THMP monographs refer to effects that cannot be considered as medicinal and may therefore create confusion with health claims.

5. Botanical species and preparations used in TPFS and THMP

For the reasons addressed in the previous sections, the distinction of the botanical species and preparations used as TPFS and THMP in the EU Member States is blurred. A number of botanical species and preparations are used as TPFS in one Member State while they are also used in THMP in other Member States. The overlap is very broad (see Tables 4–6).

Table 4 Use of individual botanical species in food supplements and medicinal products (Status in 2010)

Botanical species	Community List of traditional use (medicinal product)	Food Supplement use (No. of countries)
Calendula officinalis	Yes	8
Echinacea purpurea	Yes	7
Eleutherococcussenticosus	Yes	5
Foeniculumvulgare var. dulce	Yes	7
Foeniculumvulgare var. bitter	Yes	7
Linumusitatissimum	Yes	6
Pimpinellaanisum L.	Yes	8
Menthapiperita	Yes	7
Valerianaofficinalis	Yes	2

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Table 5 Food supplement use in different countries of traditional botanical species with an EMA Monograph concerning medicinal use (In parenthesis the number of countries in which the botanical species is used also in food supplements) (Status in 2010)

Aloe vera (7)	Passiflora spp. (3)
Althea officinalis (6)	Plantago ovata (7)
Avena sativa (8)	Polypodium vulgare (3)
Betula spp. (6)	Primula spp. (5)
Centaure cyanus (7)	Ruscus aculeatus (4)
Echinacea pallida (4)	Salix alba (4)
Equisetum arvense (7)	Sambucus nigra (9)
Frangula purshiana (2)	Solidago spp. (3)
Harpagophitum procumbens (2)	Thymus spp. (3)
Melilotus officinalis (4)	Urtica spp. (4)
Melissa officinalis (8)	Verbascum spp. (6)

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Table 6 Botanical species registered in selected countries under directive 2004/24/EC (and relative indications) that are considered acceptable in both medicinal and food supplements in the EU (In parenthesis is the number of countries in which the botanical species is used as food supplements) (status in 2010)

AU	Passiflora incarnata: uneasiness, stress, sleeping disorders and agitation (4); Pelargomium sidoides: cold (5) Arnica: muscles and joints; Capsicum: muscles and joints (3); Rhodiolaerosa: stress (4); Harpagophytum procumbens: rheumatic pain (7)
DE	Melissa officinalis: nervousness, tension, anxiety and headaches (8); Crataegus spp.: circulatory functions; Levisticum officinale (8) plus Centaurium erythraea (8) and Rosmarinus officinalis (8): inflammatory diseases of the lower urinary tract and decrease of kidney stones (8); Graminis and Valeriana: stress and sleep (2)
FI	Gingo biloba: cold hands and feet due to mild blood flow disruption in peripheral vessels (2)
GR	Harpagophytum procumbens: minor articular pain (7); Eleutherococcus senticosus: asthenia due to fatigue and weakness (5)
NL	Pelargonium sidoides: cold (5)
SL	Crataegus spp. (8): support of cardiac and circulatory functions; Crataegus spp. (8) plus Passiflora spp. (4): support of cardiac and circulatory functions and mild nervous heart complaints; Primula spp. (5) plus Thymus (3): cold Plantago spp. (6) plus Malvasylvestris (6): cold Valeriana (2) plus Malissa spp. (8), Mentha piperita (7) and Lupulus: mental stress and aid sleep
SR	Crataegus spp. (8) plus Melissa officinalis (8) and Valeriana (2): support of cardiovascular system under stress and convalescence
UK	Harpagophytum procumbens: minor articular pain (7); Tanacetum parthenium (5): migraine headaches Cimicifuga racemosa (2): symptoms of the menopause; Sereno arepens (6): benign prostatic hypertrophy; Vitex agnus castus: sleep disturbances; Valeriana officinalis (2): sleep disturbances; Aesculus hippocastanum: low mood and mild anxiety; Pelargonium sidoides (5): cold; Echinacea purpurea (7): common cold and influenza type infections; Rhodiola erosa: stress (4); Hypericum perforatum (2): low mood and slight anxiety

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In particular, Table 4 shows that botanical species included by the EMA in the Community List of substances, preparations and their combinations for which some data can be omitted in the application dossier for registration as a THMP are also used in several Member States as food supplements.

Moreover, as shown in Table 5, for a number of botanical species widely used in food supplement EMA has produced monographs to cover their medicinal use.

Lastly, a number of botanical species used in medicinal products registered in selected countries under Directive 2004/24/EC are also found in food supplements in other European countries (Table 6).

In practice, it can be said that it is very difficult to find botanical species which are only used as ingredients of food supplements or medicinal products.

In conclusion, the nature of the commercial botanical products made available to consumers as traditional medicinal products or food supplements, depends largely on the country under consideration as a consequence of how competent National Authorities and manufacturing companies interpret and apply current regulations rather than on the intrinsic properties of the botanical products and their constituents.

Currently, the European Union market is witnessing remarkable changes in customer's behavior. According to Loraine Heller from the consumer research organization Euromonitor, “there's been a big shift from treatment to prevention as people can't really afford to be sick.” Therefore, food supplements play an important role in the awareness of consumers. In 2005, more than five billion euros were spent on botanical products in the European market. Still vitamins and minerals play the most important role with a market share of about 50 percent. The so called other substances follow closely with a market share of 43 percent in Europe.¹⁹ Extrapolating research data of one of the largest European markets, Germany, products containing herbal ingredients are the largest group within the other substances with a total market share of 22 percent.¹⁹ However, what is particularly relevant is not only the global market sale of botanical products (food supplement plus traditional medicinal products), but also the share between these two categories. According to some estimates, the current market of botanical products in Italy is almost completely represented by food supplements, whereas in countries like Germany or France about only one third of such a market is represented by food supplements. Therefore, the level of implementation of Directive 2004/24/EC is very different from one European Member State to another.

6. Plant Food Supplements in the United States of America (USA) and other non-EU countries

Regulations on plant food supplements are not only different among the EU Member States; this is even more the case for countries outside the EU. National traditions and market practices differ more largely when non-EU countries are considered. Various tools have been used by non-EU countries to address botanicals, including positive and negative lists, conditions of use and pre-marketing approvals.

Codex alimentarius

The Codex Alimentarius has developed guidance on food supplements, but it only covers at this stage vitamins and minerals and no further activities on botanicals are foreseen.²⁰

ASEAN

In Asia, the ASEAN, the Association of Southeast-Asian Nations, is currently undertaking work to harmonize rules on the use of botanicals in both health supplements and traditional medicines. This work started in 2004 by the ASEAN Consultative Committee on Standards and Quality Product Working Group for Traditional Medicine and Health Supplements (ACCSQ TMHS PWG). This work covers a definition of health supplements, provisions to establish maximum levels based on the World Health Organization (WHO) model for risk assessment of nutrients, labeling requirements, a negative list of ingredients, provisions for nutrition and health claims, and standards for Good Manufacturing Practice (GMP).

USA

In the USA, the Dietary Supplement Health and Education Act (DSHEA) was signed into law in 1994 creating a new regulatory framework dietary supplements as a separate category of foods and establishing requirements for safety and labelling.²¹ The US has no separate category for traditional medicines. Under this framework, a company is responsible for determining that the dietary supplements it manufactures or distributes are safe and that any representations or claims made about them are substantiated by adequate evidence to show that they are not false or misleading. Dietary supplements do not need approval from the Food and Drug Administration (FDA) before being marketed. Companies that manufacture or distribute dietary supplements containing “new dietary ingredients” are required to submit pre-market safety notifications. Dietary supplements containing only ingredients that are “not new”, used previously as conventional foods before the law of 1994 are exempt from the notification requirement. FDA can take regulatory action to remove unsafe products from the market, including products containing new dietary ingredients for which there is inadequate evidence of safety in a pre-market safety notification.

A company does not have to provide FDA with the evidence it relies on to substantiate “structure/function claims” as a statement of nutritional support or effectiveness before or after it markets its products. FDA has published guidelines on “substantiation” of “structure/function claims” for use by manufacturers who want to substantiate a structure/function claim through the application of a substantiation standard of competent and reliable scientific evidence to claim about the benefits and safety of dietary supplements.²² Within 30 days of making a structure/function claim, the manufacturer/distributer must notify FDA of the wording of the claim. “Health claims” (e.g.reduction of risk of disease) can only be made under the authorization of a specific regulation, which may be initiated by petition to FDA. If a manufacturer or distributor wishes to claim that a product be used to diagnose, treat, cure or prevent a disease then the product by law is a drug and must meet the requirements for drugs.

Dietary supplement products must be manufactured under current good manufacturing procedures (cGMPs) established by regulation in 2007.²³ The 3-year phase-in period for the regulation was recently completed. In addition, the “Food Safety Modernization Act”, which became effective in January 2011, requires Hazard Analysis and Critical Control Points (HACCP) controls for many foods.²⁴ Dietary supplement products covered by dietary supplement cGMPs are excluded from the new HACCP requirement and it is not yet clear how the manufacture of the ingredients used to make dietary supplements will be affected by the new HACCP rules.

In July 2011 FDA has published draft guidelines on how to comply with the regulatory requirement to provide a pre-market safety notification for dietary supplements containing new dietary ingredients.²⁵ This draft contains discussions on how to determine the identity of plant-based ingredients and how to use history of use or other evidence to demonstrate the safety of plant based ingredients.

A significant issue in the US is the large number of “botanical” supplements that contain undeclared non-botanical ingredients. The problem is particularly common among products that carry claims about weight loss and male sexual performance that contain approved drugs or synthetic analogues of drugs.

7. Overall conclusions and way forward

The analysis carried out in this paper clearly shows the peculiarity of the regulatory system adopted in the EU for food supplements and traditional medicinal products of plant origin as compared, for instance, to the approach adopted in the USA. Table 7 summarizes the different aspects of the current legal frameworks for TPFS and THMP and highlights some of the major issues which characterize the current situation.

Table 7 Overview of applicable rules covering TPFS and THPM in the EU

	TPFS	THMP
Marketing procedure	National notification procedures in some Member States. National approaches may differ. (Novel foods: premarketing approval of the products when not on the market prior to 15 May 1997 – not TPFS).	Product-specific authorization procedure at a national level to obtain a marketing license.
Safety	Manufacture and labeling: in accordance with the EU food law framework, including labeling rules (Dir 2000/13), Hygiene rules (Dir 852/2004), General Food Law (Reg 2002/178), Contaminants and residues (Reg 1881/2006), etc.	Safety supported by EMA monographs/Community entries or by ad hoc assessment. Manufacture in respect to Good Manufacturing Practice; Labeling in conformity with Dir. 2001/83.
Efficacy	Conformity with the claims legislation (Reg 1924/2006) based on generally accepted scientific data (largely unavailable).	Plausible effects recognized on the basis of traditional use (Dir 2004/24).

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One key question is why the regulatory approach adopted by Directive 2004/24/EC for assessing efficacy of THMP taking into account specificities deriving from traditional use has not been adopted also for TPFS and what could be done to adopt a more balanced approach in the future.

Another probably more important question is how to reduce and, over time, eliminate the current overlap and diverging interpretations in the EU Member States relating to TPFS and THMP, in particular when consisting of the same botanical species and preparations.

In fact:

– Plant food supplements are intended to complement the normal diet and to support normal physiological functions, whereas medicinal products are intended for treating or preventing (specific symptoms of) disease;

– Indications of use for food supplements and medicinal products should therefore be clearly different, as expressed by CJEU case law.

– Plant food supplements could be for lifetime exposure (maintenance of health), whereas this is not generally the case for medicinal products (treatment of disease);

– Even for products based on the same botanical species and parts of the plant, dietetic long-term use levels would likely to be lower than those applicable to medicinal products.

Pending the above-mentioned questions it is noteworthy to see the European Commission conclusions, reported in its 2008 Report on the use of substances other than vitamins and minerals in food supplements, indicating that, in view of the new Regulations adopted (Regulation (EC) 1924/2006 on claims, Regulation (EC) 1925/2006 on fortified foods and the new Regulation (EC) 764/2008 on Mutual Recognition),“laying down specific rules applicable to substances other than vitamins and minerals for use in food supplements is not justified”.^36–38 Moreover, the Commission expressed doubts on the feasibility of such a measure, which, in any case, was considered not necessary in the short term.”

One way for addressing these issues would be to harmonize TPFS in the EU market, by developing for TPFS, in the framework of Directive 2002/46/EC, the same approach already used for harmonizing vitamins and minerals or by applying the lists as foreseen under Article 8 of Regulation (EC) 1925/2006. This could result in the adoption of (negative) lists, specifying plants that should not be used in foods, and (positive) lists of safe botanical species and plant parts (including, where necessary, relevant specifications) and of applicable harmonized descriptions of science-based intended uses, also recognizing the value of tradition.

It is relevant in this context that Directive 2002/46/EC states, in the 8th recital, that “Specific rules concerning nutrients other than vitamins and minerals or other substances with a nutritional or physiological effect, used as ingredients of food supplements, should be laid down at a later stage, provided that adequate and appropriate scientific data about them become available”.

It would be advisable in this respect, that the European Commission and Member States undertake a collaborative effort to improve the current regulatory framework by developing:

– A practical approach to better identify/characterize botanical species and preparations when used in food supplements or in medicinal products;

– A balanced approach to safety and efficacy assessment of both types of products, preferably based on traditional use, to be used throughout the EU in a substantially coherent manner.

Acknowledgements

The writing of this review was funded by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 245199. It has been carried out within the PlantLIBRA project (website: http://www.plantlibra.eu). This report does not necessarily reflect the European Commission views or its future policy on this area. The authors are grateful to Dan Levy for the revision of the USA paragraph.

Notes and references

1. EU, Directive 2002/46/EC, Official Journal of the European Union, 12 July 2002, L136/85.
2. CJEU, Joint Cases C-154/04 and C-155/04: Judgment of the Court (Grand Chamber) of 12 July 2005, Official Journal of the European Community, 3 September 2005, C217:19.
3. EU, Regulation (EC) No 258/97, Official Journal of the European Union, 14 February 1997, L043/1.
4. EU, Corrigendum to Regulation (EC) No 1924/2006, Official Journal of the European Union, 18 January 2007, L12/3.
5. AESGP, http://www.aesgp.be, 2007.
6. EFSA, EFSA J., 2009, 7(9), 1249 . Available online: http://www.efsa.europa.eu/.
7. EFSA, EFSA J., 2009, 7(9), 281 . Available online: http://www.efsa.europa.eu/.
8. EU, Corrigendum to Regulation (EC) No 852/2004, Official Journal of the European Union, 25 June 2004, L226/3.
9. EU, Commission Regulation (EC) No 1881/2006, Official Journal of the European Union, 20 December 2006, L364/5.
10. EU, Regulation (EC) no 178/2002, Official Journal of the European Union, 1 February 2002, L31/1.
11. EU, Directive 2000/13/EC, Official Journal of the European Union, 6 May 2000, L109/29.
12. EU, Regulation (EC) No 1925/2006, Official Journal of the European Union, 30 December 2006, L404/26.
13. EFSA, EFSA J., 2011, 9(4), 2135 . Available online: http://www.efsa.europa.eu/.
14. EU, European Advisory Services (EAS), 28 March 2007. Available online: http://ec.europa.eu/food/food/labellingnutrition/supplements/documents/2007_A540169_study_other_substances.pdf.
15. EAS, European Advisory Services: Report, 2008, Fifth edition. ISBN 9789080699533. http://www.eas.eu.
16. EU, Directive 2004/24/EC, Official Journal of the European Union, 30 April 2004, L136/85.
17. EU, Directive 2004/27/EC, Official Journal of the European Union, 2004, L136/34.
18. EU, Directive 2001/83/EC, Official Journal of the European Union, 28 November 2001, L311/67.
19. M. Hamm, Dtsch. Apoth. Ztg., 2010, 35, 46–53.
20. Codex Alimentarius, CAC/GL 55 – 2005, 2005. Available online: http://www.codexalimentarius.net.
21. US, Dietary Supplement Health and Education Act, 1994. Available online at http://www.fda.gov.
22. FDA, Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims – Final, 2009. Availabloe online at http://www.fda.gov.
23. FDA, Dietary Supplement Current Good Manufacturing Practices (CGMPs) and Interim Final Rule (IFR) Facts, 2007. Available online at http://www.fda.gov.
24. US, Food Modernization Act, 2011. Available online at http://www.fda.gove30%20april%202004/.
25. FDA, Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues, 2011. Available online at http://www.fda.gov.
26. CJEU, Case C227-82, European Court Reports, 1983, 3883.
27. CJEU, Case C369-88, European Court Reports, 1991, I, 1487.
28. CJEU, Case C-60/89, European Court Reports, 1991, I, 1547.
29. CJEU, Case C-112/89, European Court Reports, 1991, I, 1703.
30. CJEU, Case C-290/90, European Court Reports, 1992, I, 3317.
31. CJEU, Case C-219/91, European Court Reports, 1992, I, 5485.
32. CJEU, Joined Cases C-211/03, C-299/03 and C-316/03 to C-318/03, Official Journal of the European Community, 6 August 2005, C193/4.
33. CJEU, Case 319/05, Official Journal of the European Community, 12 January 2008, C8/3.
34. CJEU, Case C-140/07, Official Journal of the European Community, 07 March 2009, C55/2.
35. CJEU, Case C-27/08, Official Journal of the European Community, 04 July 2009, C153/10.
36. EU, Commision Report, 2008. Available online: http://ec.europa.eu/food/food/labellingnutrition/supplements/documents/COMM_PDF_COM_2008_0824_F_EN_RAPPORT.pdf.
37. EU, Regulation (EC) No 764/2008, Official Journal of the European Union, 13.08.2008, L218/21.
38. EU, European Commission Guidance document, 2010. Available online: http://ec.europa.eu/enterprise/policies/single-market-goods/files/mutual-recognition/food-supplements/food-supplements_en.pdf.

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Footnote

† This paper forms part of the themed issue on Plant Food Supplements: regulatory, scientific and technical issues concerning safety, quality and efficacy.

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