中美仿制药研发申报流程

中美仿制药研发和申报流程 涂家生 Ph D 中国药科大学药剂学教授Tel 025 83271305Email jiashengtu 2011 11郑州 我国仿制药申报 审评和研发对策 主要内容 中美关于原研药和仿制药的背景 美国仿制药 申报 基于问题的审评和研发对策 展望 1 2 3 4 CompanyLogo 3 药物经济学催生美国仿制药制度 美国社会安全制度导致政府赤字严重SSA已经破产 如何破局 降低医疗费用成为必然Hatch Waxman法案出台美国FDA药品注册申请 新药 两类 仿制药和非处方药申请 1984年后 NewDrugApplications NDAs AbbreviatedNewDrugApplications ANDAs FullReports ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations DuplicateofanalreadyapprovedproductNosafety efficacydatapermitted onlybioequivalence 505 b 1 505 b 2 505 j NDA的研发和申报 505 b 1 新药申报资料内容 IndexSummaryChemistry ManufacturingandControlSamples MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology 6 HumanPharmacokineticsandBioavailability7 Microbiology foranti microbialdrugsonly 8 ClinicalData9 SafetyUpdatereport typicallysubmitted120daysaftertheNDA ssubmission 10 Statistical11 CaseReportTabulations12 CaseReportForms13 PatentInformation14 PatentCertification 505 b 2 历史过程 HatchWaxman法案 1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry 1999 FDAResponsetoCitizen sPetition 2003 可以降低研发的费用和审评力量的浪费 505 b 2 的关键 可靠性 Whatis Reliance Bywhom Onwhat RelianceandExclusivityMarketvs DataExclusivitySafety EfficacyDatavs CM CdataFDAProcessforDeterminingRelianceWho whenandhow 505 b 2 的意义 介于全创新药物和仿制药之间具有专利保护 且不存在产权纠纷和仿制药不同 无替换的要求应有突破 505 b 2 范围 NewChemicalEntity rarely 我国1 1 1 3Newdosageform 我国5类Newdosingregimen 我国补充申请Newstrength 我国补充申请Newrouteofadministration 我国2类Newindication 我国1 6 505 b 2 情形 Newactiveingredient differentsalt ester complex chelate clathrate racemate orenantiomerofactivemoiety NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRx OTCswitchNewCombinationProducts Genericbiologics 505 b 2 排他性 Exclusivitiesavailablefor505 b 2 productsNCEExclusivity 5years NewProductExclusivity 3years OrphanDrugExclusivity 7years Pediatricexclusivityextensions 6months PatentIssues505 b 2 drugscanhaveOrangeBook listedpatents andenjoy30 monthstayprotectionagainstgenericcompetitorsBut 505 b 2 NDAsmayalsobeblockedbypatentsonReferenceDrugs 505 b 2 新药的成功例子 NCEThalomid thalidomide 1998 MarketedunapproveddrugsLevothyroxine 2000 Guaifenesinextendedrelease 2002 Quininesulfate 2005 NewDosageFormTramadolorallydisintegratingtablets 2005 Ondansetronoralspray filed2006 505 b 2 新药的例子 NewDosingRegimenTramadolextendedreleasetablets 2005 NewStrength FormulationAntara micronizedfenofibratecaps 2004 130mgisBEtoTricor200mg NewFormulation InactiveIngredientAvita tretinoingel newemollient 1998 Abraxane cremaphor freepaclitaxel 2005 Oxy ADF oxycodoneformulatedtoreducedrugabuse indevelopment 505 b 2 新药的例子 NewActiveIngredientPexeva paroxetinemesylate newsalt 2003 NewRouteofAdministrationEmezine prochlorperazine newbuccal transmucosaldelivery NDApending Oralamphotericin B pre clinical Rx OTCSwitchAlavert loratadine 2002 505 b 2 新药的例子 GenericBiologics Omnitrope rHGH 2006 Glucagen glucagonrecombinant 1998 Hyaluronidase variousapprovals2004 05 Fortical calcitoninsalmonrecombinant 2005 Examplesbasedonpubliclyavailableinformation FDANDA审评过程 FDA可以使用已有数据用于审评NDA吗 Hatch Waxman之前 国会限制FDA在审评NDAX时应用NDAY的数据 NodatainanNDAcanbeutilizedtosupportanotherNDAwithoutexpresspermissionoftheoriginalNDAholder FDA FinkelMemorandum 1978 1981 Hatch Waxman解除只适合ANDAs ANDAprocessallows genericproducerofthefullytesteddrugtorelyonthesafetyandefficacydataofapriorapplicant 505 b 2 doesnotauthorizesuchdatarelianceMerelysetsconditionsforcertainNDAsRequires fullreportsofinvestigations establishingsafetyandeffectiveness 21USC 355 b 1 A d 1 美国仿制药 Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct alsoknownasthereferencelisteddrug RLD productasidentifiedintheFDA slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations indosageform strength routeofadministration quality performancecharacteristicsandintendeduse Genericdrugapplicationsaretermed abbreviated inthattheyaregenerallynotrequiredtoincludepreclinical animal andclinical human datatoestablishsafetyandeffectiveness Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct whichisthefirstversionofthedrugproductapprovedbytheFDA FDA审评仿制药程序 二 美国仿制药的申报 审评和研发对策 由FDA的OGD审评审评方式采用QbR申报资料采用CTD资料内容也针对问题 OfficeofGenericDrugs 如何保证审评质量和效率 StructuredProductLabeling SPL MakeslabelingavailableonInternetviaNationalLibraryofMedicine NLM ReviewEfficienciesEarlyDMFreviewClusterreviews productspecialistsSupplementtriagingatteamleaderlevelDBETruncatedReviewQuestionbasedReview QbR Willhaveaverypositiveimpact NewresourcesdevelopedDissolutionDatabaseIndividualProductBioequivalenceInformationEncouragedtheuseoftelephoneinreviewprocessIncreasedthenumberof1stcycleapprovalsDecreasedthetotalnumberofreviewcyclesTotaltimetoapprovaldidnotincreaseinspiteofincreasedworkload ben ThisguidancecontainsanInternetlinktoalistingofdrugproducts eachlinkedinturntoacorrespondingbioequivalencerecommendation Clickingonaproductnameinthatlistwillbringupthebioequivalencerecommendationsforthatspecificproduct Recommendationshavebeendevelopedforseveraldrugsthatarenotyeteligibleforgenericcompetition i e newlyapprovedproducts andsomeolderproductsforwhichinformationhaspreviouslybeenprovided Asadditionalrecommendationsaredeveloped thosewillbepostedontheWebsite Whenthisguidanceisfinalized thelistingwillbeavailablethroughtheAgency sWebpage QbR 从提出到完善 1 2005 2 2005 Question basedReviewDrafted3 2005 4 2005 DivisionDirectorsDiscussion5 2005 6 2005 TeamLeadersDiscussion7 2005 8 2005 ReviewersDiscussion9 2005 1 2006 ModelPharmaceuticalDevelopmentReportandQualityOverallSummary2 2005 12 2005 DiscussionswithStakeholdersandUpperManagement1 2005 12 2006 GradualImplementation1 2007 FullImplementation QbR的内涵 Question basedReviewisageneralframeworkforascienceandrisk basedassessmentofproductqualityQuestion basedReviewcontainstheimportantscientificandregulatoryreviewquestionsto关键制备工艺及其质控产品的工艺 处方是否有设计缺陷强调QbD ANDAsUnderQbR Continued FutureGenericApplicationsgenericsponsorssubmitgenericapplicationsbasedontheformatofICHCTD preferably electronicallyModule1 AdministrativeInformationModule2 QualityOverallSummaryandClinicalSummaryModule3 QualityPharmaceuticalDevelopment QualitybyDesignModule4 NonclinicalModule5 Clinical Bioequivalence 新药申报 NDA 和仿制药申报 ANDA 的比较 NDArequirements ANDArequirements 美国仿制药申报 FDA仿制药部 OGD 鼓励申请人根据ICH对于人用药物的注册技术要求 即通用技术文件 CTD 的格式 提交ADNA 包括以下模块 OGDQBRThequestionbasedreview QBR servesasageneralframeworkfortheCMCassessmentofANDAsthatfocusesoncriticalpharmaceuticalattributesofproductquality Withjustification deviationsoralternateapproachestothisframeworkcanbeutilize asnecessary toensuretheadequacyoftheassessmentofproductqualityForeaseofdiscussion asimpledosageformisdefinedasasolutionoranimmediaterelease IR solidoraldosageform QBR DrugSubstance DescriptionandCharacterizationWhatarethenomenclature molecularstructure molecularformula andmolecularweight WhatarethepKa aqueoussolubility asfunctionofpH partitioncoefficient polymorphism hygroscopicity andmeltingpoints ControlofDrugSubstanceAppearanceandIdentificationArethespecificationsforappearanceandidentificationappropriate AssayIstheproposeddrugsubstanceassaylimitacceptable Istheanalyticalmethodvalidatedandstability indicating ImpuritiesandResidualSolventsAreallthepossibleimpuritiesaccountedfor Whatisthejustificationfortheimpurityacceptancelimits Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction AdditionalSpecificationsBasedonthereviewofthedrugproductandmanufacturingprocessarespecification s requiredonparticlesize solidstateform moisturecontent orotherpropertiesofthedrugsubstanceandwhy Foreachadditionalspecification Whatisthejustificationfortheacceptancelimit Isitsuitableforitsintendedfunction QBR DrugProduct DescriptionandCompositionWhatarethecomponentsandcompositionofthefinalproduct Whatisthefunctionofeachexcipient DoanyexcipientsexceedIIGlimitsinthecontextofmaximumdailydoseandrouteofadministration IfproductisanNTIdrugoranon simpledosageformAretheresignificantdifferencesbetweenthisformulationandtheRLDthatpresentpotentialconcernswithrespecttoproductperformance ControlofExcipientsWhatarethespecificationsfortheinactiveingredientsandaretheyappropriatepertheirintendedfunction SimpleDosageForm EitherasolutionoranIRsolidoraldosageform QBR DrugProduct Continued ManufactureForallproductsDoesthebatchformulaaccuratelyreflectthedrugproductcomposition Ifnot whatarethedifferencesandthejustifications e g potencyadjustment overage excesscoatingsolution etc IfproductisnotasolutionWhatarethekeyunitoperationsinthedrugproductmanufacturingprocess Arein processtestsidentifiedbythesponsorappropriate Whatisthedifferenceinsizebetweencommercialscaleandbiobatchanddotheyusethesameunitoperations IfproductisanNTIdrugoranon simpledosageformWhatarethecriticalstepsinthemanufacturingprocess Whatarethein processtests controlsthatensureeachcriticalstepissuccessful Intheproposedscaleupprocesswhatoperatingconditionswillbeadjustedtoensuretheproductmeetsallin processandfinalproductspecifications Whydoyoubelievethesponsorhasdemonstratedareasonableplantoscaleuptheprocess QBR DrugProduct Continued ControlofDrugProductIdentityIsthespecificationfortheidentityofthedrugproductappropriate AssayandUniformityAretheproposeddrugassaylimitsacceptable Istheassaymethodvalidatedandstability indicating Howisthecontentuniformityevaluated Isitacceptable Impurities DegradationProductsArethedegradationproductsandtheiroriginsadequatelydescribed Whatisthejustificationfortheacceptancelimitsondegradationproducts Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction DissolutionWhatarethedissolutionmethodsandacceptancecriteriaandhowweretheyselected Whatisthesignificantroleofdissolutiontestingforthisproduct AdditionalSpecificationsArethereadditionalspecificationsthatarerequiredtoensuretheproductwillperformaslabeledandwhy Foreachadditionalspecification Whatisthejustificationfortheacceptancelimit Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction QBR DrugProduct Continued ReferenceStandardArethereaqualificationreportandCOAprovidedforthereferencestandardoristhismaterialpurchasedfromanappropriatesource Container ClosureSystemHasthecontainer closuresystembeenusedinapreviouslyapprovedproductorotherwisequalifiedforthisdosageform Whatspecificcontainer closureattributesarenecessarytoensureproductperformance DrugProductStabilityDataWhatstabilitydatahasbeensubmitted Hasthesponsorprovidedstabilitydataforthedrugproductpackagedintheproposedcontainer closure AcceptancelimitsAreallattributesthatcouldchangeovertimeevaluatedinthestabilitytests Whataretheacceptablelimitsontheseattributes Shelf liferecommendationWhatisthejustificationofshelflife Isthepost approvalstabilityprotocolacceptable QBR ProductDevelopmentReportforComplexDosageFormsandNTIDrugs DrugSubstanceWhichpropertiesorphysicalchemicalcharacteristicsofthedrugsubstanceaffectdrugproductperformance ExcipientsIsthereanyevidenceofincompatibilitybetweentheexcipientsanddrugsubstance FormulationWhatistheformulationintendedtodo Whatmechanismdoesitusetoaccomplishthis Wereanyotherformulationalternativesinvestigatedandhowdidtheseperform Wereanyformulationoptimizationorsensitivitystudiescarriedoutforvariationsincompositionaroundthefinalformulation Werethesestudiessufficienttoestablishadesignspaceforformulationcomposition Istheformulationdesignconsistentwiththedosageformclassificationinthelabel DrugProductWhatarethecriticalqualityattributesthatensuretheproductwillperformaslabeled QBR ProcessDevelopmentReport ProcessDescriptionWhywasthismanufacturingprocessselectedforthisdrugproduct Werealternativeunitoperationsinvestigatedbyprocessdevelopmentstudies CriticalStepsandScaleUpHowwerethecriticalstepsintheprocessidentified Whatarethecriticalprocessparametersforeachcriticalstepandhowweretheyidentified monitoredand orcontrolled Wereprocessdevelopmentstudiesthatvariedstartingmaterialsoroperatingparametersconducted Werethesestudiessufficienttoestablishadesignspaceforprocess InprocesstestsWhyiseachinprocesstestrequired Howweretheacceptancelimitschosen Whywerethein processtestsidentifiedascriticaltoproductquality Whatscale upexperiencedoesthesponsorhavewiththeunitoperationsinthisprocess QBR RiskSummary NTIdrugClassifiedasanon NTIdrug riskscore 0ClassifiedasanNTIdrug riskscore 1DosageFormSimpleDosageForm riskscore 0OtherDosageFormsandNTIdrugs riskscore 1DevelopmentReportIfthesponsorsubmitsadevelopmentreportthataddressestheFDA squestions Riskscore 0SolutionandIRProducts ProductDevelopmentReportOtherDosageForms ProductandProcessDevelopmentReportsInsufficientormissingdevelopmentreport riskscore 1IftheapplicationisofhighoverallqualityLessthanorequalto2cycles riskscore 0 Greaterthan2cycles riskscore 1 QBR Risk BasedConclusion Shouldtheapplicationbeapproved Whatpost approvalwaiv