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1、AFRICA HERBAL ANTIMALARIAL MEETING ORGANISED BY THE WORLD AGROFORESTRY CENTRE (ICRAF) AND THE ASSOCIATION FOR THE PROMOTION OF TRADITIONAL MEDICINE (PROMETRA),MARCH, 20th TO 22nd 2006 ICRAF HOUSE NAIROBI, KENYA,NEW EUROPEAN LEGISLATION FOR HERBAL MEDICINAL PRODUCTS (HMPs) - NEW OPPORTUNITIES FOR AFR
2、ICAN PHARMACEUTICAL INDUSTRIES?, CHAIRMAN OF THE GROUP OF EXPERTS 13A OF THE EUROPEAN PHARMACOPOEIA (EP) MEMBER OF THE COMMITTEE ON HERBAL MEDICINAL PRODUCTS (HMPC) OF THE EUROPEAN MEDICINES AGENCY (EMEA),CONTENTS 1. INTRODUCTION 2. LEGAL FRAMEWORK FOR HMPs IN THE EU 2.1. MARKETING AUTHORISATION (MA
3、) PROCEDURES 2.2. MA OF WELL-ESTABLISHED HMPs 2.3. REGISTRATION OF TRADITIONAL HMPs 3. EUROPEAN PHARMACOPOEIA MONOGRAPHS OF HERBAL DRUGS AND HERBAL PREPARATIONS 4. NOTE FOR GUIDANCE ON SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA 5. MA OR REGISTRATION OF ANTIMALARIALS FROM ARTEMISIA ANNUA
4、 6. CONCLUSION,LEGAL STATUS OF HERBAL PRODUCTS WORLDWIDE,DIETARY SUPPLEMENTS,NUTRACEUTICALS,HERBAL PRODUCTS,FUNCTIONAL FOODS,HERBAL MEDICINAL PRODUCTS,DESIGNER FOODS,FITNESS FOODS,FOODACEUTICALS,LONGEVITY FOODS,MEDICINAL FOODS,NUTRITIONAL FOODS,.,THERAPEUTIC FOODS,HERBAL MEDICINAL PRODUCTS PRESCRIBE
5、D BY MEDICAL DOCTORS PRESCRIPTION SHARES BY COUNTRY IN %,CURRENT LEGAL FRAMEWORK FOR HMPs IN THE EU,DIRECTIVE 2001/83/EC, AS AMENDED (12.06.2003), ART. 1 : DEFINITION OF MEDICINAL PRODUCTS (a) ANY SUBSTANCE OR COMBINATION OF SUBSTANCES PRESENTED AS HAVING PROPERTIES FOR TREATING OR PREVENTING DISEAS
6、E IN HUMAN BEINGS (b) ANY SUBSTANCE OR COMBINATION OF SUBSTANCES WHICH MAY BE USED IN OR ADMINISTERED TO HUMAN BEINGS WITH A VIEW TO MAKING A MEDICAL DIAGNOSIS OR TO RESTORING, CORRECTING OR MODIFYING PHYSIOLOGICAL FUNCTIONS BY EXERTING A PHARMACOLOGICAL, IMMUNOLOGICAL OR METABOLIC ACTION, WHEREBY “
7、SUBSTANCE . ANY MATTER E.G. VEGETABLE: PLANTS, PARTS OF PLANTS, VEGETABLE SECRETIONS, EXTRACTS ” ESTABLISHES THAT PROOF OF QUALITY, SAFETY AND EFFICACY IS A PRECONDITION FOR DELIVERING A MARKETING AUTHORIZATION FOR A MEDICINAL PRODUCT.,CURRENT LEGAL FRAMEWORK FOR HERBAL MEDICINAL PRODUCTS MA PROCEDU
8、RES,National,Mutual recognition,Centralised (?),Marketing authorisation : “A medicinal product may only be placed on the market in the European Union when a marketing authorisation has been issued by the competent authority of a Member State for its own territory (national authorisation) or when an
9、authorisation has been granted in accordance with Regulation (EEC) No. 2309/93 for the entire Community (a Community authorisation).”,FRIAS, 2004,HERBAL MEDICINAL PRODUCTS (HMPs) IN THE EU, REGULATORY GUIDANCE ON SOLID GROUNDS,DIRECTIVE 2001/83/EC AS AMENDED BY DIRECTIVE 2004/24.EC AND DIRECTIVE 200
10、4/27/EC OF 31.03.2004, HMPs IN THE EU : ACCESS TO THE MARKET MARKETING AUTHORIZATION (MA) 1. FULL DOCUMENTATION WITH NEW TESTS AND TRIALS 2. FULL BIBLIOGRAPHIC DOCUMENTATION (WELL-ESTABLISHED USE) 3. MIXED APPLICATIONS REGISTRATION 4. SIMPLIFIED DOSSIER FOR TRADITIONAL HERBAL MEDICINAL PRODUCTS,REGU
11、LATION No 726/2004 (EC) OF 31.03.2004 TITLE IV, THE EUROPEAN MEDICINES AGENCY (EMEA) RESPONSIBILITIES AND ADMINISTRATIVE STRUCTURE ARTICLE 56 1. (d) HMPs,CURRENT LEGAL FRAMEWORK FOR HMPs IN THE EU,* DIRECTIVE 2003/63/EC (UPDATED ANNEX I TO THE DIR. 2001/83/EC) DOSSIER REQUIREMENTS SPECIFIC REQUIREME
12、NTS FOR THE DOCUMENTATION AND EXPERT REPORTS ON QUALITY, SAFETY AND EFFICACY SPECIFIC PART ON APPLICATIONS FOR HMPs SPECIFIC PART ON BIBLIOGRAPHIC APPLICATIONS, PRESENTATION AND FORMAT OF AN APPLICATION - OLD NOTICE TO APLLICANTS (NTA) 1998 EDITION (PARTS I- IV) - NEW COMMON TECHNICAL DOCUMENT (CTD)
13、 2001 EDITION (MODULES 1 - 5) TRANSITION FOR “OLD” HMPs APPLICATIONS UNTIL 30.04. 2005 MANDATORY FOR “NEW” HMPs APPLICATIONS SINCE 01.07.2003,LEGAL BASIS FOR SUBMISSION OF HMPs IN THE EU,* COMPLETE AND INDEPENDENT APPLICATION / STAND ALONE APPLICATION ART. 8. 3 (i) OF DIR. 2001/83/EC “COMPLETE DOSSI
14、ER APPLICATION” BASED ON THE MANUFACTURERS OWN QUALITY, PRECLINICAL AND CLINICAL RESEARCH DATA,* BIBLIOGRAPHIC APPLICATION ART. 10.1 (a) (ii) OF DIR. 2001/83/EC 1. IN DEROGATION OF ART. 8.3.(i), AND (a) THE APPLICANT SHALL NOT BE REQUIRED TO PROVIDE THE RESULTS OF PHARMACOLOGICAL AND TOXICOLOGICAL T
15、ESTS OR THE RESULTS OF CLINICAL 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 RECOGNIZED EFFICACY AND AN ACCEPTABLE LEVEL OF SAFETY, C
16、AN BE A “MIXED DOSSIER” APPLICATION INCLUDING BOTH EXISTING BIBLIOGRAPHIC EVIDENCE SUPPLEMENTED WITH THE APPLICANTS OWN RESEARCH DATA.,* ALTHOUGH THE FULL AND BIBLIOGRAPHIC LEGAL BASES HAVE BEEN TRANSPOSED INTO THE NATIONAL LEGISLATION, THERE ARE MAJOR DISCREPANCIES BETWEEN THE MS IN THE CLASSIFICAT
17、ION AS WELL AS IN THE DOSSIER REQUIREMENTS FOR OBTAINING A MARKETING AUTHORIZATION.,“ WELL-ESTABLISHED USE” DEMONSTRATION (WEU) (1),CTD 3.2 (a) : THE TIME OVER WHICH A SUBSTANCE HAS BEEN USED, NOT LESS THAN 10 YEARS FROM FIRST AND SYSTEMATIC USE AS A MEDICINAL PRODUCT; QUANTITATIVE ASPECTS OF THE US
18、E OF THE SUBSTANCE; THE DEGREE OF SCIENTIFIC INTEREST IN THE USE OF THE SUBSTANCE, AND THE COHERENCE OF SCIENTIFIC ASSESSMENTS.,CTD 3.2 (b) : BIBLIOGRAPHY “SHOULD COVER ALL ASPECTS OF THE SAFETY AND/OR EFFICACY ASSESSMENT AND MUST INCLUDE OR REFER TO A REVIEW OF THE RELEVANT LITERATURE, TAKING INTO
19、ACCOUNT PRE-AND POST-MARKETING STUDIES AND PUBLISHED SCIENTIFIC LITERATURE CONCERNING EXPERIENCE IN THE FORM OF EPIDEMIOLOGICAL STUDIES AND IN PARTICULAR OF COMPARATIVE EPIDEMIOLOGICAL STUDIES”.,ANNEX 1 TO CD 2001/83 EC AMENDED BY CD 2003/63 (25.06.2003),“ WELL-ESTABLISHED USE” DEMONSTRATION (WEU) (
20、2),CTD 3.2 (d) : NON-CLINICAL AND /OR CLINICAL OVERVIEWS MUST EXPLAIN RELEVANCE OF ANY DATA SUBMITTED WHICH CONCERN A PRODUCT DIFFERENT FROM THE PRODUCT INTENDED FROM MARKETING. CTD 3.2 (e) : POST-MARKETING EXPERIENCE WITH OTHER PRODUCTS CONTAINING THE SAME CONSTITUENTS IS OF PARTICULAR IMPORTANCE A
21、ND APPLICANTS SHOULD PUT A SPECIAL EMPHASIS ON THIS ISSUE.,CTD 3.2 (c) : MISSING INFORMATION : JUSTIFICATION MUST BE GIVEN,ANNEX 1 TO CD 2001/83 EC AMENDED BY CD 2003/63 (25.06.2003),DIRECTIVE 2004 / 24 / EC ON TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (2),* NEW LEGAL BASIS AND PROCEDURE SIMPLIF
22、IED REGISTRATION OF TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) UNDER ARTICLE 16A DOES NOT APPLY IN CASE THE “TRADITIONAL” HERBAL PRODUCT FULFILS THE CRITERIA FOR A FULL MARKETING AUTHORISATION APPLICATION TO THE COMPETENT AUTHORITY OF THE MEMBER STATE (MS) TIMEFRAME FOR IMPLEMENTATION - 210 DAYS
23、REVIEW - MEMBER STATES : MAX. 18 MONTHS - EMEA : MAX. 18 MONTHS (STARTING ON 22.09.2004) - THMPs ALREADY ON THE MARKET IN THE MS : COMPLIANCE WITHIN 7 YEARS (04.2011).,DIRECTIVE 2004 / 24 / EC ON TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (3),* SCOPE INDICATION (S) EXCLUSIVELY APPROPRIATE TO THMP
24、s AND DESIGNED FOR USE WITHOUT SUPERVISION OF A MEDICAL PRACTITIONER FOR DIAGNOSIS, PRESCRIPTION OR MONITORING OF TREATMENT SPECIFIED STRENGTH AND POSOLOGY ONLY ORAL OR EXTERNAL USE AND INHALATION PERIOD OF TRADITIONAL USE : 30 YEARS (15 YEARS IN AND 15 YEARS OUTSIDE THE EU), UNLESS OTHERWISE DECIDE
25、D BY THE HMPC VITAMINS AND MINERALS MAY BE ADDED IF THEIR ACTION IS ANCILLARY TO THE HERBAL CONSTITUENT(S),DIRECTIVE 2004 / 24 / EC ON TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (4),* DOSSIER REQUIREMENTS ADMINISTRATIVE DOSSIER : APPLICATION FORM, EXPERT REPORTS, SPC PHARMACEUTICAL DOSSIER : IDEN
26、TICAL TO A “ FULL” MARKETING AUTHORISATION BIBLIOGRAPHIC OR EXPERT EVIDENCE THAT THE PRODUCT OR A CORRESPONDING MEDICINAL PRODUCT HAS BEEN IN MEDICINAL USE FOR AT LEAST 30 YEARS ( NOT NECESSARY IF LISTED OR MONOGRAPH), BIBLIOGRAPHIC REVIEW OF SAFETY DATA TOGETHER WITH AN EXPERT REPORT (NOT NECESSARY
27、 IF LISTED OR MONOGRAPH) MS MAY REQUEST FURTHER SAFETY DATA, IF NECESSARY,DIRECTIVE 2004 / 24 / EC ON TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (6),* TASKS OF THE HERBAL COMMITTEE (HMPC) ESTABLISH A LIST OF HERBAL SUBSTANCES, PREPARATIONS AND COMBINATIONS THEREOF FOR USE IN THMPs ESTABLISH COMMU
28、NITY HERBAL MONOGRAPHS FOR WELL-ESTABLISHED MARKETING AUTHORISATIONS OR TRADITIONAL REGISTRATIONS OF HMPs. MONOGRAPHS SHALL BE USED AS THE BASIS FOR ANY APPLICATION, AT THE REQUEST OF A MS DRAW UP AN OPINION ON THE ADEQUACY OF THE EVIDENCE OF THE LONG-STANDING USE BE RESPONSIBLE FOR ARBITRATION / RE
29、FERRAL PROCEDURES ON THMPs GIVE AN OPINION ON OTHER MEDICINAL PRODUCTS CONTAINING HERBAL SUBSTANCES REFERRED TO THE EMEA/CHMP,DIRECTIVE 2004/24/EC ON TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (7), PHARMACOVIGILANCE REQUIREMENTS MANUFACTURING AND IMPORT PROVISIONS VARIATIONS - TAKING INTO TECHNIC
30、AL PROGRESS INSPECTION ACTIVITIES GMP COMPLIANCE WITH EU PHARMACOPOEIA MONOGRAPHS PHARMACOVIGILANCE,* POST- AUTHORISATION ACTIVITIES,DIRECTIVE 2004/24/EC ON TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (8),SHALL CONTAIN A STATEMENT “THE PRODUCT IS A TRADITIONAL HERBAL MEDICINAL PRODUCT FOR USE IN S
31、PECIFIED INDICATION(S) EXCLUSIVELY BASED UPON LONG STANDING USE” “THE USER SHOULD CONSULT A DOCTOR OR QUALIFIED HEALTH CARE PRACTIONER IF THE SYMPTOMS PERSIST DURING THE USE OF THE PRODUCT OR IF ADVERSE EFFECTS NOT MENTIONED IN THE PACKAGE LEAFLET OCCUR - A MS MAY REQUIRE TO MENTION THE NATURE OF TH
32、E TRADITION IN QUESTION,* LABELLING AND USER PACKAGE LEAFLET,Herbal medicinal product for. (treatment, prevention .),Legal basis,Art. 8.3(i) 2001/83/EC “Complete application”,Art. 10.1(a)(ii) 2001/83/EC ”Bibliographical application”,Medicinal use, 10 years, 10 years,Conditions,Serious and minor dise
33、ases Possible intervention of medical practitioner No restrictions regarding strength, posology, route of administration,New product,Major claim,Minor claim,LEVEL OF EVIDENCE,+ demonstration of “well established use”,X,T,C,B,A,Art. 16.a of the proposed Directive on Traditional Herbal Medicinal Produ
34、cts, 30 years,+ demonstration of “traditional use”,Minor conditions Self-medication,Limited route of administration., strength & posology,Traditionally used for (no or limited scientific evidence),Fraudulent or misleading claims,Labelling,OVERVIEW LEGAL FRAMEWORK FOR HERBAL MPS IN THE EU,FRIAS, 2004
35、,DIRECTIVE 2004/24/EC ON TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (9) * PERSPECTIVES PURPOSE TO ESTABLISH A HARMONISED LEGISLATION FRAMEWORK FOR TRADITIONAL HERBAL MEDICINAL PRODUCTS IN EUROPE IMPLEMENTATION IN ORDER TO PROMOTE THIS HARMONISATION MS SHOULD RECOGNISE NATIONAL REGISTRATIONS OF TH
36、MPs GRANTED BY ANOTHER MS BASED ON COMMUNITY HERBAL MONOGRAPHS, LIMITATIONS BORDERLINE MEDICINE-FOOD PRODUCTS - THE DIRECTIVE ALLOWS NON-MEDICINAL HERBAL PRODUCTS TO BE REGULATED UNDER FOOD LEGISLATION IN THE COMMUNITY - HERBAL PRODUCTS THAT ARE USED FOR HEALTH ENHANCEMENT/MAINTENANCE, REDUCTION OF
37、RISK FACTOR FOR A DISEASE/ DISORDER/CONDITION OR GENERAL PROMOTION OF WELL-BEING/ FUNCTION OF THE HEALTHY BODY/ORGAN WILL PROBABLY BE REGULATED WITHIN THE AREA OF FOOD SUPPLEMENTS,* GROUPS OF EXPERTS 13A AND 13B : PHYTOCHEMISTRY SETTING STANDARDS FOR * PRODUCTION OF HERBAL DRUGS * PHARMACEUTICAL IND
38、USTRY * QUALITY CONTROL LABORATORIES * REGULATORY AUTHORITIES * COMMUNITY PHARMACISTS MONOGRAPHS (TILL 2003) * HERBAL DRUGS : PUBLISHED : 106 UNDER STUDY : 40 * HERBAL DRUG PREPARATIONS : PUBLISHED : 58 UNDER STUDY : 48,* CERTIFICATION OF SUITABILITY TO THE MONOGRAPHS OF THE EP PUBLIC COMMITTEE RESO
39、LUTION AP-CSP (99) 4 EXTENSION OF THE EDQM CERTIFICATION PROCEDURE TO HERBAL DRUG PREPARATIONS (MARCH, 2003).,EUROPEAN DIRECTORATE FOR THE QUALITY OF MEDICINE (EDQM) www.edqm.org,EUROPEAN PHARMACOPOEIA,OVERVIEW OF HERBAL SUBSTANCES/PREPARATIONS,EUR. PH. SUPPL. 2002,CPMP/QWP/2819/00, CORR. EMEA/CVMP/
40、814/00, CORR.,HERBAL DRUGS,HERBAL SUBSTANCES,(PLANTAE MEDICINALES),HERBAL DRUG PREPARATIONS,HERBAL PREPARATIONS,(PLANTAE MEDICINALES PRAEPARATORE),COMMINUTED OR POWDERED DRUGS,EXTRACTS (EXTRACTA),ESSENTIAL OILS (AETHEROLEA),HERBAL MEDICINAL PRODUCTS,TRADITIONAL HERBAL MEDICINAL PRODUCTS,HERBAL TEAS,
41、(PLANTAE AD PTISANAM),EXPRESSED JUICES,PROCESSED EXUDATES,DIFFERENT TYPES OF HERBAL EXTRACTS, EUR. PH. 2002, SUPPL. 4.3,HERBAL PREPARATIONS (HP),HERBAL EXTRACTS (HE), LIQUID SOFT: SEMI-SOLID NOT NATIVE HPs,TYPE A : STANDARDIZED (ADJUSTED) EXTRACTS,TYPE B1 : QUANTIFIED EXTRACTS,TYPE B2 : OTHER EXTRAC
42、TS,REFINED “EXTRACTS (“PURIFIED”, “ENRICHED” EXTRACTS), NATIVE (GENUINE) EXTRACTS CONSIST SOLELY OF GENUINE HERBAL EXTRACTABLE MATTER NOT NATIVE EXTRACTS CONTAIN ALSO TECHNICAL EXCIPIENTS, EXCIPIENTS NEEDED FOR STANDARDISATION AND/OR EXTRACTION SOLVENTS. DER = THE RATIO OF THE STARTING MATERIAL TO T
43、HE GENUINE EXTRACT (20:1 = 5% OF EXTRACTABLE MATTER),CLASSIFICATION OF PLANT CONSTITUENTS,1. THERAPEUTICALLY ACTIVE CONSTITUENTS,CHEMICALLY DEFINED SUBSTANCES OR GROUPS OF SUBSTANCES WHICH, IN AN ISOLATED STATE, EXERT THE SAME OR SIMILAR THERAPEUTIC EFFECT AS THE TOTAL EXTRACT.,EXAMPLES: SILYMARIN,
44、AESCIN, ANTRAQUINONES, ALKALOIDS, CARDIAC GLYCOSIDES, .,2. ACTIVE CONSTITUENTS (PHARMACAEUTICALLY RELEVANT CONSTITUENTS),CHEMICALLY DEFINED SUBSTANCES OR GROUPS OF SUBSTANCES WHICH, IN AN ISOLATED STATE, DO NOT EXERT THE SAME THERAPEUTIC EFFECT AS THE TOTAL EXTRACT, BUT WHICH ARE ACCEPTED TO CONTRIB
45、UTE TO THE THERAPEUTIC ACTIVITY OF THE HERBAL DRUG PREPARATION.,EXAMPLES: HYPERICINS, PROCYANIDINES, FLAVONOIDS.,3. MARKERS,CHEMICALLY DEFINED SUBSTANCES OR GROUPS OF SUBSTANCES WHICH ONLY SERVE ANALYTICAL PURPOSES.,3.1. CHARACTERISTIC MARKERS,CHARACTERISTIC FOR THE RESPECTIVE GENUS OR FAMILY OF THE
46、 PLANT, SUITABLE FOR IDENTIFICATION, TESTS AND ASSAY (E.G. BATCH-TO-BATCH CONTROL).,EXAMPLES: VALERENIC ACIDS, ECHINACOSIDE, ELEUTHEROSIDES B AND E.,3.2. UBIQUITOUS MARKERS,OCCUR UBIQUITOUSLY IN PLANTS, SUITABLE FOR ASSAY (E.G. BATCH-TO-BATCH CONTROL).,EXAMPLES: CHLOROGENIC ACID, RUTIN.,NOTE FOR GUI
47、DANCE ON SPECIFICATIONS : TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR HERBAL SUBSTANCES, HERBAL PREPARATIONS AND HERBAL MEDICINAL PRODUCTS (CPMP/QWP/2820/00/EMEA/CVMP/815/00) GENERAL CONCEPTS 1. CHARACTERISATION 2. DESIGN AND DEVELOPMENT CONSIDERATIONS 3. PHARMACOPOEIAL TESTS AND ACCEPTANCE CRITERIA
48、 4. PERIODIC/SKIP TESTING 5. RELEASE VERSUS SHELF-LIFE ACCEPTANCE CRITERIA 6. IN-PROCESS TESTS 7. ALTERNATIVE PROCEDURES 8. EVOLVING TECHNOLOGIES 9. REFERENCE STANDARD 10. STATISTICAL CONCEPTS, GUIDELINES 1. SPECIFICATIONS : DEFINITION AND JUSTIFICATION 2. UNIVERSAL TESTS/CRITERIA HERBAL SUBSTANCES HERBAL PREPARATIONS HERBAL MEDICINAL PRODUCTS 3. SPECIFIC TESTS/CRITERIA HERBAL SUBSTANCES HERBAL PREPARATIONS HERBAL MEDICINAL PRODUCTS,SPECIFICATIONS OF HERBAL SUBSTANCES,NOTE FOR GUIDANCE ON SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR HERBAL SUBSTANC