欧盟药政法规及产品注册的程序和要求课件.ppt

1、Overview of the Regulation for the Medicinal Products in the EU Outline of Presentation1.Regulatory structure2.Marketing authorization3.How to prepare the documents4.Traditional herbal product/TCMs5.Taslys practice&experience 1.The regulatory structure for the medicinal productThe European Union Tot

2、al area:4.322 million sq.km.Countries:27 Population:over 5亿 GDP：Over 1.2 trillion USD 赫尔曼赫尔曼范龙佩范龙佩,欧洲理事会常任主席欧洲理事会常任主席(右一右一)European Regulatory OrganizationEU CommitteeEU Parliament EU Commission EU Committee EDQM(European Directorate for the Quality of Medicine&Healthcare)EMA(EMEA)(European Medicine

3、s Agency)CEP/COSOMCLEP 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 pr

4、oducts(HMPC)Committee for Human Medicinal products(CHMP)Committee for Orphan Medicinal products(COMP)Management BoardCommittee for veterinaryMedicinal products(CVMP)New scientific committees of the EMEA Committee for paediatric Medicinal products (2006)Committee for advanced therapy Medicinal produc

5、ts(2007)ATMP 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 WP Efficacy WP Pharmacovigilance WPEMA About 360

6、 staff members Operates 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 System Treaty binding to all of the member states Regulation di

7、rectly binding -E.G.Regulation 2309/93 Directive 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 authorisations Recommendation and opinions not binding“Rule control Life”Pharmaceutical legislation

8、-backgroundThalidomide Event-1960 1965/65/EEC 1975/318/EEC,1975/319/EEC 1993/93/EC 2001/83/EC 2004/426/EC,2004/24/EC,2004/27/ECEuropean Pharmaceutical Legislation System-evolution More 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 System 2.Registration of the medicinal products in the EUGlobal pharmaceutical market US: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 approvalQualityRati

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

11、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 authorities Recognized

12、Yes yes1.Please login www.pheur.org for more information regarding the COS/CEP application2.Please login www.ema.europa.eu/ema for more information regarding the EDMF application Drug product:Marketing authorization application(MAA)Product holder,wholesaler or manufacturer Manufacturing authorizatio

13、n application(MAA)Manufacturer for GMP complianceRegistration of the medicinal product in EU(2)3 types of documentations to access to the market Full documentation(full study data)demonstration of quality,efficacy and safety Well established use(bibliographic application)(systematic and well documen

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

15、MP)III.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-rapport

16、eur(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 report All other member states comment on the assessment report

17、and the information in the dossier Submit to HMPC for the decision Timeline: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 othersNew acti

18、ve 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 dysfunctions Viral diseases Other extensions to be approved by the

19、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 regulation

20、EC726/2004 Products 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 product Products which a

21、re in the interest of patients at community level:Generic of a national/MRP product Pandemic medicinal products Scope: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 extensions to national

22、authorisations Abridged 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-submission mee

23、tingValidation/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 DocumentPhase 2=Evalu

24、ation 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 MA1.Mutual recognition procedure(MRP)Where the medicinal product has already receiv

25、ed in a MS a MA at the time of application or 2.Decentralised procedure(DCP)Where the medicinal product has not received in a MS a MA at the time of applicationMRP/DCP-general Applicant selects reference member state(RMS)and files first(national)application RMS assesses the dossier and clarifies ope

26、n issues,draft the assessment report RMS grants marketing authorisation and writes assessment report Selected concerned member states(CMS)evaluate the assessment report and commentMRP-timelines and responsibilities Application to first member stateNational procedure210 daysFirst authorisationAssessm

27、ent 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 MRP If no agreement between RMS/CMS can be reached a

28、t the end of procedure Referred 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 to the agency Arbitration,re

29、ferral to CHMP MSs 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(and centralised)authorised ref

30、erence medicinal products(if not a biotechnological medicinal product)Well established use(bibliographic applications)Informed consentMRP/DCP:Scope-(2)Cont.Line extension to national authorisations Known substances in new combination Homeopathics Traditional herbal medicinal productsWhich one is the

31、 best?Technical requirement:no difference Economic aspect:CPMRPNP Target time for approval:MRPCPNP(210 days,MRP plus 90 days)Benefit&Risk:CPMRPNP Strategy:mostly NP firstly,then MRP or CP Specific product and indicationExample:MRP procedure Language Dossier submitted Marketing consideration Time con

32、suming Different 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 Recognition Procedure where LT acts as CMS:a pa

33、per 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 requirements on the documentationModule 1RegionalAdmin

34、InformationModule 3QualityModule 4NonclinicalStudy ReportsModule 5ClinicalStudy ReportsQualityOverallSummaryNonclinicalSummaryNonclinicalOverviewClinicalSummaryClinicalOverviewModule 2NOT Part of the CTD The CTDICH M4:2003 SummaryFor QOSKey results,conclusionsBody of ReportModule 4 dataDiscussionSum

35、mary 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 Study reports4.2.1 Pharmacology4.2.2 Pharmacokinetics4.

36、2.3 Toxicology4.3 Literature references4.2.1 Pharmacology4.2.1.1 Primary pharmacodynamics4.2.1.2 Secondary pharmacodynamics4.2.1.3 Safety pharmacology4.2.1.4 Pharmacodynamic drug interactions4.2.1.1 Primary Pharmacodynamics Study report identification number and related information Legacy study repo

37、rt Synopsis Study report body Protocol and amendments Signatures of principal or coordinating investigator(s)Audit certifications and reports4.2.1.1 Primary Pharmacodynamics Documentation of statistical methods and interim analysis plans Documentation of inter laboratory standardization methods of q

38、uality assurance procedures if used Publications based on the study Important publications referenced in the report Compliance and/or drug concentration data Individual subject data listings4.2.1.1 Primary Pharmacodynamics Data tabulation Data tabulation datasets Data definitions Data listing datase

39、ts Data listing datasets Data definitions Analysis datasets Analysis datasets Analysis programs Data definitions IND safety reports 4.2.1.2 Secondary Pharmacodynamics See the template showed above for movingFolder Structure of Module 4 4.Regulation of Traditional herbal products/TCMs in EUEuropean h

40、erbal marketEuropean herbals 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 information Adverse drug reac

41、tions Interactions with pharmaceuticals Erratic standards examples from Herbal Safety News Repeated examples of unlicensed“herbal”products containing:Lead Mercury Arsenic Undeclared potent pharmaceuticalsExaggerated claims for herbal medicines seen on products and clinic leaflets!“Our herbal remedie

42、s are 100%safe”“Our medicines 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)?L

43、ack of awareness of side effects,interactions with other medicines,use in pregnancy,babies,children,elderly Failure 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 ha

44、d cancer.Wrong plant!Aristolochia species Cause kidney failure and cancer Belgium-110 cases renal failure,18 cancers UK cases Aristolochia Banning Order 2001What changed since 1998/1999?European Commission concerned seriously about the lack of single market;2004/24/EC-implementation 31 March,2004:Me

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

46、al or inhalation at least 30 years in medicinal use including at least 15 years within the EU Applicant and registration holder established in the EU Sufficient data on the traditional use of the product,especially to prove safety2004/24/EC-principle Quality:full dossier Safety:no harmful effects kn

47、own in literature Efficacy:duration of use,30years GMP certificate Monograph 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

48、pancreasGenetic 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 res

49、piratory 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 infections Minor acute inflammatory conditions of th

50、e buccal cavity and pharynx Minor skin infections,relief of pruritus or exanthematous rashes 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 r