REGULATORY ISSUES FOR THE REGISTRATION PROCESS OF HERBAL PHARMACEUTICAL PRODUCTS IN EUROPE

1. Dr. F. Qadan, PhD-Germany University of Petra-Amman REGULATORY ISSUES FOR THE REGISTRATION PROCESS OF HERBAL PHARMACEUTICAL PRODUCTS IN EUROPE

2. Legal Provisions Relating to Efficacy and Safety of Herbal Medicinal Products 1- Evidence of efficacy and safety required for herbal medicinal products, including the well established medicinal uses . 2- Attempts to harmonize the assessment criteria. 3- Special requirements for fixed combinations. 4- Marketing authorization of “traditionally used” herbal medicinal products: the national ways and future European options.

3. Evidence of Efficacy and Safety Required for Herbal Medicinal Products • For herbal medicinal products which are further developed from a documented traditional use, e.g. products containing highly processed extracts and/or products with “ high level” or “modern” indications, a “full” license is required. • Proper pharmacological and toxicological examinations are requested. Furthermore, efficacy and safety have to be proven by clinical studies.

4. In general, the toxicological and pharmacological tests must show: a.The potential toxicity of the product, in addition to any dangerous or undesirable toxic effects that may occur under the proposed conditions of use in human beings. These should be evaluated in relation to the pathological conditions concerned. b. The pharmacological properties of the products, both qualitative and quantitative, in relationship to the proposed use in human beings.

5. Part 3. Toxicological and Pharmacological Tests - Toxicity (single dose toxicity and repeated dose toxicity)- Reproductive toxicity (Embryo/foetal and perinatal toxicity) - Mutagenic potential, Carcinogenic potential - Pharmacodynamics - Pharmakakinetiks - Local tolerance

6. Part 4. Clinical Documentation • Conduct of trials • Presentation of results • Clinical pharmacology • Bioavailability/bioequivalence • Clinical safety and safety • Documentation for applications in exceptional circumstances • Post marketing-experience

7. Examples on the Utilization of Bibliographic Data in Member States of the EU Germany • According to Section 5 of the Guidelines for Medicines Testing “Arzneimittel-Pruefrichtlinien”, bibliographic data may be used as a reference for well-known substances. • Acceptable data include pharmacological, toxicological and clinical studies, observational field reports and scientifically documented medicinal experience.

8. Germany • Between 1978 and 1994, monographs specific expert commission, on the basis of Section 25 paragraph 7 of the German Medicines Law, was established to be the responsible body for herbal medicinal products, the so-called Commission E. This commission evaluated more than 300 medicinal plants. The results (monographs) have been published in the federal Gazette “bundesanzeiger”.

9. Germany • However, by the 5th amendment of the Medicines Law in August 1994, the work of all review commissions, including Commission E, regarding the evaluation of bibliographic data and the preparation of monographs was finished. • Although no further monographs can be published due to the absence of a legal basis, the existing texts remain valid unless they are superseded by new scientific knowledge resulting e.g. from clinical studies.

10. Germany • For products with well-established medicinal use, a complete quality dossier has to be submitted (like in every case), as all the expert reports and detailed documentation on efficacy and safety. The latter is due to the 10th amendment of the Medicines law in July 2000.

11. Finland Applications using the option of bibliographic applications are accepted as almost the only way to prove or support the safety and efficacy of herbal medicinal products, the following requirements have to be fulfilled: 1- Compliance with the definition of herbal medicinal products as laid down in the Medicines law

12. Finland 2- Quality and manufacturing in accordance with the requirements for normal medicinal products, taking into account the special characteristics of herbal medicinal products 3- Safety and efficacy in accordance with bibliographic data 4- Experts’ reports 5- Labeling with the term “ herbal medicinal products”

13. European Guidelines on Efficacy and Safety Further clarification on a European level has been achieved by two draft notes for guidance prepared by the HMPWP: 1-Draft points to consider on the evidence of safety and efficacy required for well-established herbal medicinal products in bibliographic applications. 2-Proposal for new guidance “non-clinical testing of herbal drug preparations with long term marketing experience-Guidance to facilitate mutual reorganization and use of bibliographic data”.

14. Evidence of Safety and Efficacy • As a general principle, this draft guideline provides that in case of well-established herbal medicinal products, the requirements for the proof of efficacy and the documentation required to support the claims should depend on the nature and the level of indications. • Bibliographic documents that may be taken into consideration may comprise controlled clinical trials, other clinical trials, case controlled studies, other collections of single cases allowing a scientific evaluation, scientific literature and expertise from scientific associations.

15. The current level of evidence can be identified by a review of the respective literature. In accordance with recommendations of the US Agency for Health Care Policy and Research (AHCPR) and the World Health Organization (WHO), different levels and types of evidence are proposed in the document.

16. Note for Guidance on Non-Clinical Testing • This draft note for guidance refers to the general principle that all aspects of safety must be covered by appropriate bibliographic data and the respective expert report. • However, certain tests do not have to be carried out if sufficient experience is available in humans. • New tests on single and repeated dose toxicity and local tolerance are not required if there is sufficient experience available in humans.

17. Note for Guidance on Non-Clinical Testing Tests on reproductive toxicity are not necessary if one of the following criteria is fulfilled: a. Results from epidemiological or post-marketing safety studies are available b. Results from investigations in pregnant women and neonates exist c. The product is not intended to be used in women during child-bearing age or during pregnancy and lactation.

18. Attempts to Harmonize the Assessment Criteria In order to provide scientifically based assistance for a harmonized assessment of herbal medicinal products, ESCOP, the European Scientific Cooperative on Phytotherapy, was founded in 1989 by six national scientific associations, and during further associations have joined ESCOP.

19. The main objectives for this European scientific umbrella organization are: 1- To establish harmonized criteria for the assessment of herbal medicinal products 2- To give support to scientific research 3- To contribute to the acceptance of Phytotherapy on a European level.

20. ESCOP • In October 1990, the first five monographs were presented at a symposium in Brussels and were officially handed over to representatives of the European Community. • Since the end of 1992, the ESCOP Scientific Committee has been working on monographs, structured like SOCs (Summary of Product Characteristic), for individual plant drugs, primarily those for which European or national pharmacopoeial monographs exist.

21. ESCOP • An ESCOP monograph describing a medicinal plant and its preparations refers to a Pharmacopeia monograph with respect to quality, and the most important constituents, which are possibly able to contribute to the claimed effect, are listed. • The most relevant parts of the monographs (as for an SPC) are: the therapeutic indications, the dosage and the pharmacological properties. The latter paragraph gives details as possible on phramcodynamic properties, pharmacokinetic properties and preclinical safety data, each statement supported by references.

22. ESCOP • In the detailed reference list, all literature data and scientific papers are listed which support the statement given in the monograph. • Each ESCOP monograph takes into account the available scientific literature as well as national viewpoints and the advice of many authorities on the subject. • ESCOP monographs present an overview of the current scientific data on a medicinal plant, but they cannot replace either an expert report or a documentation. They can be used as a “harmonized” scientific background for an application. • Sixty monographs have been published between 1996 and 1999.

23. Members of the ESCOP Oestereichische Gesellschaft fuer Phytortherapie Austria Société Belge de Phytothérapi Belgium Dansk Selskab for Fytoterapi Denmark Gesellschaft fuer Phytotherapie Germany Irish Phytotherapy Association Ireland British Herbal Medicine Association United Kingdom Schweizerische Medizinische Gesellschaft fuer Phytotherapie Switzerland Norweigian Society for Phytotherapy Norway Nederlandse Vereniging voor Fytotherapie Netherlands Società Italiana di Fitochimica Italy Svenska Sällskapet för Fytoterapie Sweden Association Francaise pour le Médicament de Phytothérapie France Turkish Society of Phytoterapy Turkey

24. Special Requirements for Fixed Combinations • On a European level, guidance on combinations of active ingredients is provided in the “Guideline on fixed combination products” issued by the Committee for Proprietary Medicinal Products (CPMP). • As a general principle, applicants are required to justify the particular combination of active substances which is proposed. The presence of each active substance should make a contribution to the claimed effect, and the potential advantages and disadvantages of the combination have to be assessed.

25. Special Requirements for Fixed Combinations • Moreover, the EMEA Herbal Medicinal Products Working Party finished a proposal for new guidance on “fixed combinations of herbal medicinal products with long term marketing experience” in 1998. The principles are the same as outlined in the above-mentioned general guideline. Taking into consideration the specific characteristics of herbal medicinal products, the quantitative composition of “usually combined substances” can be adjusted to current scientific knowledge. The combination itself is still classified as well-known, thus, clinical data do not need to be presented.

26. 4- Marketing authorization of “traditionally used” herbal medicinal products: the national ways and future European options 4-1 Austria: • According to Section 17a of the Austrian Medicines Law, neither efficacy nor safety need be demonstrated in detail for a simplified registration procedure. • Respective documents do not need to be submitted if the active ingredient(s) is/are included in a specific list published in 1989 and amended in 1992. • If quality complies with the specification needs to be submitted, e.g. Flores Arnicae ÖAB (Austrian Pharmacopeia), no individual specification needs to be submitted. • The list includes approximately five hundred substances, medicinal plants, part of plants, essential oils etc., for which a simplified registration procedure can be used, e.g. Arnicae flos, Crataegi folium cum flore, Urticae herba, Gentainae radix or Valerianae radix.

27. 4-2 France • The French health authority (Agence du Médicament) grants marketing authorization based on abridged dossiers by marketing reference to traditional use. The shortened procedure requires limited or no pharmacological, toxicological and clinical tests in detailed in the Agency Instruction No. 3 • The traditional use has been recognized for minor indications of approximately 200 herbal drugs as well as most of the preparations derived from these drugs. • Except for plant-based laxatives, indications are introduced by the statement “Traditionally used in………………” • This guideline includes a description of the required contents of the dossiers and medicinal products (with special recommendations for laxatives). • The need for toxicological evaluation (category 1 and 2) depends on its traditional use, pharmaceutical form and the presence of undesirable constituents in the drug: a. Category 1: No study is required for most of herbal drugs and herbal drug preparations, in particular for herbal teas and laxative herbal drugs. b. Category 2: A reduced toxicological study may be required for some herbal drug preparations, in particular powdered drugs.

28. The guideline also contains specific requirements for combinations: the number of therapeutic indications allowed for a herbal medicinal product usually been limited to two: they are chosen by the applicant from the list of indications are desired, they should belongs to the same therapeutic category.

29. 5-3 Germany • The 5th Amendment of the German Medicines Law provided a new procedure for old products with respect to proof of quality and efficacy. • Section 109a simplifies the requirements for products already on the market since 1978. The regulations are not specific to herbal medicinal products. A traditional use instead of proof of efficacy is accepted for these products, which are mostly sold outside pharmacies. All of these products must be labeled as “traditionally used” and have a mild indication claim (e.g. for supporting various functions or as a tonic).

30. In accordance with Section 109a of the Medicines Law, the BfArM has complies lists for old products stating which preparations are allowed to refer to this regulations and traditional uses can be claimed. Approximately 1000 positions consisting of substances or their combinations and indications have been covered. By the end of January 2001, the applicant had to decide weather his product should go through this traditional procedure or not. If this option was chosen, the applicant had to refer to a position on the list and did not need to submit proof on efficacy and safety.

31. Examples on the “Traditional List” According to Section 109a of the German Law

32. Examples on Some Plants and Their Indications According to Annex II of the Spanish Draft Royal Decree