中美仿制药研发和申报流程概述专家讲座

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背景美国仿制药：申报、基于问题审评和研发对策展望1234中美仿制药研发和申报流程概述专家讲座第1页药品经济学催生美国仿制药制度美国社会安全制度造成政府赤字严重SSA已经破产：怎样破局？降低医疗费用成为必定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2Ceryak中美仿制药研发和申报流程概述专家讲座第2页1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)

“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?

DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)中美仿制药研发和申报流程概述专家讲座第3页NDA研发和申报中美仿制药研发和申报流程概述专家讲座第4页505(b)(1)新药申报资料内容IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology中美仿制药研发和申报流程概述专家讲座第5页6.HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)中美仿制药研发和申报流程概述专家讲座第6页10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification中美仿制药研发和申报流程概述专家讲座第7页505(b)(2):历史过程HatchWaxman法案:1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizen’sPetition()能够降低研发费用和审评力量浪费中美仿制药研发和申报流程概述专家讲座第8页505(b)(2)关键:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?中美仿制药研发和申报流程概述专家讲座第9页505(b)(2)意义介于全创新药品和仿制药之间含有专利保护,且不存在产权纠纷和仿制药不一样,无替换要求应有突破中美仿制药研发和申报流程概述专家讲座第10页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中美仿制药研发和申报流程概述专家讲座第11页505(b)(2)情形Newactiveingredient(differentsalt,ester,complex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRx

OTCswitchNewCombinationProducts“Genericbiologics”中美仿制药研发和申报流程概述专家讲座第12页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中美仿制药研发和申报流程概述专家讲座第13页505(b)(2)新药成功例子NCEThalomid®(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine()Guaifenesinextendedrelease()Quininesulfate()NewDosageFormTramadolorallydisintegratingtablets()Ondansetronoralspray(filed)中美仿制药研发和申报流程概述专家讲座第14页505(b)(2)新药例子NewDosingRegimenTramadolextendedreleasetablets()NewStrength/FormulationAntara(micronizedfenofibratecaps)()(130mgisBEtoTricor200mg)NewFormulation/InactiveIngredientAvita(tretinoingel)(newemollient)(1998)Abraxane(cremaphor-freepaclitaxel)()Oxy-ADF(oxycodoneformulatedtoreducedrugabuse)(indevelopment)中美仿制药研发和申报流程概述专家讲座第15页505(b)(2)新药例子NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)()NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)Rx

OTCSwitchAlavert(loratadine)()中美仿制药研发和申报流程概述专家讲座第16页505(b)(2)新药例子“GenericBiologics”Omnitrope(rHGH)()Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals-05)Fortical(calcitoninsalmonrecombinant)()*Examplesbasedonpubliclyavailableinformation中美仿制药研发和申报流程概述专家讲座第17页FDANDA审评过程中美仿制药研发和申报流程概述专家讲座第18页FDA能够使用已经有数据用于审评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)]中美仿制药研发和申报流程概述专家讲座第19页美国仿制药

Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.中美仿制药研发和申报流程概述专家讲座第20页

Genericdrugapplicationsaretermed“abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.中美仿制药研发和申报流程概述专家讲座第21页FDA审评仿制药程序中美仿制药研发和申报流程概述专家讲座第22页二、美国仿制药申报、审评和研发对策由FDAOGD审评审评方式采取QbR申报资料采取CTD资料内容也针对问题中美仿制药研发和申报流程概述专家讲座第23页中美仿制药研发和申报流程概述专家讲座第24页中美仿制药研发和申报流程概述专家讲座第25页中美仿制药研发和申报流程概述专家讲座第26页OfficeofGenericDrugs中美仿制药研发和申报流程概述专家讲座第27页怎样确保审评质量和效率？StructuredProductLabeling(SPL)MakeslabelingavailableonInternetviaNationalLibraryofMedicine(NLM)ReviewEfficienciesEarlyDMFreviewClusterreviews–productspecialistsSupplementtriagingatteamleaderlevelDBETruncatedReviewQuestionbasedReview(QbR)Willhaveaverypositiveimpact中美仿制药研发和申报流程概述专家讲座第28页NewresourcesdevelopedDissolutionDatabaseIndividualProductBioequivalenceInformationEncouragedtheuseoftelephoneinreviewprocessIncreasedthenumberof1stcycleapprovalsDecreasedthetotalnumberofreviewcyclesTotaltimetoapprovaldidnotincreaseinspiteofincreasedworkload中美仿制药研发和申报流程概述专家讲座第29页DissolutionMethodsforDrugProductsNew!!中美仿制药研发和申报流程概述专家讲座第30页ben中美仿制药研发和申报流程概述专家讲座第31页中美仿制药研发和申报流程概述专家讲座第32页ThisguidancecontainsanInternetlinktoalistingofdrugproducts,eachlinkedinturntoacorrespondingbioequivalencerecommendation.Clickingonaproductnameinthatlistwillbringupthebioequivalencerecommendationsforthatspecificproduct.Recommendationshavebeendevelopedforseveraldrugsthatarenotyeteligibleforgenericcompetition(i.e.,newlyapprovedproducts)andsomeolderproductsforwhichinformationhaspreviouslybeenprovided.Asadditionalrecommendationsaredeveloped,thosewillbepostedontheWebsite.Whenthisguidanceisfinalized,thelistingwillbeavailablethroughtheAgency’sWebpage.中美仿制药研发和申报流程概述专家讲座第33页OFFICEOFGENERICDRUGSTABLEOFBIOEQUIVALENCERECOMMENDATIONSActiveIngredientPotencyDosageFormRouteofAdministrationDateFinalizedAlmotriptanMalate12.5mgTabletOral5/16/Alosetron1mgTabletOral5/31/Atazanavir200mgCapsuleOral3/18/Atomoxetine60mgCapsuleOral6/13/CefditorenPivoxil200mgTabletOral3/18/Dutasteride0.5mgCapsuleOral7/5/Eplerenone50mgTabletOral3/18/FosamprenavirCalcium700mgTabletOral3/18/Memantine10mgTabletOral7/8/Rosuvastatin40mgTabletOral3/18/Tadalafil20mgTabletOral3/18/VardenafilHCl20mgTabletOral4/11/中美仿制药研发和申报流程概述专家讲座第34页QbR:从提出到完善1/–2/:Question-basedReviewDrafted3/–4/:DivisionDirectorsDiscussion5/–6/:TeamLeadersDiscussion7/–8/:ReviewersDiscussion9/–1/:ModelPharmaceuticalDevelopmentReportandQualityOverallSummary2/–12/:DiscussionswithStakeholdersandUpperManagement1/–12/:Gradual Implementation1/:FullImplementation中美仿制药研发和申报流程概述专家讲座第35页QbR内涵Question-basedReviewisageneralframeworkforascienceandrisk-basedassessmentofproductqualityQuestion-basedReviewcontainstheimportantscientificandregulatoryreviewquestionsto关键制备工艺及其质控产品工艺、处方是否有设计缺点强调QbD中美仿制药研发和申报流程概述专家讲座第36页ANDAsUnderQbR(Continued)FutureGenericApplications

genericsponsorssubmitgenericapplicationsbasedontheformatofICHCTD,preferably,electronicallyModule1:AdministrativeInformationModule2:QualityOverallSummaryandClinicalSummaryModule3:QualityPharmaceuticalDevelopment;QualitybyDesignModule4:NonclinicalModule5:Clinical(Bioequivalence)中美仿制药研发和申报流程概述专家讲座第37页新药申报（NDA）

和仿制药申报（ANDA）比较1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.AnimalStudies7.ClinicalStudies8.BioavailabilityNDArequirementsANDArequirements1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Bioequivalence中美仿制药研发和申报流程概述专家讲座第38页美国仿制药申报模块1包含了管理和处方信息，这个是区域特异。在美国应包含以下信息：①申请书3674；②专利认证信息；③原研药信息，包含NDA号、药名和生产商；④仿制药和原研药对比，包含使用条件、有效成份、非有效成份、给药路径、剂型和剂量；⑤环境影响分析；⑥药品说明书（初稿）。

模块2模块2为概论。它包含药理作用分类，作用模式以及临床适应证。模块3应该包含原料药和制剂相关化学、生产和质量控制信息。FDA仿制药部（OGD）勉励申请人依据ICH对于人用药品注册技术要求，即通用技术文件（CTD）格式，提交ADNA。包含以下模块:中美仿制药研发和申报流程概述专家讲座第39页模块4模块4是关于动物试验信息，并不是ANDA要求。所以，仿制药申请普通不包含模块4。

模块5模块5是临床研究汇报。对于ADNA，生物等效性信息应该在这个部分表达，包含：①生物等效性研究；②体外－体内相关性研究；③生物分析方法开发。案例汇报，包含不良反应事件汇报也应包含在此。

中美仿制药研发和申报流程概述专家讲座第40页OGDQBR

Thequestionbasedreview(QBR)servesasageneralframeworkfortheCMCassessmentofANDAsthatfocusesoncriticalpharmaceuticalattributesofproductquality.Withjustification,deviationsoralternateapproachestothisframeworkcanbeutilize,asnecessary,toensuretheadequacyoftheassessmentofproductquality

Foreaseofdiscussion,asimpledosageformisdefinedasasolutionoranimmediaterelease(IR)solidoraldosageform.中美仿制药研发和申报流程概述专家讲座第41页QBR:DrugSubstanceDescriptionandCharacterizationWhatarethenomenclature,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?中美仿制药研发和申报流程概述专家讲座第42页QBR:DrugProductDescriptionandCompositionWhatarethecomponentsandcompositionofthefinalproduct?Whatisthefunctionofeachexcipient?DoanyexcipientsexceedIIGlimitsinthecontextofmaximumdailydoseandrouteofadministration?IfproductisanNTIdrugoranon-simpledosageformAretheresignificantdifferencesbetweenthisformulationandtheRLDthatpresentpotentialconcernswithrespecttoproductperformance?

ControlofExcipientsWhatarethespecificationsfortheinactiveingredientsandaretheyappropriatepertheirintendedfunction?SimpleDosageForm:EitherasolutionoranIRsolidoraldosageform中美仿制药研发和申报流程概述专家讲座第43页QBR:DrugProduct(Continued)ManufactureForallproductsDoesthebatchformulaaccuratelyreflectthedrugproductcomposition?Ifnot,whatarethedifferencesandthejustifications(e.g.potencyadjustment,overage,excesscoatingsolution,etc.)?IfproductisnotasolutionWhatarethekeyunitoperationsinthedrugproductmanufacturingprocess?Arein-processtestsidentifiedbythesponsorappropriate?Whatisthedifferenceinsizebetweencommercialscaleandbiobatchanddotheyusethesameunitoperations?IfproductisanNTIdrugoranon-simpledosageformWhatarethecriticalstepsinthemanufacturingprocess?Whatarethein-processtests/controlsthatensureeachcriticalstepissuccessful?Intheproposedscaleupprocesswhatoperatingconditionswillbeadjustedtoensuretheproductmeetsallin-processandfinalproductspecifications?Whydoyoubelievethesponsorhasdemonstratedareasonableplantoscaleuptheprocess?中美仿制药研发和申报流程概述专家讲座第44页QBR:DrugProduct(Continued)ControlofDrugProductIdentityIsthespecificationfortheidentityofthedrugproductappropriate?AssayandUniformityAretheproposeddrugassaylimitsacceptable?Istheassaymethodvalidatedandstability-indicating?Howisthecontentuniformityevaluated?Isitacceptable?Impurities/DegradationProductsArethedegradationproductsandtheiroriginsadequatelydescribed?Whatisthejustificationfortheacceptancelimitsondegradationproducts?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?Dissolution

Whatarethedissolutionmethodsandacceptancecriteriaandhowweretheyselected?Whatisthesignificantroleofdissolutiontestingforthisproduct?AdditionalSpecificationsArethereadditionalspecificationsthatarerequiredtoensuretheproductwillperformaslabeledandwhy?Foreachadditionalspecification:Whatisthejustificationfortheacceptancelimit?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?中美仿制药研发和申报流程概述专家讲座第45页QBR:DrugProduct(Continued)ReferenceStandardArethereaqualificationreportandCOAprovidedforthereferencestandardoristhismaterialpurchasedfromanappropriatesource?Container/ClosureSystemHasthecontainer/closuresystembeenusedinapreviouslyapprovedproductorotherwisequalifiedforthisdosageform?Whatspecificcontainer/closureattributesarenecessarytoensureproductperformance?DrugProductStabilityDataWhatstabilitydatahasbeensubmitted?Hasthesponsorprovidedstabilitydataforthedrugproductpackagedintheproposedcontainer/closure?AcceptancelimitsAreallattributesthatcouldchangeovertimeevaluatedinthestabilitytests?Whataretheacceptablelimitsontheseattributes?

Shelf-liferecommendationWhatisthejustificationofshelflife?Isthepost-approvalstabilityprotocolacceptable?中美仿制药研发和申报流程概述专家讲座第46页QBR:ProductDevelopmentReportforComplexDosageFormsandNTIDrugsDrugSubstanceWhichpropertiesorphysicalchemicalcharacteristicsofthedrugsubstanceaffectdrugproductperformance?ExcipientsIsthereanyevidenceofincompatibilitybetweentheexcipientsanddrugsubstance?FormulationWhatistheformulationintendedtodo?Whatmechanismdoesitusetoaccomplishthis?Wereanyotherformulationalternativesinvestigatedandhowdidtheseperform?Wereanyformulationoptimizationorsensitivitystudiescarriedoutforvariationsincompositionaroundthefinalformulation?Werethesestudiessufficienttoestablishadesignspaceforformulationcomposition?Istheformulationdesignconsistentwiththedosageformclassificationinthelabel?DrugProductWhatarethecriticalqualityattributesthatensuretheproductwillperformaslabeled?中美仿制药研发和申报流程概述专家讲座第47页QBR:ProcessDevelopmentReportProcessDescriptionWhywasthismanufacturingprocessselectedforthisdrugproduct?Werealternativeunitoperationsinvestigatedbyprocessdevelopmentstudies?CriticalStepsandScaleUpHowwerethecriticalstepsintheprocessidentified?Whatarethecriticalprocessparametersforeachcriticalstepandhowweretheyidentified,monitoredand/orcontrolled?Wereprocessdevelopmentstudiesthatvariedstartingmaterialsoroperatingparametersconducted?Werethesestudiessufficienttoestablishadesignspaceforprocess?InprocesstestsWhyiseachinprocesstestrequired?Howweretheacceptancelimitschosen?Whywerethein-processtestsidentifiedascriticaltoproductquality?Whatscale-upexperiencedoesthesponsorhavewiththeunitoperationsinthisprocess?中美仿制药研发和申报流程概述专家讲座第48页QBR:RiskSummaryNTIdrugClassifiedasanon-NTIdrug,riskscore=+0ClassifiedasanNTIdrug,riskscore=+1DosageFormSimpleDosageForm,riskscore=+0OtherDosageFormsandNTIdrugs,riskscore=+1DevelopmentReportIfthesponsorsubmitsadevelopmentreportthataddressestheFDA’squestions:Riskscore=+0SolutionandIRProducts:ProductDevelopmentReportOtherDosageForms:ProductandProcessDevelopmentReportsInsufficientormissingdevelopmentreport,riskscore=+1IftheapplicationisofhighoverallqualityLessthanorequalto2cycles,riskscore=+0.