Phytomedicine 22 (2015) 400–405
Contents lists available at ScienceDirect
Phytomedicine journal homepage: www.elsevier.com/locate/phymed
Could EU herbal monographs contribute to Malta’s treatment armamentarium? B. Micallef a, E. Attard b, A. Serracino-Inglott a,c, J.J. Borg a,d,∗ a
Medicines Authority, 203 Level 3, Rue D’Argens, Gzira, GZR 1368, Malta Institute of Earth Systems, University of Malta, Malta c Department of Pharmacy, Faculty of Medicine and Surgery, University of Malta, Msida, Malta d Department of Biology, School of Pharmacy, University of Tor Vergata, Rome, Italy b
a r t i c l e
i n f o
Article history: Received 24 September 2014 Revised 15 December 2014 Accepted 2 January 2015
Keywords: EU herbal monographs ATC classification system Therapeutic coverage
a b s t r a c t Ten years have passed since Directive 2004/24/EC regulating herbal medicinal products across the EU were published. The directive created the Committee on Herbal Medicinal Products within the European Medicines Agency whose remit includes the creation and publishing of official EU monographs on herbal medicinal products. These monographs include the official uses of the products and their evidence for efficacy and safety. To this effect, we are interested in analysing the potential impact herbal product EU monographs could have on the therapeutic treatment options available for prescribers in Malta. Therefore our aim was two-fold. First, to rationalise the spread of indications of the herbal substances listed in the community herbal monograph inventory and subsequently determine if these herbal substances could potentially contribute to the treatment options available in our local scenario (Malta). 128 EU monographs were analysed resulting in a total of 230 indications which subsequently codified into 42 unique ATC codes. The Malta Medicines List contains 1456 unique ATC codes. Comparative analysis of the Malta Medicines List revealed that the 21 therapeutic areas had 4 or less pharmaceutically used substances (5th level ATC codes) registered and therefore in our opinion are areas with limited therapeutic choice. The following 4 therapeutic areas, A05 bile and liver therapy, A13 tonics, A15 appetite stimulants and D03 preparations for treatment of wounds and ulcers, could potentially benefit from the registration of herbal medicinal products according to the EU herbal monographs. If such registration is effected the aforementioned areas would no longer be considered limited because more than 4 therapeutic choices would be available to prescribers. This study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and confirms the notion that herbal products could potentially increase the treatment options available in areas where few medical products have been registered due to Malta’s small market size. © 2015 Elsevier GmbH. All rights reserved.
Introduction Directive 2004/24/EC (hereafter referred to as the “directive”) has had an effect on the regulatory framework of herbal medicinal products across Europe. The directive sets a framework for the registration of "traditional herbal medicinal products" through a simplified registration procedure for these traditional-use products (The European Parliament and the Council of the European Union 2004a). To be placed on the market, in the European Union (EU), a medicinal product needs a marketing authorisation. To obtain a marketing authorisation an application consisting of a dossier supporting the medicinal product’s quality, safety and efficacy needs to be
∗ Corresponding author at: Medicines Authority, 203 Level 3, Rue D’Argens, Gzira, GZR 1368, Malta. Tel.: +356 23439129; fax: +356 23439161. E-mail address: [email protected] (J.J. Borg).
http://dx.doi.org/10.1016/j.phymed.2015.01.005 0944-7113/© 2015 Elsevier GmbH. All rights reserved.
submitted to regulatory authorities. The dossier can either be a full stand-alone dossier consisting of the results of studies (clinical and preclinical as well as quality) conducted by the prospective marketing authorisation holder usually for an “on patent” medicinal product (originator/innovator medicine) or a dossier consisting of a full package of quality documentation, but a reduced clinical and pre-clinical program which is usually the case for medicines outside their data exclusivity such as generics, well established use medicinal products, hybrid (mixed bibliographic applications) and biosimilar medicinal products and herbal medicinal products. The aim of this EU directive was to enhance the protection of public health whilst promoting the free movement of traditional medicinal products in the EU (Routledge 2008) through harmonised procedures. This directive also established the Committee on Herbal Medicinal Products (HMPC) (The European Parliament and the Council of the European Union 2004a) whose aim is to aid in the harmonisation of procedures and provisions concerning herbal medicinal products in
B. Micallef et al. / Phytomedicine 22 (2015) 400–405
401
Table 1 The structure of the coding system as illustrated by the complete classification of metformin. Code
Description
Level description
A A10 A10B A10BA A10BA02
Alimentary tract and metabolism Drugs used in diabetes Blood glucose lowering drugs, excl. insulins Biguanides Metformin
1st level – Anatomical main group 2nd level – Therapeutic subgroup 3rd level – Pharmacological subgroup 4th level – Chemical subgroup 5th level – Chemical substance
Adapted from WHO Collaborating Centre for Drug Statistics Methodology (2014).
EU Member States whilst further integrating herbal medicinal products in the European regulatory framework. One of the activities of the HPMC is the preparation of Community herbal monographs, which comprise the scientific opinion of the HMPC on the safety and efficacy1 data concerning a herbal substance and its preparations intended for medicinal use, based on the experience of use within the community. EU herbal monographs are intended to be used as reference material in herbal marketing-authorisation applications (both for wellestablished-use and traditional-use applications) (The European Parliament and the Council of the European Union 2004a). The aim of this study was therefore to investigate the potential impact herbal product EU monographs could have on the therapeutic treatment options available for prescribers in Malta. Our objectives were two: (1) to rationalise the spread of indications of the herbal substances listed in the community herbal monograph inventory; (2) to determine if these herbal substances could potentially contribute to the treatment options available in our local scenario (Malta). To our knowledge, this study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and lends support to the notion that herbal products could increase treatment options in areas where few medical products have been registered due to Malta’s small market size. Method Data source and inclusion criteria All the EU monographs published by the HPMC were retrieved from the European Medicines Agency website (European Medicines Agency 2014). The filter function on the website was used to retrieve herbal products for which a monograph was available. The inclusion criteria for a monograph to be used for analysis included those monographs with the following statuses "Draft published", "Assessment close to finalisation (pre-final)" and "Assessment finalised". A total of 128 Community herbal monographs were included in the analysis. The final and draft EU monographs included were published between July 2006 to January 2014 and July 2011 to November 2013 respectively. All EU herbal monographs were analysed and relevant information was compiled using Excel (Microsoft, Redmond, WA). Data extraction and association rationale The following data was captured: The EU Document Reference number of the monograph; the date of HMPC adoption; the scientific name; the common name of herbal substance; the legal basis for registration (Traditional use/Well Established Use) and all listed indications. In addition, information on the herbal preparation and pharmaceutical form was also captured. 1
Although the HPMC review the efficacy of an herbal medicinal product, it must be qualified that the robustness and amount of evidence based data to prove efficacy for a traditional herbal product is less than that for a new compound, which in turn explains why the claims of a traditional herbal product are restricted. The efficacy of a herbal medicinal product and a standard drug should not be treated as equivalent unless the herbal medicinal product has undergone the same clinical development path as a standard drug with randomised Clinical Trials.
The Anatomical Therapeutic Chemical (ATC) classification system was used to classify the captured indications. The ATC system used is a pharmaceutical coding system that divides drugs into different groups according to the organ or system on which they act and their therapeutic and chemical characteristics. Each bottom-level ATC code stands for a pharmaceutically used substance, or a combination of substances, in a single indication or use. It is important to note that using this coding system one drug can have more than one ATC code (WHO Collaborating Centre for Drug Statistics Methodology 2014). For clarity’s sake readers should keep in mind the following principles behind the ATC classification system’s structure. The 1st level is the anatomical area and is denoted by a single letter for example: A for “Alimentary tract and metabolism”. The 2nd level is the therapeutic subgroup area and is denoted by two digits for example: A10 which corresponds to "Drugs used in diabetes". The 3rd level is the pharmacological subgroup and is denoted by a single letter for example A10B which corresponds to "Blood glucose lowering drugs excluding insulins". The 4th level is the chemical subgroup and is denoted by another single letter for example A10BA which corresponds to Biguanides. Finally the 5th level or bottom level corresponds to a chemical substance or combination of substances and is denoted by two digits (WHO Collaborating Centre for Drug Statistics Methodology 2014). The full code therefore consists of 6 characters (refer to Table 1). All indications per herbal product within the EU monograph were then subsequently analysed in order to associate an ATC code. Where the active substance considered had a specific ATC code as was the case for some herbal substance having a "Well-Established Use" for example Senna code A06AB06, Cascara code A06AB07, Valerian code N05CM09, etc. as per ATC/DDD Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014) this association was straightforward. However when there was no specified ATC code, the association between the active substance in question and a relevant ATC code was made based on the wording of the specified indication in the EU monograph. For example we classified the Traditional-Use of Achillea millefolium L., herba (Yarrow) worded as "Traditional herbal medicinal product used in temporary loss of appetite" with an ATC code of A15: Appetite stimulant. We arrived to this classification rationalising both anatomical and therapeutic reasons to associate an ATC code. In this example, Achillea millefolium L., herba is used to treat a “temporary loss of appetite” therefore, this herbal product affects the alimentary system, further to that, its clinical effect is to promote appetite. Therefore the ATC classification A15: Appetite stimulant is a reasoned association. It must be kept in mind that the ATC codes assigned in this manuscript are for reasons of comparison only and not generally transferable. Determining the therapeutic coverage of the community herbal monographs; creation of the “Herbal Monograph ATC database” Once the association exercise was completed, a database of 3rd, 4th and 5th level ATC codes corresponding to each indication was developed. Since a number of herbal substances had similar indications the database contained duplicate entries. Duplicate ATC codes
402
B. Micallef et al. / Phytomedicine 22 (2015) 400–405
Comparision of Anatomical Area Coverage
Total number of unique 2nd level ATC codes
18 16 14
Complete Coverage
12
MaltaMedicines List Frequencies
10
Herbal List Frequencies
8 6 4 2 0 A
B
C
D
G
H
J
L
M
N
P
R
S
V
1st level ATC areas Fig. 1. Comparison of anatomical area coverage. The blue bars represent the maximum number of therapeutic areas divided according to the 14 Anatomical Areas as per the WHO/ATC Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014). The red and green bars represent the number of observations per therapeutic areas for the Malta Medicines List and Herbal Monograph ATC database respectively. Abbreviations used: Alimentary tract and metabolism (A); blood and blood forming organs (B); cardiovascular system (C); dermatologicals (D); genito-urinary system and sex hormones (G); systemic hormonal preparations, excluding sex hormones and insulins (H); antiinfectives for systemic use (J); antineoplastic and immunomodulating agents (L); musculo-skeletal system (M); nervous system (N); respiratory system (R); sensory organs (S); antiparasitic products, insecticides and repellents (P); various (V)]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
were then removed. To assess the therapeutic coverage, 2nd level ATC codes were used. All 2nd level duplicates were removed and a database of unique therapeutic areas was established. Determining the therapeutic coverage in Malta of authorised medicinal products The Malta Medicines List was used (Malta Medicines Authority 2014). The list includes all medicinal products authorised in Malta, through any possible regulatory procedure that is National Procedures [Regulation 4(1) and 4(2) of the Medicines (Marketing Authorisation) Regulations] (Malta Government 2007), European Procedures [Mutual Recognition (MR) and Decentralised (DC) Procedures] (The European Parliament and the Council of the European Union 2004b) and Centralised Procedure (The European Parliament and the Council of the European Union 2004c). The list also provides the ATC codes for each medicinal product. Utilising the 2nd level ATC code the Malta Medicines List was reduced to unique 2nd level ATC codes. Data and statistical analysis The raw data on ATC codes obtained from herbal monographs as well as from Malta Medicines List were imported in Access (Microsoft, Redmond, WA) so that SQL queries (refer to graphical abstract for the SQL coding) and analysis could be run on the dataset. A query was designed to highlight unmatched records comparing the therapeutic subgroup coverage of the Malta Medicines List and the Community herbal monograph inventory to the complete ATC classification list at the second level and also comparing the therapeutic subgroup coverage of the Community herbal monograph inventory with the coverage of the Malta Medicines List. This query clearly showed the spread of products and any therapeutic gaps. Descriptive statistics were calculated using Excel (Microsoft, Redmond, WA).
Results From the 128 EU monographs analysed, a total of 230 indications resulted which were subsequently codified into 230 ATC codes. Following the removal of duplicate ATC codes entries, 42 unique 3rd and 4th level ATC codes (chemical/pharmacological subdivisions) remained. Fig. 1 depicts the number observations of therapeutic areas for the Malta Medicines List and Herbal Monograph ATC database when compared to the maximum possible number of therapeutic areas divided according to the 14 Anatomical Areas as per the ATC/DDD Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014). The frequency of therapeutic areas subdivided according to the 14 Anatomical Areas for Herbal Monograph ATC database are in the following frequency sequence. Alimentary tract and metabolism (A) [9 out of 16 (56%)] > dermatologicals (D) [6 out of 11 (55%)] > genitourinary system and sex hormones (G) [2 out of 4 (50%)] > nervous system (N) [3 out of 7 (43%)] > cardiovascular system (C) [3 out of 9 (33%)] = respiratory system (R) [2 out of 6 (33%)] = musculoskeletal system (M) [2 out of 6 (33%)] = sensory organs (S) [1 out of 3 (33%)] > various (V) [0 out of 9] = anti-infectives for systemic use (J) [0 out of 6] = systemic hormonal preparations, excluding sex hormones and insulins (H) [0 out of 5] = blood and blood forming organs (B) [0 out of 5] = antineoplastic and immunomodulating agents (L) [0 out 4] = antiparasitic products, insecticides and repellents (P) [0 out of 3]. Analysis of the Malta Medicines List revealed that 16747 single units are authorised in Malta (a single unit refers to a unique authorisation number and the data also includes centralised marketing authorisations where an EU number is issued also per pack size), corresponding to 1456 unique ATC codes. The ATC codes of Malta Medicines List covered all 14 Anatomical areas however 2 therapeutic gaps were observed as compared to the ATC/DDD index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014). The therapeutic areas not covered were “A14” corresponding to ”Anabolic
B. Micallef et al. / Phytomedicine 22 (2015) 400–405
403
Table 2 Comparison of analysis of 2nd level ATC codes (therapeutic areas) for the ATC/DDD Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014), the Malta Medicines List and EU Herbal Monograph ATC database. Full list ATC second level codes
MML second level codes
Herbals second level codes
Full list ATC second level codes
MML second level codes
A01 A02 A03 A04 A05 A06 A07 A08 A09 A10 A11 A12 A13 A14 A15 A16 B01 B02 B03 B04 B05 B06 C01 C02 C03
A01 A02 A03 A04 A05 A06 A07 A08 A09 A10 A11 A12 A13
A01
C04 C05 C06 C07 C08 C09 C10 D01 D02 D03 D04 D05 D06 D07 D08 D09 D10 D11 G01 G02 G03 G04 H01 H02 H03
C04 C05 C06 C07 C08 C09 C10 D01 D02 D03 D04 D05 D06 D07 D08 D09 D10 D11 G01 G02 G03 G04 H01 H02 H03
A03 A04 A05 A06 A07 A08
A13
A15 A16 B01 B02 B03 B04 B05 B06 C01 C02 C03
A15
C01 C03
Herbals second level codes
C05
D01 D02 D03 D04
D10 D11 G02 G04
Full list ATC MML second second level codes level codes H04 H05 J01 J02 J03 J04 J05 J06 J07 L01 L02 L03 L04 M01 M02 M03 M04 M05 M09 N01 N02 N03 N04 N05 N06
Herbals second level codes
H04 H05 J01 J02 J03 J04 J05 J06 J07 L01 L02 L03 L04 M01 M02 M03 M04 M05 M09 N01 N02 N03 N04 N05 N06
M01 M02
N02
N05 N06
Full list ATC second level codes
MML second level codes
N07 P01 P02 P03 R01 R02 R03 R04 R05 R06 R07 S01 S02 S03 V01 V02 V03 V04 V05 V06 V07 V08 V09 V10 V20
N07 P01 P02 P03 R01 R02 R03 R04 R05 R06 R07 S01 S02 S03 V01 V02 V03 V04 V05 V06 V07 V08 V09 V10
Herbals second level codes
R02
R05
S01
The first column shows all possible 2nd level ATC codes, derived from the ATC/DDD Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014), and is used a standard reference to compare the therapeutic coverage of the Malta Medicines List and EU Herbal Monograph ATC database respectively. This figure also compares the therapeutic coverage of the EU Herbal Monograph ATC database to that of the Malta Medicines List. Table 3a Comparison of the number of unique chemicals substance authorised (5th level ATC codes ) within a therapeutic area (2nd level ATC division) identified from the Malta Medicines List with the corresponding number of herbs from EU Herbal Monograph ATC database. Code
Description
Malta Medicines List
Herbal Monograph ATC database
Combined
A05 A08 A09 A13 A14 A15 B06 C04 D03 D05 D09 H04 M04 M09
Bile and liver therapy Antiobesity preparations, excluding diet products Digestives, including enzymes Tonics Anabolic agents for systemic use Appetite stimulants Other haematological agents Peripheral vasodilators Preparations for treatment of wounds and ulcers Antipsoriatics Medicated dressings Pancreatic hormones Antigout preparations Other drugs for disorders of the musculo-skeletal system Anthelmintics Ectoparasiticides including scabicides, insecticides and repellents Ophthalmological and otological preparations Allergens General nutrients All other non-therapeutic products Surgical dressings
4 1 1 1 0 1 3 3 1 4 1 1 4 4
2 1 0 6 0 10 0 0 5 0 0 0 0 0
6 2 1 7 0 11 3 3 6 4 1 1 4 4
1 4
0 0
1 4
1 1 1 1 0
0 0 0 0 0
1 1 1 1 0
P02 P03 S03 V01 V06 V07 V20
agents for systemic use” and “V20” corresponding to ”Surgical dressings”. Further analysis of the EU Herbal Monograph ATC database indicates that the two therapeutic gaps identified would not be resolved by registration of herbal medicinal products according to the EU herbal monographs, since there is no coverage for the “A14” and “V20” therapeutic areas within the EU Herbal Monograph ATC database (refer to Table 2).
In order to explore further where therapeutic coverage of authorised medicinal products on the Maltese market is lacking, we analysed the ATC codes within the Malta Medicines List and identified the therapeutic areas (i.e. 2nd level ATC codes) where less than 5 unique 5th level ATC codes (i.e. substances or a combination of substances, in a single indication) were authorised. The results are presented in Tables 3a and 3b. Therapeutic areas where
404
B. Micallef et al. / Phytomedicine 22 (2015) 400–405 Table 3b Highlight of therapeutic areas which could potentially benefit from the registration of herbal medicinal products according to the EU herbal monographs. Code
Description
Malta Medicines List
Herbal Monograph ATC database
Combined
A05 A13 A15 D03
Bile and liver therapy Tonics Appetite stimulants Preparations for treatment of wounds and ulcers
4 1 1 1
2 6 10 5
6 7 11 6
Table 4 List of indications of herbal substances/preparations contributing to treatment choices. Scientific name
Plant part
English name
Indication as worded in EU Official herbal monograph
Therapeutic area: A15 Achillea millefolium L., flos
Dried inflorescence
Yarrow flower
Achillea millefolium L., herba
Not applicable
Yarrow
Arctium lappa L., radix
Not applicable
Burdock root
Artemisia absinthium L., herba
Not applicable
Wormwood herb
Centaurium Erythraea Rafn, herba
Not applicable
Centaury herb
Cichorium intybus L., radix
Not applicable
Chicory root
Harpagophytum Procumbens DC and/or Harpagophytum Zeyheri Decne, radix Marrubium vulgare L., herba
Cut dried tuberous secondary root Not applicable
Devil’s claw root
Trigonella foenum-graecum L., semen
As defined in the Ph. Eur. monograph
Fenugreek
Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite
Whole dried leaf
Green tea leaf
Not applicable
Cola
Not applicable
Eleutherococcus root
Not applicable
Maté Leaf
Not applicable
Guarana seed
Therapeutic area: A05 Curcuma Longa L., rhizoma
Not applicable
Turmeric root
Fumaria officinalis L., herba
Not applicable
Fumitory
The dried inflorescence
Yarrow flower
Achillea millefolium L., herba
Not applicable
Yarrow
Commiphora molmol Engler, gummi-resina
Not applicable
Myrrh
Echinacea purpurea (L.) Moench, radix
Not applicable
Purple coneflower root
Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
Not applicable
Tea tree oil
Therapeutic area: A13 Camellia sinensis (L.) Kuntze, non fermentatum folium Cola nitida (Vent.) Schott et Endl. and its varieties and Cola acuminata (P. Beauv.) Schott et Endl., semen Eleutherococcus Senticosus (Rupr. Et Maxim.) Maxim., radix Ilex paraguariensis St. Hilaire, folium Paullinia cupana Kunth ex H.B.K. var. sorbilis (Mart.) Ducke, semen
Therapeutic area: D03 Achillea millefolium L., flos
less than 5 unique 5th level ATC codes are authorised are considered by the investigators as areas of limited therapeutic coverage. The results show that 21 therapeutic areas have limited therapeutic choices. A comparison of the therapeutic areas identified from the Malta Medicines List with limited options versus the therapeutic areas from the EU Herbal Monograph ATC database is presented in Table 3a. The results show that for therapeutic areas A05, A13, A15
White horehound
Traditional herbal medicinal product for relief of fatigue and sensation of weakness Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness Traditional herbal medicinal product for symptoms of asthenia such as fatigue and weakness Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness Traditional herbal medicinal product used to increase bile flow for the relief of symptoms of indigestion (such as sensation of fullness, flatulence, and slow digestion) Traditional herbal medicinal product used to increase bile flow for the relief of symptoms of indigestion (such as sensation of fullness, flatulence and slow digestion) Traditional herbal medicinal product for the treatment of small superficial wounds Traditional herbal medicinal product for the treatment of small superficial wounds Traditional herbal medicinal product for treatment of minor wounds and small boils (furuncles) Traditional herbal medicinal product for treatment of small superficial wounds Traditional herbal medicinal product for treatment of small superficial wounds and insect bites
and D03, registration of herbal substances according to EU Herbal Product Monographs would increase the therapeutic coverage such that more than 4, 5th level ATC codes (refer to Table 3b) would be available for use. In our opinion, the EU Herbal Product Monographs would contribute in increasing treatment choices available by at least 19% of therapeutically limited areas in the Maltese Scenario.
B. Micallef et al. / Phytomedicine 22 (2015) 400–405
Discussion The data within the present study supports the notion that EU Herbal Product Monographs could have an impact especially in minor indications where limited therapeutic choices are available due to the limited registration of medicinal products (chemicals or biologicals) in small markets. The data also indicates that herbal products could contribute to therapeutic areas traditionally associated with herbal products such as the alimentary tract and the skin, which is not entirely unexpected. The 4 therapeutic areas identified to potentially have the largest impact are A05, A13, A15 and D03. Analysis of the EU Herbal Monograph ATC database shows that the areas with the absolute highest number of products were A03, R05 and G04 having 33, 31 and 25 herbal substances respectively. Yet, the potential impact on increasing the treatment choices is small due to high number of chemical/biological medicinal products already registered in these areas. Although there are examples of herbal medicinal products used in moderate disease (e.g. Hypericum perforatum L. (St Johns Wart) and motherwort), analysis of the indications complied within the EU Herbal Monograph ATC database shows that the EU community herbal monographs are intended for the treatment of minor ailments. The indications of herbal products which would significantly contribute in increasing treatment choices in therapeutically deficient areas are listed for convenience in Table 4. Once a marketing authorisation is granted,2 the marketing status of the product has to be specified. The marketing status assigned by the member state will determine if that medicinal product will subject to medical prescription or not and will therefore be sold over the counter (OTC). Readers should keep in mind that for a product to be authorised as an OTC, then the criteria qualified in Directive 2001/83/EC (The European Parliament and the Council of the European Union 2001) setting the standards for medicinal products subject to a prescription must not be met. Thus medicinal products shall NOT be subject to medical prescription where they: - are NOT likely to present a danger either directly or indirectly, even when used incorrectly, if utilised without medical supervision, or - are NOT frequently and to a very wide extent used incorrectly, and as a result are likely to present a direct or indirect danger to human health, or - do NOT contain substances or preparations thereof, the activity and/or adverse reactions of which require further investigation, or - are NOT prescribed by a doctor to be administered parenterally. In our opinion, even though EU community herbal monographs are aimed at treating minor ailments, this does not by default extend to the classification of a herbal medicinal product as OTC. When considering such classifications, regulators face the challenge of evaluating the subtle complexities of possible underlying pathophysiological conditions that need to be ruled out at the diagnosis stage, 2 To be placed on the market, in the European Union (EU), a medicinal product needs a marketing authorisation. To obtain a marketing authorisation an application consisting of a dossier supporting the medicinal product’s quality, safety and efficacy needs to be submitted to regulatory authorities. The dossier can either be a full standalone dossier consisting of the results of studies (clinical and preclinical as well as quality) conducted by the prospective marketing authorisation holder usually for an “on patent” medicinal product (originator/innovator medicine) or a dossier consisting of a full package of quality documentation, but a reduced clinical and pre-clinical program which is usually the case for medicines outside their data exclusivity such as generics, well established use medicinal products, hybrid (mixed bibliographic applications) and biosimilar medicinal products and herbal medicinal products.
405
so that a herbal medicinal product is classified as OTC. For example, the monograph Cucurbita pepo L., semen (Pumpkin seed) has an indication of "Traditional herbal product for the relief of lower urinary tract symptoms related to benign prostatic hyperplasia or related to an overactive bladder, after serious conditions have been excluded by a medical doctor". Thus, this product could be classified as OTC as the indication is relatively minor once the diagnosis of benign prostatic hyperplasia has been made by the medical practitioner. Conclusion This study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and confirms the notion that herbal products could potentially increase the treatment options available in areas where few medicinal products have been registered due to Malta’s small market size. A limitation of this study was that we have not studied how the identified herbal medicinal products could be used. However, in Malta’s scenario, it is clinically reasonable to first use all the drugs listed on the Malta Medicines List for a particular therapeutic area before evaluating herbal medicinal products. For the sake of clarity, it should be kept in mind that the results obtained in this study focussing on the number of treatment options for a given area rather than addressing areas of unmet medical need. Conflict of interest The authors declare no direct or indirect potential conflicts of interest. Disclaimer The views expressed in this article are the personal views of the authors and may not be used or quoted as being made on behalf of, or reflecting the position of, any national competent authority, the EMA or one of its committees or working parties or any University. References European Medicines Agency, 2014. Herbal Medicines for Human Use Online Database. Malta Government, 2007. Subsidiary Legislation 458.34, Laws of Malta. Legal Notice 324 of 2007. Medicines (Marketing Authorisation) Regulations, 2007. Government Gazette of Malta 18139. Malta Medicines Authority, 2014. Malta Medicines List. Routledge, P.A., 2008. The European Herbal Medicines Directive: could it have saved the lives of Romeo and Juliet? Drug Saf. 31, 416–418. The European Parliament and the Council of the European Union, 2001. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Off. J. Eur. Commun. 67–128. The European Parliament and the Council of the European Union, 2004a. Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use. Off. J. Eur. Commun. L136, 85–90. The European Parliament and the Council of the European Union, 2004b. Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Off. J. Eur. Commun. L136, 34–57. The European Parliament and the Council of the European Union, 2004c. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. Off. J. Eur. Commun. 1–33. WHO Collaborating Centre for Drug Statistics Methodology, 2014. Norwegian Institute of Public Health “ATC/DDD Index.” Oslo, Norway. http://www.whocc.no/atc_ddd_index/.
Contents lists available at ScienceDirect
Phytomedicine journal homepage: www.elsevier.com/locate/phymed
Could EU herbal monographs contribute to Malta’s treatment armamentarium? B. Micallef a, E. Attard b, A. Serracino-Inglott a,c, J.J. Borg a,d,∗ a
Medicines Authority, 203 Level 3, Rue D’Argens, Gzira, GZR 1368, Malta Institute of Earth Systems, University of Malta, Malta c Department of Pharmacy, Faculty of Medicine and Surgery, University of Malta, Msida, Malta d Department of Biology, School of Pharmacy, University of Tor Vergata, Rome, Italy b
a r t i c l e
i n f o
Article history: Received 24 September 2014 Revised 15 December 2014 Accepted 2 January 2015
Keywords: EU herbal monographs ATC classification system Therapeutic coverage
a b s t r a c t Ten years have passed since Directive 2004/24/EC regulating herbal medicinal products across the EU were published. The directive created the Committee on Herbal Medicinal Products within the European Medicines Agency whose remit includes the creation and publishing of official EU monographs on herbal medicinal products. These monographs include the official uses of the products and their evidence for efficacy and safety. To this effect, we are interested in analysing the potential impact herbal product EU monographs could have on the therapeutic treatment options available for prescribers in Malta. Therefore our aim was two-fold. First, to rationalise the spread of indications of the herbal substances listed in the community herbal monograph inventory and subsequently determine if these herbal substances could potentially contribute to the treatment options available in our local scenario (Malta). 128 EU monographs were analysed resulting in a total of 230 indications which subsequently codified into 42 unique ATC codes. The Malta Medicines List contains 1456 unique ATC codes. Comparative analysis of the Malta Medicines List revealed that the 21 therapeutic areas had 4 or less pharmaceutically used substances (5th level ATC codes) registered and therefore in our opinion are areas with limited therapeutic choice. The following 4 therapeutic areas, A05 bile and liver therapy, A13 tonics, A15 appetite stimulants and D03 preparations for treatment of wounds and ulcers, could potentially benefit from the registration of herbal medicinal products according to the EU herbal monographs. If such registration is effected the aforementioned areas would no longer be considered limited because more than 4 therapeutic choices would be available to prescribers. This study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and confirms the notion that herbal products could potentially increase the treatment options available in areas where few medical products have been registered due to Malta’s small market size. © 2015 Elsevier GmbH. All rights reserved.
Introduction Directive 2004/24/EC (hereafter referred to as the “directive”) has had an effect on the regulatory framework of herbal medicinal products across Europe. The directive sets a framework for the registration of "traditional herbal medicinal products" through a simplified registration procedure for these traditional-use products (The European Parliament and the Council of the European Union 2004a). To be placed on the market, in the European Union (EU), a medicinal product needs a marketing authorisation. To obtain a marketing authorisation an application consisting of a dossier supporting the medicinal product’s quality, safety and efficacy needs to be
∗ Corresponding author at: Medicines Authority, 203 Level 3, Rue D’Argens, Gzira, GZR 1368, Malta. Tel.: +356 23439129; fax: +356 23439161. E-mail address: [email protected] (J.J. Borg).
http://dx.doi.org/10.1016/j.phymed.2015.01.005 0944-7113/© 2015 Elsevier GmbH. All rights reserved.
submitted to regulatory authorities. The dossier can either be a full stand-alone dossier consisting of the results of studies (clinical and preclinical as well as quality) conducted by the prospective marketing authorisation holder usually for an “on patent” medicinal product (originator/innovator medicine) or a dossier consisting of a full package of quality documentation, but a reduced clinical and pre-clinical program which is usually the case for medicines outside their data exclusivity such as generics, well established use medicinal products, hybrid (mixed bibliographic applications) and biosimilar medicinal products and herbal medicinal products. The aim of this EU directive was to enhance the protection of public health whilst promoting the free movement of traditional medicinal products in the EU (Routledge 2008) through harmonised procedures. This directive also established the Committee on Herbal Medicinal Products (HMPC) (The European Parliament and the Council of the European Union 2004a) whose aim is to aid in the harmonisation of procedures and provisions concerning herbal medicinal products in
B. Micallef et al. / Phytomedicine 22 (2015) 400–405
401
Table 1 The structure of the coding system as illustrated by the complete classification of metformin. Code
Description
Level description
A A10 A10B A10BA A10BA02
Alimentary tract and metabolism Drugs used in diabetes Blood glucose lowering drugs, excl. insulins Biguanides Metformin
1st level – Anatomical main group 2nd level – Therapeutic subgroup 3rd level – Pharmacological subgroup 4th level – Chemical subgroup 5th level – Chemical substance
Adapted from WHO Collaborating Centre for Drug Statistics Methodology (2014).
EU Member States whilst further integrating herbal medicinal products in the European regulatory framework. One of the activities of the HPMC is the preparation of Community herbal monographs, which comprise the scientific opinion of the HMPC on the safety and efficacy1 data concerning a herbal substance and its preparations intended for medicinal use, based on the experience of use within the community. EU herbal monographs are intended to be used as reference material in herbal marketing-authorisation applications (both for wellestablished-use and traditional-use applications) (The European Parliament and the Council of the European Union 2004a). The aim of this study was therefore to investigate the potential impact herbal product EU monographs could have on the therapeutic treatment options available for prescribers in Malta. Our objectives were two: (1) to rationalise the spread of indications of the herbal substances listed in the community herbal monograph inventory; (2) to determine if these herbal substances could potentially contribute to the treatment options available in our local scenario (Malta). To our knowledge, this study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and lends support to the notion that herbal products could increase treatment options in areas where few medical products have been registered due to Malta’s small market size. Method Data source and inclusion criteria All the EU monographs published by the HPMC were retrieved from the European Medicines Agency website (European Medicines Agency 2014). The filter function on the website was used to retrieve herbal products for which a monograph was available. The inclusion criteria for a monograph to be used for analysis included those monographs with the following statuses "Draft published", "Assessment close to finalisation (pre-final)" and "Assessment finalised". A total of 128 Community herbal monographs were included in the analysis. The final and draft EU monographs included were published between July 2006 to January 2014 and July 2011 to November 2013 respectively. All EU herbal monographs were analysed and relevant information was compiled using Excel (Microsoft, Redmond, WA). Data extraction and association rationale The following data was captured: The EU Document Reference number of the monograph; the date of HMPC adoption; the scientific name; the common name of herbal substance; the legal basis for registration (Traditional use/Well Established Use) and all listed indications. In addition, information on the herbal preparation and pharmaceutical form was also captured. 1
Although the HPMC review the efficacy of an herbal medicinal product, it must be qualified that the robustness and amount of evidence based data to prove efficacy for a traditional herbal product is less than that for a new compound, which in turn explains why the claims of a traditional herbal product are restricted. The efficacy of a herbal medicinal product and a standard drug should not be treated as equivalent unless the herbal medicinal product has undergone the same clinical development path as a standard drug with randomised Clinical Trials.
The Anatomical Therapeutic Chemical (ATC) classification system was used to classify the captured indications. The ATC system used is a pharmaceutical coding system that divides drugs into different groups according to the organ or system on which they act and their therapeutic and chemical characteristics. Each bottom-level ATC code stands for a pharmaceutically used substance, or a combination of substances, in a single indication or use. It is important to note that using this coding system one drug can have more than one ATC code (WHO Collaborating Centre for Drug Statistics Methodology 2014). For clarity’s sake readers should keep in mind the following principles behind the ATC classification system’s structure. The 1st level is the anatomical area and is denoted by a single letter for example: A for “Alimentary tract and metabolism”. The 2nd level is the therapeutic subgroup area and is denoted by two digits for example: A10 which corresponds to "Drugs used in diabetes". The 3rd level is the pharmacological subgroup and is denoted by a single letter for example A10B which corresponds to "Blood glucose lowering drugs excluding insulins". The 4th level is the chemical subgroup and is denoted by another single letter for example A10BA which corresponds to Biguanides. Finally the 5th level or bottom level corresponds to a chemical substance or combination of substances and is denoted by two digits (WHO Collaborating Centre for Drug Statistics Methodology 2014). The full code therefore consists of 6 characters (refer to Table 1). All indications per herbal product within the EU monograph were then subsequently analysed in order to associate an ATC code. Where the active substance considered had a specific ATC code as was the case for some herbal substance having a "Well-Established Use" for example Senna code A06AB06, Cascara code A06AB07, Valerian code N05CM09, etc. as per ATC/DDD Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014) this association was straightforward. However when there was no specified ATC code, the association between the active substance in question and a relevant ATC code was made based on the wording of the specified indication in the EU monograph. For example we classified the Traditional-Use of Achillea millefolium L., herba (Yarrow) worded as "Traditional herbal medicinal product used in temporary loss of appetite" with an ATC code of A15: Appetite stimulant. We arrived to this classification rationalising both anatomical and therapeutic reasons to associate an ATC code. In this example, Achillea millefolium L., herba is used to treat a “temporary loss of appetite” therefore, this herbal product affects the alimentary system, further to that, its clinical effect is to promote appetite. Therefore the ATC classification A15: Appetite stimulant is a reasoned association. It must be kept in mind that the ATC codes assigned in this manuscript are for reasons of comparison only and not generally transferable. Determining the therapeutic coverage of the community herbal monographs; creation of the “Herbal Monograph ATC database” Once the association exercise was completed, a database of 3rd, 4th and 5th level ATC codes corresponding to each indication was developed. Since a number of herbal substances had similar indications the database contained duplicate entries. Duplicate ATC codes
402
B. Micallef et al. / Phytomedicine 22 (2015) 400–405
Comparision of Anatomical Area Coverage
Total number of unique 2nd level ATC codes
18 16 14
Complete Coverage
12
MaltaMedicines List Frequencies
10
Herbal List Frequencies
8 6 4 2 0 A
B
C
D
G
H
J
L
M
N
P
R
S
V
1st level ATC areas Fig. 1. Comparison of anatomical area coverage. The blue bars represent the maximum number of therapeutic areas divided according to the 14 Anatomical Areas as per the WHO/ATC Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014). The red and green bars represent the number of observations per therapeutic areas for the Malta Medicines List and Herbal Monograph ATC database respectively. Abbreviations used: Alimentary tract and metabolism (A); blood and blood forming organs (B); cardiovascular system (C); dermatologicals (D); genito-urinary system and sex hormones (G); systemic hormonal preparations, excluding sex hormones and insulins (H); antiinfectives for systemic use (J); antineoplastic and immunomodulating agents (L); musculo-skeletal system (M); nervous system (N); respiratory system (R); sensory organs (S); antiparasitic products, insecticides and repellents (P); various (V)]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
were then removed. To assess the therapeutic coverage, 2nd level ATC codes were used. All 2nd level duplicates were removed and a database of unique therapeutic areas was established. Determining the therapeutic coverage in Malta of authorised medicinal products The Malta Medicines List was used (Malta Medicines Authority 2014). The list includes all medicinal products authorised in Malta, through any possible regulatory procedure that is National Procedures [Regulation 4(1) and 4(2) of the Medicines (Marketing Authorisation) Regulations] (Malta Government 2007), European Procedures [Mutual Recognition (MR) and Decentralised (DC) Procedures] (The European Parliament and the Council of the European Union 2004b) and Centralised Procedure (The European Parliament and the Council of the European Union 2004c). The list also provides the ATC codes for each medicinal product. Utilising the 2nd level ATC code the Malta Medicines List was reduced to unique 2nd level ATC codes. Data and statistical analysis The raw data on ATC codes obtained from herbal monographs as well as from Malta Medicines List were imported in Access (Microsoft, Redmond, WA) so that SQL queries (refer to graphical abstract for the SQL coding) and analysis could be run on the dataset. A query was designed to highlight unmatched records comparing the therapeutic subgroup coverage of the Malta Medicines List and the Community herbal monograph inventory to the complete ATC classification list at the second level and also comparing the therapeutic subgroup coverage of the Community herbal monograph inventory with the coverage of the Malta Medicines List. This query clearly showed the spread of products and any therapeutic gaps. Descriptive statistics were calculated using Excel (Microsoft, Redmond, WA).
Results From the 128 EU monographs analysed, a total of 230 indications resulted which were subsequently codified into 230 ATC codes. Following the removal of duplicate ATC codes entries, 42 unique 3rd and 4th level ATC codes (chemical/pharmacological subdivisions) remained. Fig. 1 depicts the number observations of therapeutic areas for the Malta Medicines List and Herbal Monograph ATC database when compared to the maximum possible number of therapeutic areas divided according to the 14 Anatomical Areas as per the ATC/DDD Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014). The frequency of therapeutic areas subdivided according to the 14 Anatomical Areas for Herbal Monograph ATC database are in the following frequency sequence. Alimentary tract and metabolism (A) [9 out of 16 (56%)] > dermatologicals (D) [6 out of 11 (55%)] > genitourinary system and sex hormones (G) [2 out of 4 (50%)] > nervous system (N) [3 out of 7 (43%)] > cardiovascular system (C) [3 out of 9 (33%)] = respiratory system (R) [2 out of 6 (33%)] = musculoskeletal system (M) [2 out of 6 (33%)] = sensory organs (S) [1 out of 3 (33%)] > various (V) [0 out of 9] = anti-infectives for systemic use (J) [0 out of 6] = systemic hormonal preparations, excluding sex hormones and insulins (H) [0 out of 5] = blood and blood forming organs (B) [0 out of 5] = antineoplastic and immunomodulating agents (L) [0 out 4] = antiparasitic products, insecticides and repellents (P) [0 out of 3]. Analysis of the Malta Medicines List revealed that 16747 single units are authorised in Malta (a single unit refers to a unique authorisation number and the data also includes centralised marketing authorisations where an EU number is issued also per pack size), corresponding to 1456 unique ATC codes. The ATC codes of Malta Medicines List covered all 14 Anatomical areas however 2 therapeutic gaps were observed as compared to the ATC/DDD index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014). The therapeutic areas not covered were “A14” corresponding to ”Anabolic
B. Micallef et al. / Phytomedicine 22 (2015) 400–405
403
Table 2 Comparison of analysis of 2nd level ATC codes (therapeutic areas) for the ATC/DDD Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014), the Malta Medicines List and EU Herbal Monograph ATC database. Full list ATC second level codes
MML second level codes
Herbals second level codes
Full list ATC second level codes
MML second level codes
A01 A02 A03 A04 A05 A06 A07 A08 A09 A10 A11 A12 A13 A14 A15 A16 B01 B02 B03 B04 B05 B06 C01 C02 C03
A01 A02 A03 A04 A05 A06 A07 A08 A09 A10 A11 A12 A13
A01
C04 C05 C06 C07 C08 C09 C10 D01 D02 D03 D04 D05 D06 D07 D08 D09 D10 D11 G01 G02 G03 G04 H01 H02 H03
C04 C05 C06 C07 C08 C09 C10 D01 D02 D03 D04 D05 D06 D07 D08 D09 D10 D11 G01 G02 G03 G04 H01 H02 H03
A03 A04 A05 A06 A07 A08
A13
A15 A16 B01 B02 B03 B04 B05 B06 C01 C02 C03
A15
C01 C03
Herbals second level codes
C05
D01 D02 D03 D04
D10 D11 G02 G04
Full list ATC MML second second level codes level codes H04 H05 J01 J02 J03 J04 J05 J06 J07 L01 L02 L03 L04 M01 M02 M03 M04 M05 M09 N01 N02 N03 N04 N05 N06
Herbals second level codes
H04 H05 J01 J02 J03 J04 J05 J06 J07 L01 L02 L03 L04 M01 M02 M03 M04 M05 M09 N01 N02 N03 N04 N05 N06
M01 M02
N02
N05 N06
Full list ATC second level codes
MML second level codes
N07 P01 P02 P03 R01 R02 R03 R04 R05 R06 R07 S01 S02 S03 V01 V02 V03 V04 V05 V06 V07 V08 V09 V10 V20
N07 P01 P02 P03 R01 R02 R03 R04 R05 R06 R07 S01 S02 S03 V01 V02 V03 V04 V05 V06 V07 V08 V09 V10
Herbals second level codes
R02
R05
S01
The first column shows all possible 2nd level ATC codes, derived from the ATC/DDD Index 2014 (WHO Collaborating Centre for Drug Statistics Methodology 2014), and is used a standard reference to compare the therapeutic coverage of the Malta Medicines List and EU Herbal Monograph ATC database respectively. This figure also compares the therapeutic coverage of the EU Herbal Monograph ATC database to that of the Malta Medicines List. Table 3a Comparison of the number of unique chemicals substance authorised (5th level ATC codes ) within a therapeutic area (2nd level ATC division) identified from the Malta Medicines List with the corresponding number of herbs from EU Herbal Monograph ATC database. Code
Description
Malta Medicines List
Herbal Monograph ATC database
Combined
A05 A08 A09 A13 A14 A15 B06 C04 D03 D05 D09 H04 M04 M09
Bile and liver therapy Antiobesity preparations, excluding diet products Digestives, including enzymes Tonics Anabolic agents for systemic use Appetite stimulants Other haematological agents Peripheral vasodilators Preparations for treatment of wounds and ulcers Antipsoriatics Medicated dressings Pancreatic hormones Antigout preparations Other drugs for disorders of the musculo-skeletal system Anthelmintics Ectoparasiticides including scabicides, insecticides and repellents Ophthalmological and otological preparations Allergens General nutrients All other non-therapeutic products Surgical dressings
4 1 1 1 0 1 3 3 1 4 1 1 4 4
2 1 0 6 0 10 0 0 5 0 0 0 0 0
6 2 1 7 0 11 3 3 6 4 1 1 4 4
1 4
0 0
1 4
1 1 1 1 0
0 0 0 0 0
1 1 1 1 0
P02 P03 S03 V01 V06 V07 V20
agents for systemic use” and “V20” corresponding to ”Surgical dressings”. Further analysis of the EU Herbal Monograph ATC database indicates that the two therapeutic gaps identified would not be resolved by registration of herbal medicinal products according to the EU herbal monographs, since there is no coverage for the “A14” and “V20” therapeutic areas within the EU Herbal Monograph ATC database (refer to Table 2).
In order to explore further where therapeutic coverage of authorised medicinal products on the Maltese market is lacking, we analysed the ATC codes within the Malta Medicines List and identified the therapeutic areas (i.e. 2nd level ATC codes) where less than 5 unique 5th level ATC codes (i.e. substances or a combination of substances, in a single indication) were authorised. The results are presented in Tables 3a and 3b. Therapeutic areas where
404
B. Micallef et al. / Phytomedicine 22 (2015) 400–405 Table 3b Highlight of therapeutic areas which could potentially benefit from the registration of herbal medicinal products according to the EU herbal monographs. Code
Description
Malta Medicines List
Herbal Monograph ATC database
Combined
A05 A13 A15 D03
Bile and liver therapy Tonics Appetite stimulants Preparations for treatment of wounds and ulcers
4 1 1 1
2 6 10 5
6 7 11 6
Table 4 List of indications of herbal substances/preparations contributing to treatment choices. Scientific name
Plant part
English name
Indication as worded in EU Official herbal monograph
Therapeutic area: A15 Achillea millefolium L., flos
Dried inflorescence
Yarrow flower
Achillea millefolium L., herba
Not applicable
Yarrow
Arctium lappa L., radix
Not applicable
Burdock root
Artemisia absinthium L., herba
Not applicable
Wormwood herb
Centaurium Erythraea Rafn, herba
Not applicable
Centaury herb
Cichorium intybus L., radix
Not applicable
Chicory root
Harpagophytum Procumbens DC and/or Harpagophytum Zeyheri Decne, radix Marrubium vulgare L., herba
Cut dried tuberous secondary root Not applicable
Devil’s claw root
Trigonella foenum-graecum L., semen
As defined in the Ph. Eur. monograph
Fenugreek
Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite Traditional herbal medicinal product used for temporary loss of appetite
Whole dried leaf
Green tea leaf
Not applicable
Cola
Not applicable
Eleutherococcus root
Not applicable
Maté Leaf
Not applicable
Guarana seed
Therapeutic area: A05 Curcuma Longa L., rhizoma
Not applicable
Turmeric root
Fumaria officinalis L., herba
Not applicable
Fumitory
The dried inflorescence
Yarrow flower
Achillea millefolium L., herba
Not applicable
Yarrow
Commiphora molmol Engler, gummi-resina
Not applicable
Myrrh
Echinacea purpurea (L.) Moench, radix
Not applicable
Purple coneflower root
Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
Not applicable
Tea tree oil
Therapeutic area: A13 Camellia sinensis (L.) Kuntze, non fermentatum folium Cola nitida (Vent.) Schott et Endl. and its varieties and Cola acuminata (P. Beauv.) Schott et Endl., semen Eleutherococcus Senticosus (Rupr. Et Maxim.) Maxim., radix Ilex paraguariensis St. Hilaire, folium Paullinia cupana Kunth ex H.B.K. var. sorbilis (Mart.) Ducke, semen
Therapeutic area: D03 Achillea millefolium L., flos
less than 5 unique 5th level ATC codes are authorised are considered by the investigators as areas of limited therapeutic coverage. The results show that 21 therapeutic areas have limited therapeutic choices. A comparison of the therapeutic areas identified from the Malta Medicines List with limited options versus the therapeutic areas from the EU Herbal Monograph ATC database is presented in Table 3a. The results show that for therapeutic areas A05, A13, A15
White horehound
Traditional herbal medicinal product for relief of fatigue and sensation of weakness Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness Traditional herbal medicinal product for symptoms of asthenia such as fatigue and weakness Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness Traditional herbal medicinal product for symptoms of fatigue and sensation of weakness Traditional herbal medicinal product used to increase bile flow for the relief of symptoms of indigestion (such as sensation of fullness, flatulence, and slow digestion) Traditional herbal medicinal product used to increase bile flow for the relief of symptoms of indigestion (such as sensation of fullness, flatulence and slow digestion) Traditional herbal medicinal product for the treatment of small superficial wounds Traditional herbal medicinal product for the treatment of small superficial wounds Traditional herbal medicinal product for treatment of minor wounds and small boils (furuncles) Traditional herbal medicinal product for treatment of small superficial wounds Traditional herbal medicinal product for treatment of small superficial wounds and insect bites
and D03, registration of herbal substances according to EU Herbal Product Monographs would increase the therapeutic coverage such that more than 4, 5th level ATC codes (refer to Table 3b) would be available for use. In our opinion, the EU Herbal Product Monographs would contribute in increasing treatment choices available by at least 19% of therapeutically limited areas in the Maltese Scenario.
B. Micallef et al. / Phytomedicine 22 (2015) 400–405
Discussion The data within the present study supports the notion that EU Herbal Product Monographs could have an impact especially in minor indications where limited therapeutic choices are available due to the limited registration of medicinal products (chemicals or biologicals) in small markets. The data also indicates that herbal products could contribute to therapeutic areas traditionally associated with herbal products such as the alimentary tract and the skin, which is not entirely unexpected. The 4 therapeutic areas identified to potentially have the largest impact are A05, A13, A15 and D03. Analysis of the EU Herbal Monograph ATC database shows that the areas with the absolute highest number of products were A03, R05 and G04 having 33, 31 and 25 herbal substances respectively. Yet, the potential impact on increasing the treatment choices is small due to high number of chemical/biological medicinal products already registered in these areas. Although there are examples of herbal medicinal products used in moderate disease (e.g. Hypericum perforatum L. (St Johns Wart) and motherwort), analysis of the indications complied within the EU Herbal Monograph ATC database shows that the EU community herbal monographs are intended for the treatment of minor ailments. The indications of herbal products which would significantly contribute in increasing treatment choices in therapeutically deficient areas are listed for convenience in Table 4. Once a marketing authorisation is granted,2 the marketing status of the product has to be specified. The marketing status assigned by the member state will determine if that medicinal product will subject to medical prescription or not and will therefore be sold over the counter (OTC). Readers should keep in mind that for a product to be authorised as an OTC, then the criteria qualified in Directive 2001/83/EC (The European Parliament and the Council of the European Union 2001) setting the standards for medicinal products subject to a prescription must not be met. Thus medicinal products shall NOT be subject to medical prescription where they: - are NOT likely to present a danger either directly or indirectly, even when used incorrectly, if utilised without medical supervision, or - are NOT frequently and to a very wide extent used incorrectly, and as a result are likely to present a direct or indirect danger to human health, or - do NOT contain substances or preparations thereof, the activity and/or adverse reactions of which require further investigation, or - are NOT prescribed by a doctor to be administered parenterally. In our opinion, even though EU community herbal monographs are aimed at treating minor ailments, this does not by default extend to the classification of a herbal medicinal product as OTC. When considering such classifications, regulators face the challenge of evaluating the subtle complexities of possible underlying pathophysiological conditions that need to be ruled out at the diagnosis stage, 2 To be placed on the market, in the European Union (EU), a medicinal product needs a marketing authorisation. To obtain a marketing authorisation an application consisting of a dossier supporting the medicinal product’s quality, safety and efficacy needs to be submitted to regulatory authorities. The dossier can either be a full standalone dossier consisting of the results of studies (clinical and preclinical as well as quality) conducted by the prospective marketing authorisation holder usually for an “on patent” medicinal product (originator/innovator medicine) or a dossier consisting of a full package of quality documentation, but a reduced clinical and pre-clinical program which is usually the case for medicines outside their data exclusivity such as generics, well established use medicinal products, hybrid (mixed bibliographic applications) and biosimilar medicinal products and herbal medicinal products.
405
so that a herbal medicinal product is classified as OTC. For example, the monograph Cucurbita pepo L., semen (Pumpkin seed) has an indication of "Traditional herbal product for the relief of lower urinary tract symptoms related to benign prostatic hyperplasia or related to an overactive bladder, after serious conditions have been excluded by a medical doctor". Thus, this product could be classified as OTC as the indication is relatively minor once the diagnosis of benign prostatic hyperplasia has been made by the medical practitioner. Conclusion This study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and confirms the notion that herbal products could potentially increase the treatment options available in areas where few medicinal products have been registered due to Malta’s small market size. A limitation of this study was that we have not studied how the identified herbal medicinal products could be used. However, in Malta’s scenario, it is clinically reasonable to first use all the drugs listed on the Malta Medicines List for a particular therapeutic area before evaluating herbal medicinal products. For the sake of clarity, it should be kept in mind that the results obtained in this study focussing on the number of treatment options for a given area rather than addressing areas of unmet medical need. Conflict of interest The authors declare no direct or indirect potential conflicts of interest. Disclaimer The views expressed in this article are the personal views of the authors and may not be used or quoted as being made on behalf of, or reflecting the position of, any national competent authority, the EMA or one of its committees or working parties or any University. References European Medicines Agency, 2014. Herbal Medicines for Human Use Online Database. Malta Government, 2007. Subsidiary Legislation 458.34, Laws of Malta. Legal Notice 324 of 2007. Medicines (Marketing Authorisation) Regulations, 2007. Government Gazette of Malta 18139. Malta Medicines Authority, 2014. Malta Medicines List. Routledge, P.A., 2008. The European Herbal Medicines Directive: could it have saved the lives of Romeo and Juliet? Drug Saf. 31, 416–418. The European Parliament and the Council of the European Union, 2001. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Off. J. Eur. Commun. 67–128. The European Parliament and the Council of the European Union, 2004a. Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use. Off. J. Eur. Commun. L136, 85–90. The European Parliament and the Council of the European Union, 2004b. Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Off. J. Eur. Commun. L136, 34–57. The European Parliament and the Council of the European Union, 2004c. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. Off. J. Eur. Commun. 1–33. WHO Collaborating Centre for Drug Statistics Methodology, 2014. Norwegian Institute of Public Health “ATC/DDD Index.” Oslo, Norway. http://www.whocc.no/atc_ddd_index/.
