歐盟藥政法規(guī)及產(chǎn)品注冊的程序和要求課件

1、Overview of the Regulation for the Medicinal Products in the EU Outline of PresentationRegulatory structureMarketing authorizationHow to prepare the documentsTraditional herbal product/TCMsTaslys practice & experience 1. The regulatory structure for the medicinal productThe European UnionTotal area:

2、 4.322 million sq.km. Countries : 27Population: over 5億GDP：Over 1.2 trillion USD 赫爾曼范龍佩, 歐洲理事會常任主席(右一)European Regulatory OrganizationEU CommitteeEU Parliament EU Commission EU Committee EDQM (European Directorate for the Quality of Medicine & Healthcare)EMA (EMEA) (European Medicines Agency)CEP/COS

3、OMCLEP PhrNational AuthoritiesAuthorization Inspection OMCLNational PhrOMCL: Official Medicines Control Laboratories How is EMA organized?27 National competentAuthorities (4000 European Experts )EU Institution:Commission-parliament-councilEMEASecretariatCommittee for Herbal Medicinal products(HMPC )

4、Committee for Human Medicinal products(CHMP) Committee for Orphan Medicinal products(COMP) Management BoardCommittee for veterinaryMedicinal products(CVMP)New scientific committees of the EMEACommittee for paediatric Medicinal products (2006)Committee for advanced therapy Medicinal products (2007)AT

5、MP is new medical products based on genes (gene therapy), cells (cell therapy) and tissues (tissue engineering). Scientific committees supported by working parties (WPS) Quality WP (joint human/veterinary )Biologics WP (formerly biotechnology WP)Safety WPEfficacy WPPharmacovigilance WPEMAAbout 360 s

6、taff membersOperates in partnership with national competent authorities (health authorities)Scientific network of approx 4000 European experts who assist the Agency in performing its scientific tasksEuropean Pharmaceutical Legislation SystemTreaty binding to all of the member states Regulation direc

7、tly binding -E.G. Regulation 2309/93Directive binding as to the result achieved -E.G. Directive 65/65/EEC(now 2001/83) Decisions-binding on those to whom they are addressed -E.G. Centralised marketing authorisationsRecommendation and opinions not binding“Rule control Life”Pharmaceutical legislation-

8、backgroundThalidomide Event -19601965/65/EEC1975/318/EEC, 1975/319/EEC1993/93/EC2001/83/EC2004/426/EC, 2004/24/EC, 2004/27/ECEuropean Pharmaceutical Legislation System-evolutionMore than 500 guidance covering the regulatory, CMC, preclinical and clinical technical requirement.More information could

9、be found at:http:/www.ema.europa.euEuropean Pharmaceutical Legislation System2. Registration of the medicinal products in the EUGlobal pharmaceutical marketUS: 320 billion USD 42.5% EU: 250 billion USD 30%JP: 100 billion USD 12.5%Total 670 billion USD 85%Global: 800 billion USD Drug approvalQualityR

10、ational DrugEfficacySafetyFrom Prof. Gerhard FranzEUROPEAN PHARMACEUTICAL LEGISLATION REGULATION-principleRegistration of the medicinal product in EU (1)Active substanceCOS (Certificate of suitability) -Should meet European Pharmacopoeia monographs (if they exist )If no national pharmacopoeias ,then

11、 foreign pharmacopoeias (in that order).EDMF (Drug Master File)COS/CEP vs EDMFCos/CEPEDMFListed in EPMandatory Not mandatory Applicant API ManufacturerMarketing Authorization holder Certificate Yes No, Reference NoDossier Opinion CTD formatGMP Inspection Randomized, EDQMMandatory, competent authorit

12、ies RecognizedYes yesPlease login for more information regarding the COS/CEP applicationPlease login www.ema.europa.eu/ema for more information regarding the EDMF applicationDrug product:Marketing authorization application (MAA)Product holder, wholesaler or manufacturerManufacturing authorization ap

13、plication (MAA)Manufacturer for GMP complianceRegistration of the medicinal product in EU (2)3 types of documentations to access to the marketFull documentation (full study data)demonstration of quality, efficacy and safetyWell established use (bibliographic application)(systematic and well document

14、ed use of a substance in the Community for at least ten yearsTraditional application (Herbal product)Well traditionally market useRegistration of the medicinal product in EU (3)EUROPEAN MEDICINES REGULATION-procedureMarketing authorization procedures:Centralized Procedure (CP)National Procedure (MP)

15、 Mutual Recognition Procedure (MRP) or Decentralized procedure (DCP) Where to apply for a centralized MA? EMA/EMEA (European Medicines Agency) Who will grant a centralized MA? Decision by the European commissionI. Centralised procedure (CP)General process of CP(1)CHMP appoints rapporteur and co-rapp

16、orteur (among its own members)Rapporteur and co-rapporteur (from different MS) select their team of experts according to the criteria mentioned aboveGeneral process of CP(2)Rapporteur and co-rapporteur perform assessment and draft assessment reportAll other member states comment on the assessment re

17、port and the information in the dossierSubmit to HMPC for the decisionTimeline: 210 days Centralised procedure (CP)-mandatory scopeDeveloped by one of the following biotechnological processes:Recombinant DNA technologyControlled expression of gene coding for biologically active proteins, or othersNe

18、w active substances for the indicationsDiabetesCancerAcquired immune deficiency syndrome (HIV)Neurodegenerative disorder (Alzheimer,) Orphan medicinal productsCP-Mandatory Scope(2)Cont From 20th May 2008:Auto-immune diseases and other immune dysfunctionsViral diseases Other extensions to be approved

19、 by the council upon proposal from the EC CP-Mandatory Scope(3) Bio-similar medicinal products (Bio-generics) if biotechnological medicinal products mandatory for the centralized procedure CP-optional Scope(1)Products containing a new active substance not authorized before coming into force of the r

20、egulation EC726/2004Products constituting a significant therapeutic, scientific or technical innovation will be evaluated on a case by case basis (consultation of two sponsors out of CHMP and, when needed, the relevant working parties)CP-optional Scope(2)Generic of a centrally-authorized productProd

21、ucts which are in the interest of patients at community level:Generic of a national/MRP productPandemic medicinal productsScope: Marketing authorisation in one MS ONLY! New active substance (if not mandatory for the centrailised procedure) Known substance alone or in a new combination Line extension

22、s to national authorisationsAbridged applicant to national authorisations Generic products to nationally authorised originators/innovators Bibliographic applications.The National Marketing AuthorisationNational Marketing Authorisation Procedure-GermanyApplicant submits dossierScientific Advice Pre-s

23、ubmission meetingValidation/ClearingPhase 1= Evaluation of dossier-Quality (Chemical ,Pharmaceutical and Biological Documentation)-Safety (Toxicological-Pharmacological Documentation)-Efficacy (Clinical Documentation)Deficiency letter to applicant/oral discussion if necessaryApplicants Responses Doc

24、umentPhase 2= Evaluation of the response documentQuality ,Toxicology-Pharmacology ,ClinicDecision on the applicationNational committee/boardBFArMMarketing authorisationPre-submission meeting for the MRP. MRP and DCPTwo routes to receive a MAMutual recognition procedure (MRP) Where the medicinal prod

25、uct has already received in a MS a MA at the time of application or Decentralised procedure (DCP) Where the medicinal product has not received in a MS a MA at the time of applicationMRP/DCP-generalApplicant selects reference member state (RMS) and files first (national) applicationRMS assesses the d

26、ossier and clarifies open issues, draft the assessment report RMS grants marketing authorisation and writes assessment reportSelected concerned member states (CMS) evaluate the assessment report and commentMRP-timelines and responsibilities Application to first member stateNational procedure210 days

27、First authorisationAssessment reportMutual recognition processApplicant request mutual recognition of the reference authorisation50 days35 days5 daysObjectionsClarification and dialogue/point of view of applicant Resolution of issuesFurther National Authorisation(s)DCP and MRPIf no agreement between

28、 RMS/CMS can be reached at the end of procedureReferred to coordination group (CG)60 days for negotiation between the MS concerned (RMS and CMSs)Consultation of the applicant in written or oral formDCP and MRP (2)Still disagreement after this consultation-the elements of disagreement are forwarded t

29、o the agencyArbitration, referral to CHMPMSs that are in agreement with the AR and SPC may authorise the medicinal product, without waiting for the outcome of the procedureMRP/DCP: Scope- (1)New active substances (if not mandatory for the centralised procedure)Generic medicinal products to national

30、(and centralised) authorised reference medicinal products (if not a biotechnological medicinal product)Well established use (bibliographic applications)Informed consentMRP/DCP: Scope- (2)Cont.Line extension to national authorisationsKnown substances in new combinationHomeopathicsTraditional herbal m

31、edicinal productsWhich one is the best?Technical requirement: no differenceEconomic aspect: CPMRPNPTarget time for approval: MRPCPNP (210 days, MRP plus 90 days)Benefit & Risk: CPMRPNPStrategy: mostly NP firstly, then MRP or CPSpecific product and indicationExample: MRP procedureLanguageDossier subm

32、ittedMarketing considerationTime consumingDifferent regulatory submission: application form and etc. Others Preparation of dossier languagePreparation of dossier number of copiesEE Modules 4 and 5 should be provided on CD-ROM version only. Paper copy should be available on requestLT Mutual Recogniti

33、on Procedure where LT acts as CMS: a paper copy of 1&2 modules +all modules on CD-ROMLV Additional copy of all modules on CD ROMQuestions:A anti-cancer drug to the EU market- where to start?- how to proceed?- why?3. How to prepare the documents?Different licensing procedures ,but identical requireme

34、nts on the documentationModule 1RegionalAdminInformationModule 3QualityModule 4NonclinicalStudy ReportsModule 5ClinicalStudy ReportsQualityOverallSummaryNonclinicalSummaryNonclinicalOverviewClinicalSummaryClinicalOverviewModule 2NOT Part of the CTD The CTDICH M4: 2003 SummaryFor QOSKey results, conc

35、lusionsBody of ReportModule 4 dataDiscussionSummary of methodsKey Tables, Figures, GraphsAppendicesMay not be submitted, on fileComplete dataProtocolsGLP InfoExample: Levels of Submission-Ready Reports (Module 4)CTD Introduction: SafetyModule 4NonclinicalStudy Reports44.1 T of CModule 4: Safety4.2 S

36、tudy reports4.2.1 Pharmacology4.2.2 Pharmacokinetics4.2.3 Toxicology4.3 Literature references4.2.1 Pharmacology Primary pharmacodynamics Secondary pharmacodynamics Safety pharmacology Pharmacodynamic drug interactions Primary PharmacodynamicsStudy report identification number and related information

37、Legacy study reportSynopsisStudy report bodyProtocol and amendmentsSignatures of principal or coordinating investigator(s) Audit certifications and reports Primary PharmacodynamicsDocumentation of statistical methods and interim analysis plansDocumentation of inter laboratory standardization methods

38、 of quality assurance procedures if used Publications based on the studyImportant publications referenced in the report Compliance and/or drug concentration data Individual subject data listings Primary PharmacodynamicsData tabulationData tabulation datasetsData definitionsData listing datasetsData

39、listing datasetsData definitionsAnalysis datasetsAnalysis datasetsAnalysis programsData definitionsIND safety reports Secondary PharmacodynamicsSee the template showed above for movingFolder Structure of Module 4 4. Regulation of Traditional herbal products/TCMs in EUEuropean herbal marketEuropean h

40、erbals marketSource: IMS 2005Total Market 09/2003-09/2004: 3.7 billion Herbal medicines:Situation before new regulationWhat can go wrong with herbal medicines?Wrong plant Contamination Deliberate adulteration/substitution/addition Foreign matter Poor informationAdverse drug reactionsInteractions wit

41、h pharmaceuticals Erratic standards examples from Herbal Safety NewsRepeated examples of unlicensed “herbal” products containing:LeadMercuryArsenicUndeclared potent pharmaceuticalsExaggerated claims for herbal medicines seen on products and clinic leaflets!“Our herbal remedies are 100% safe”“Our med

42、icines have no side effects”“Herbal remedies are safe because they are natural”“Chinese medicines will not interfere with any western medicines”“Treats heart disease”“Safer than western medicine”“Fights cancer”What can go wrong with practitioner supply of herbal medicines (i)?Lack of awareness of si

43、de effects, interactions with other medicines, use in pregnancy, babies, children, elderlyFailure to diagnose accurately; Delaying effective treatment for serious conditions Belgium renal diseaseAristolochia incident in Belgium in mid 1990s. 100+ women with renal failure; many later had cancer. Wron

44、g plant!Aristolochia species Cause kidney failure and cancerBelgium -110 cases renal failure, 18 cancersUK casesAristolochia Banning Order 2001What changed since 1998/1999?European Commission concerned seriously about the lack of single market; 2004/24/EC - implementation31 March, 2004:Member states

45、 shall comply by 1 October 2005Shall comply at the latest 7 years after the entry into force of the directive, i.e. in April 2011.Inclusion criteriaIndication without the supervision of a medical practioner for diagnostic purposes or for prescription or monitoring of treatment Oral, external or inha

46、lationat least 30 years in medicinal use including at least 15 years within the EUApplicant and registration holder established in the EU Sufficient data on the traditional use of the product, especially to prove safety2004/24/EC - principleQuality: full dossierSafety: no harmful effects known in li

47、teratureEfficacy: duration of use, 30yearsGMP certificateMonograph and the listRequirements for registrationExamples of Indications Not Likely To BePermitted for THMPD ProductsBone diseasesCardiovascular diseasesDiabetes and other metabolic diseasesDiseases of the liver, biliary system and pancreasG

48、enetic disordersJoint, rheumatic and collagen diseasesPsychiatric diseasesSerious disorders of the eye and earSerious gastrointestinal diseasesSerious infectious diseases including HIV-relateddiseases and tuberculosisSerious neurological and muscular diseasesSerious renal diseasesSerious respiratory

49、 diseasesSerious skin disordersSexually transmitted diseasesInfections including viral, bacterial and fungal diseases: symptomatic relief of:Common colds, coughs, conditions commonly referred to as influenza and similar upper respiratory tract infectionsMinor acute inflammatory conditions of the buc

50、cal cavity and pharynx Minor skin infections, relief of pruritus or exanthematousrashes of childhood infection and boils, athletes footExamples of Permitted Indications for THMPD ProductsBy 2009, more than 140 traditional registrations have been granted in the EU. The first UK traditional herbal reg

51、istration.First THR granted Oct 2006A.Vogel Rheuma-Gel is a fresh plant preparation extracted from arnica flowers and has an anti-inflammatory, soothing effect. The gel is easy to apply, is virtually odourless and does not heat the skin. A.Vogel Rheuma-Gel can be used as a supplementary measure for

52、external use to treat pain and inflammation of the joints and muscles, DoseAdults: Apply an approx. 4 cm long bead to be affected area twice a day and gently massage in.Composition1g contains 500mg of extract of fresh arnica blossomKlosterfrau Melisana, the 1st THMP registered in EU (2006.3)Approved

53、 Traditional combination herbal productNAMEHERBALINDICATIONSOURCE復(fù)方制劑NiteHerb Plus西番蓮+纈草見表2歐洲Botanova貫葉連翹+西番蓮+纈草見表2歐洲Esberitox野生藍靛根+淡白紫錐菊+紫錐菊+金鐘柏緩解感冒癥狀歐洲、北美Melisana13種植物見表1世界各國非歐盟傳統(tǒng)草藥Kabola狹花天竺葵上呼吸道感染南非Ginsana人參調(diào)整和改善整體狀況東亞Vitano紅景天改善由于緊張和壓抑引起的疲勞、倦怠和焦慮。俄羅斯以及蒙古、卡薩克斯坦、烏克蘭等TCM products are available all

54、 over Europe and the demand is on the increase year by year. TCM provides remedies for many chronic and difficult medical conditions for which modern medicine has no satisfactory solutions. It also helps to lessen the healthcare cost and generate employment. Current development of TCMs in the EUTher

55、e are over 120,000 TCM practitioners and acupuncturists in Europe. Each year over 5,000 TCM students graduate from about 300 TCM training schools in Europe. More than 5 million people in Europe visit TCM practitioners each year in Europe. There are over 300 TCM products distributors all over Europe.

56、Current Development of TCMs in the EU國 家Country中醫(yī)/針灸師人 數(shù)TCM practitioners中 醫(yī) 藥 學(xué) 校 TCM Schools中醫(yī)藥學(xué)會TCM associations中醫(yī)藥產(chǎn)品供應(yīng)商TCM product suppliers資料來源Data source全日制Full-time非全日制Part-time年畢業(yè)生人數(shù)Year graduates畢業(yè)要求平均學(xué)時Study hours奧地利 Austria650019150140-500610W. Eichwer保加利亞 Bulgaria150120400-80012Z. Gorano

57、va比利時 Belgium900480108034V. Herv丹麥 Denmark500850250-80035I. Holm芬蘭 Finlan國光法國 France7000140500650-3250615-20F. Marguer德國 Germany5000030600140-3502535M. Wark希臘 Greece35076045匈牙利 Hungary3004703-52愛爾蘭 Ireland600250-60150033B. Ward意大利 Italy300015250600255C.M. Giovanardi荷蘭 Netherlands4000712

58、0280-760715M. de Boer拉脫維亞 Latvia9601236048004N. Nickolaev立陶宛 Lituania200130011N. Vitalijus挪威 Norway175010150-20080043N.E. Volden波蘭 Poland300015100310A. Curzytek葡萄牙 Portugal20007100-300100-500054P. Choi西班牙 Spain770014801600-300042R.M. Calduch瑞士 Switzerland130030400310F. Urbahn英國 UK1135061131080-36001

59、528張鵬合計 TOTAL101690111943180126171TCM situation in 20 European countries TCM is yet to be officially recognized in Europe. Like other complementary therapies, TCM has no official legal status in most European countries. Chinese traditional herbal products can only be imported and sold as foodstuffs

60、or cosmetics. Current status of TCMs in the EUChallenges for TCMsNo regiatration has been granted to TCM products because No EU GMP certification; Difficulty in the traditional evidence; Complexity in composition and quality control; Compliance problems with self-medication indications;Route of admi