The European Union CD 1999/83/EEC on well-established use - application to herbal medicinal products - Dr. Konstantin Keller Chair of the Herbal Medicinal Products Working Group European Medicines Evaluation Agency, London European Council Directive 65/65 EEC of 26 January 1965 Article 4 No. 8 a) ii The applicant shall not be required to provide the results of... trials if he can demonstrate: (ii)... by detailed reference to published scientific literature... that the constituent or constituents of the proprietary medicinal product have a well established medicinal use, with recognised efficacy and an acceptable level of safety.
Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 1999/83/EC of 8 September 1999 amending the Annex to Council Directive 75/318/EEC on the approximation of the laws of the Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of medicinal products Official Journal of the European Communities 15.9.1999 L 243/9 Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 1999/83/EC of 8 September 1999... (6) Whereas it is in particular necessary to clarify that bibliographic reference to other sources of evidence (postmarketing studies, epidemiological studies, studies conducted with similar products, etc.) and not just tests and trials may serve as a valid proof of safety and efficacy of a product if an applicant explains and justifies the use of these sources of information satisfactorily...
Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 1999/83/EC of 8 September 1999 New Section I in Part 3 and 4 of the Annex to Directive 75/318/EEC I. Well-established medicinal use For the purpose of demonstrating, pursuant to Article 4(8)(a)(ii) of Directive 65/65/EEC, that the constituent(s) of a medicinal product have a well established use, with an acceptable level of safety, the following specific rules shall apply:... Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 1999/83/EC of 8 September 1999 (a) Factors which have to be taken into account the time over which a substance has been used quantitative aspects of the use of the substance the degree of scientific interest in the use of the substance (reflected in the published scientific literature) the coherence of scientific assessments different periods of time may be necessary for establishing well established use of different substances minimum of one decade from the first systematic and documented use of that substance as a medicinal product in the EU.
Herbal Medicinal Products in the EU Results COMMISSION DIRECTIVE 1999/83/EC (b) The documentation submitted should cover all aspects of the safety and efficacy assessment and must include or refer to a review of the relevant literature, taking into account pre-and postmarketing studies and published scientific literature concerning experience in the form of epidemiological studies and in particular of comparative epidemiological studies. All documentation, both favourable and unfavourable, should be communicated Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 1999/83/EC (c) Particular attention must be paid to any missing information and justification must be given why demonstration of an acceptable level of safety/efficacy can be supported although some studies are lacking.
Interpretation of Art. 4(8)a ii of CD 65/65 EEC 49th Meeting of the Pharmaceutical Committee, March 2000 Bibliographic dossiers must always be full dossiers. Whenever information on specific points is missing, justification must be given why demonstration of an acceptable level of safety and efficacy can be supported although some studies are lacking. Well-established use always refers to the use of a specific substance for a specific therapeutic use. If well-known substances are used for entirely new therapeutic indications, it is not possible to refer to well-established use. Interpretation of Art. 4(8)a ii of CD 65/65 EEC 49th Meeting of the Pharmaceutical Committee, March 2000 Interpretative Guidance on the application of Directive 99/83 will be given both by the Commission (through the updated NTA) and the CPMP (through Guidance documents on the safety and efficacy of old substances)
Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 1999/83/EC (d) The Expert report must explain the relevance of any data submitted which concern a product different from the product intended for marketing. A judgement must be made whether the product studied can be considered as similar to the product which will be granted a marketing authorisation in spite of the existing differences. Points to consider on the evidence of safety and efficacy required for well-established herbal medicinal products in bibliographic applications 3. Well-established use Can published literature on one herbal medicinal product be used in the assessment of another herbal medicinal product? Complex biological mixtures produced by different manufacturers are never identical. Sufficiently identical, if the specification is the same and no relevant differences in the manufacturing process exists. Particularly important in highly purified extracts or a new method of preparation of an extract
Points to consider on the evidence of safety and efficacy required for well-established herbal medicinal products in bibliographic applications 3. Well-established use In the case of classical herbal drug preparations such as tinctures and extracts described in pharmacopoeias and used for long time, a comprehensive specification will not be available from published literature in most cases. For these preparations the starting material and the extraction solvent must be identical. If there are reasons to expect a different pharmacological or toxicological profile, additional data and an update of the specification and/or appropriate data on bioavailability may be necessary. Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 1999/83/EC (e) Post-marketing experience with other products containing the same constituents is of particular importance and applicants should put a special emphasis on this issue.
Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 75/318/EEC Part 3: Toxicological and pharmacological Tests I. Introduction The toxicological and pharmacological tests must show: a) the potential toxicity... and any dangerous or undesirable toxic effects that may occur under the proposed conditions of use in human beings;... b) the pharmacological properties of the product, in both qualitative and quantitative relationship to the proposed use NON-CLINICAL TESTING OF HERBAL DRUG PREPARATIONS WITH LONG-TERM MARKETING EXPERIENCE Guidance to facilitate mutual recognition and use of bibliographic data September 1998 Effects that are difficult, even impossible to detect clinically - Toxicity to Reproduction - Genotoxicity - Carcinogenicity Expert-Report points out the necessity or not of new studies
NON-CLINICAL TESTING It is appropriate to assess genotoxicity initially in a bacterial reverse mutation test using a test battery of different bacterial strains and metabolic activation (s. CPMP/ICH and OECD Guidelines). This test has been shown to detect relevant genetic changes and the majority of genotoxic rodent carcinogens. If positive results can not be clearly attributed to specific constituents with a well-established safety-profile (e.g. Quercetin) additional in vitro and, if necessary, in vivo studies should be performed. A co-operative approach is encouraged to investigate herbal drug preparations with the same specification. NON-CLINICAL TESTING Tests not required, if sufficient experience in humans is available: single dose toxicity, repeated dose toxicity, immunotoxicity local tolerance testing pharmacological tests including safety pharmacology, pharmacokinetic studies. The expert report must address these aspects and give the grounds why the documented medical experience justifies a safe use of the herbal drug preparation.
Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 75/318/EEC Part 4: Clinical Documentation Evaluation of the application for marketing authorisation shall be based on clinical trials including clinical pharmacological trials designed to determine the efficacy and safety of the product under normal conditions of use, having regard to the therapeutic indications for use in human beings. Therapeutic advantages must outweight potential risks. Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 75/318/EEC Part 4: Clinical documentation A. General Requirements The clinical particulars to be provided pursuant to point 8 of Article 4(2) of Directive 65/65/EEC must enable a sufficiently well-founded and scientifically valid opinion to be formed as to whether the medicinal product satisfies the criteria governing the granting of a marketing authorisation.... an essential requirement is that the results of all clinical trials should be communicated, both favourable and unfavourable.
Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 75/318/EEC Part 4: Clinical documentation F. Clinical Efficacy and Safety 1. In general, clinical trials shall be done as controlled clinical trials and if possible, randomised; any other design shall be justified.... As far as possible, and particularly in trials where the effect of the product cannot be objectively measured, steps shall be taken to avoid bias... Herbal Medicinal Products in the EU COMMISSION DIRECTIVE 75/318/EEC Part 4: Clinical documentation F. Clinical Efficacy and Safety 8. A critical assessment of relative safety, taking into account adverse reactions, shall be made in relation to: the disease to be treated, other therapeutic approaches, particular characteristics in sub-groups of patients, pre-clinical data on toxicology and pharmacology.
Points to consider on the evidence of safety and efficacy required for well-established herbal medicinal products in bibliographic applications 4. Recognised efficacy The requirements for... the documentation required to support the indicated claims should depend on the nature and the level of the indication(s). For treatment of minor disorders a lower level of evidence may be adequate, especially when the extent of long-term use, the experience with that particular herbal medicinal product and supportive pharmacological data are taken into account. The level of evidence and the grading of recommendations must correspond to the nature of the disease that is to be treated. The therapeutic alternatives available, the risks of a delayed or insufficient treatment and the risks of the herbal drug preparation have to be taken into account. Grading of Recommendations Grade A: Evidence Ia, Ib Requires at least one randomised controlled trial as part of the body of literature of overall good and consistency addressing the specific recommendation. Grade B: Evidence IIa, IIb, III Requires availability of well-conducted clinical studies but no randomised clinical trials on the topic of recommendation Grade C: Evidence IV Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates absence of directly applicable studies of good quality
a lity o f I Truth Quality of Information Gossip Lies Grading of Recommendations A B C X expert committee reports opinions and/or clinical experience of respected authorities; minimum: documented long term use and supportive experimental data No or negative expert committee reports, no or negative opinions / clinical experience of respected authorities; documented or notdocumented long or short term use without supportive experimental data Truth Qu nformatio n Grading of Recommendations A B well-conducted clinical studies but no randomised clinical trials expert committee reports opinions and / or clinical C experience of respected authorities; documented long term use and supportive Gossip experimental data,... Lies X Stories and tales... Spectacular new uses Fraud solely based on experimental data,
Qual Truth ity of Information Gossip Lies Fraud Grading of Recommendations A B C X At least one well-conducted RCT well-conducted clinical studies but no randomised clinical trials expert committee reports opinions or clinical experience of respected authorities; documented long term use and supportive experimental data,... Stories and tales... Spectacular new uses solely based on experimental data core-spc for Isphagula Husk (January 1999 - final draft march 2000) Submission to CPMP March 2000 4.1. THERAPEUTIC INDICATIONS Herbal medicinal product for a) the treatment of habitual constipation; conditions in which easy defecation with soft stools is desirable, e.g. in cases of painful defecation after rectal or anal surgery; (II-III) b) adjuvant symptomatic therapy in cases of diarrhoea from various causes; (III-IV, Decision by Majority) c) conditions which need an increased fibre intake, e.g. irritable bowel syndrome. (IIb-III; Decision by Majority)
Notice to Applicants Chapter I Marketing Authorisations, Section 4 Stand Alone Applications for a Marketing Authorisation... Scientific monographs... (e.g. those drafted by the European Scientific Co-operative on Phytotherapy (ESCOP) and the World Health Organisation (WHO) for herbal drugs) offer a valuable and updated overview on published scientific literature, which together may be used in support of the demonstration of the safety and efficacy of a medicinal product in a bibliographical application in... These monographs may help to avoid duplication of work and bring about gradual harmonisation in the evaluation of medicinal products, e.g. herbal medicinal products. Therefore the Commission and Member States recommend that both applicants and competent authorities should make use of these monographs... The Role of core-spcs 49th Meeting of the Pharmaceutical Committee, March 2000 The so-called core-spcs (e.g. those elaborated by the Herbal Working Group of the EMEA) are legally not binding. The value of these core-spcs is based on their persuasive power, underpinned by the fact that technical experts of all EU competent authorities have considered and agreed upon them.
The Role of core-spcs Joint Meeting of the Human and Veterinary Pharmaceutical Committees, November 2000 The intention to progressively harmonise generic medicinal products by agreeing upon core-spcs was in general supported by the Member States. Draft core-spc for Hop Strobile (draft march 2000) Submission to CPMP March 2000 4.1. THERAPEUTIC INDICATIONS None accepted on the basis of bibliographic data provided by the ESCOP monograph. (Decision by Majority)
Traditional Evidence X1 documented long term use without supportive experimental data / plausibility Quality of Information Fraud - Lies - Gossip X X2 negative expert committee reports, negative opinions / clinical experience of respected authorities; short term/new use; extrapolation of experimental data Perspectives Herbal medicinal Products are a reality in the European market Public Health concerns related to uncontrolled herbal medicinal products and starting material are a reality in the European market Lack of Interest in the Industry? Mutual recognition of herbal medicinal products not feasible?
Herbal medicinal products with successful MR TM Year RMS CS Mucivital flavoured 1996 DE AU; BE; GR; I; (Isphagula husk) PORT; UK Nozoil 1997 SE FI (Sesame oil nasal spray) Minolest 1997 DE AU; BE; LUX; SE (Isphagula husk, Guar gum) Valerian Caps. 1998 UK AU; GR; I; PORT (Valerian root) Gammaderm 1999 UK DE; IR (Evening primrose oil cream) Capsicum Pain Plaster (Capsicum extract) 2000 DE AU; DK; F; FI; LUX; NOR; SE; UK Herbal medicinal products with successful MR 6 applications for Mutual Recognition replacing 31 national applications
Phase of consolidation Perspectives European legislation / Update of procedures improvement of the current MR procedure responsibilities of scientific bodies / centers of excellence Implementation of expertise Implementation of scientific standards Exchange of information and transparency of criteria Constant update of standards in the light of experiences gathered by competent authorities and applicants harmonization of the EU market by core-spcs