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Telmail:jiashengtu@2011.11郑州中美仿制药研发申报流程共59页，您现在浏览的是第1页!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1234中美仿制药研发申报流程共59页，您现在浏览的是第2页!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3Ceryak中美仿制药研发申报流程共59页，您现在浏览的是第3页!1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)

“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?

DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)中美仿制药研发申报流程共59页，您现在浏览的是第4页!505(b)(1)新药申报资料内容IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology中美仿制药研发申报流程共59页，您现在浏览的是第5页!10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification中美仿制药研发申报流程共59页，您现在浏览的是第6页!505(b)(2)的关键:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?中美仿制药研发申报流程共59页，您现在浏览的是第7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中美仿制药研发申报流程共59页，您现在浏览的是第8页!505(b)(2)排他性Exclusivitiesavailablefor505(b)(2)productsNCEExclusivity(5years)NewProductExclusivity(3years)OrphanDrugExclusivity(7years)Pediatricexclusivityextensions(6months)PatentIssues505(b)(2)drugscanhaveOrangeBook-listedpatents,andenjoy30-monthstayprotectionagainstgenericpetitorsBut,505(b)(2)NDAsmayalsobeblockedbypatentsonReferenceDrugs中美仿制药研发申报流程共59页，您现在浏览的是第9页!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)中美仿制药研发申报流程共59页，您现在浏览的是第10页!505(b)(2)新药的例子“GenericBiologics”Omnitrope(rHGH)(2006)Glucagen(glucagonrebinant)(1998)Hyaluronidase(variousapprovals2004-05)Fortical(calcitoninsalmonrebinant)(2005)*Examplesbasedonpubliclyavailableinformation中美仿制药研发申报流程共59页，您现在浏览的是第11页!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)]中美仿制药研发申报流程共59页，您现在浏览的是第12页!

Genericdrugapplicationsaretermed“abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.中美仿制药研发申报流程共59页，您现在浏览的是第13页!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中美仿制药研发申报流程共59页，您现在浏览的是第14页!中美仿制药研发申报流程共59页，您现在浏览的是第15页!OfficeofGenericDrugs中美仿制药研发申报流程共59页，您现在浏览的是第16页!NewresourcesdevelopedDissolutionDatabaseIndividualProductBioequivalenceInformationEncouragedtheuseoftelephoneinreviewprocessIncreasedthenumberof1stcycleapprovalsDecreasedthetotalnumberofreviewcyclesTotaltimetoapprovaldidnotincreaseinspiteofincreasedworkload中美仿制药研发申报流程共59页，您现在浏览的是第17页!ben中美仿制药研发申报流程共59页，您现在浏览的是第18页!ThisguidancecontainsanInternetlink

toalistingofdrugproducts,eachlinkedinturntoacorrespondingbioequivalenceremendation.Clickingonaproductnameinthatlistwillbringupthebioequivalenceremendationsforthatspecificproduct.Remendationshavebeendevelopedforseveraldrugsthatarenotyeteligibleforgenericpetition(i.e.,newlyapprovedproducts)andsomeolderproductsforwhichinformationhaspreviouslybeenprovided.Asadditionalremendationsaredeveloped,thosewillbepostedontheWebsite.Whenthisguidanceisfinalized,thelistingwillbeavailablethroughtheAgency’sWebpage.中美仿制药研发申报流程共59页，您现在浏览的是第19页!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:Gradual Implementation1/2007:FullImplementation中美仿制药研发申报流程共59页，您现在浏览的是第20页!ANDAsUnderQbR(Continued)FutureGenericApplications

genericsponsorssubmitgenericapplicationsbasedontheformatofICHCTD,preferably,electronicallyModule1:AdministrativeInformationModule2:QualityOverallSummaryandClinicalSummaryModule3:QualityPharmaceuticalDevelopment;QualitybyDesignModule4:NonclinicalModule5:Clinical(Bioequivalence)中美仿制药研发申报流程共59页，您现在浏览的是第21页!美国仿制药申报模块1包含了管理和处方信息，这个是区域特异的。在美国应包括以下信息：①申请书3674；②专利认证信息；③原研药信息，包括NDA号、药名和生产商；④仿制药和原研药的对比，包括使用条件、有效成分、非有效成分、给药途径、剂型和剂量；⑤环境影响分析；⑥药品说明书（草稿）。

模块2模块2为概论。它包括药理作用分类，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的化学、生产和质量控制信息。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：中美仿制药研发申报流程共59页，您现在浏览的是第22页!

OGDQBR

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

Foreaseofdiscussion,asimpledosageformisdefinedasasolutionoranimmediaterelease(IR)solidoraldosageform.中美仿制药研发申报流程共59页，您现在浏览的是第23页!QBR:DrugProductDescriptionandCompositionWhataretheponentsandpositionofthefinalproduct?Whatisthefunctionofeachexcipient?DoanyexcipientsexceedIIGlimitsinthecontextofmaximumdailydoseandrouteofadministration?IfproductisanNTIdrugoranon-simpledosageformAretheresignificantdifferencesbetweenthisformulationandtheRLDthatpresentpotentialconcernswithrespecttoproductperformance?

ControlofExcipientsWhatarethespecificationsfortheinactiveingredientsandaretheyappropriatepertheirintendedfunction?SimpleDosageForm:EitherasolutionoranIRsolidoraldosageform中美仿制药研发申报流程共59页，您现在浏览的是第24页!QBR:DrugProduct(Continued)ControlofDrugProductIdentityIsthespecificationfortheidentityofthedrugproductappropriate?AssayandUniformityAretheproposeddrugassaylimitsacceptable?Istheassaymethodvalidatedandstability-indicating?Howisthecontentuniformityevaluated?Isitacceptable?Impurities/DegradationProductsArethedegradationproductsandtheiroriginsadequatelydescribed?Whatisthejustificationfortheacceptancelimitsondegradationproducts?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?Dissolution

Whatarethedissolutionmethodsandacceptancecriteriaandhowweretheyselected?Whatisthesignificantroleofdissolutiontestingforthisproduct?AdditionalSpecificationsArethereadditionalspecificationsthatarerequiredtoensuretheproductwillperformaslabeledandwhy?Foreachadditionalspecification:Whatisthejustificationfortheacceptancelimit?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?中美仿制药研发申报流程共59页，您现在浏览的是第25页!QBR:ProductDevelopmentReportforComplexDosageFormsandNTIDrugsDrugSubstanceWhichpropertiesorphysicalchemicalcharacteristicsofthedrugsubstanceaffectdrugproductperformance?ExcipientsIsthereanyevidenceofinpatibilitybetweentheexcipientsanddrugsubstance?FormulationWhatistheformulationintendedtodo?Whatmechanismdoesitusetoacplishthis?Wereanyotherformulationalternativesinvestigatedandhowdidtheseperform?Wereanyformulationoptimizationorsensitivitystudiescarriedoutforvariationsinpositionaroundthefinalformulation?Werethesestudiessufficienttoestablishadesignspaceforformulationposition?Istheformulationdesignconsistentwiththedosageformclassificationinthelabel?DrugProductWhatarethecriticalqualityattributesthatensuretheproductwillperformaslabeled?中美仿制药研发申报流程共59页，您现在浏览的是第26页!QBR:RiskSummaryNTIdrugClassifiedasanon-NTIdrug,riskscore=+0ClassifiedasanNTIdrug,riskscore=+1DosageFormSimpleDosageForm,riskscore=+0OtherDosageFormsandNTIdrugs,riskscore=+1DevelopmentReportIfthesponsorsubmitsadevelopmentreportthataddressestheFDA’squestions:Riskscore=+0SolutionandIRProducts:ProductDevelopmentReportOtherDosageForms:ProductandProcessDevelopmentReportsInsufficientormissingdevelopmentreport,riskscore=+1IftheapplicationisofhighoverallqualityLessthanorequalto2cycles,riskscore=+0.Greaterthan2cycles,riskscore=+1中美仿制药研发申报流程共59页，您现在浏览的是第27页!生物等效性豁免生物等效性豁免是指基于体外数据审批的管理程序。固体制剂往往采用溶出度、释放度作为证据。中美仿制药研发申报流程共59页，您现在浏览的是第28页!II、基于剂型剂量比例的生物等效性豁免当最高剂量的BE数据具备时，下列情况可生物等效性豁免：1、 同样的剂型；2、 主药和辅料的比例相当；3、 对于缓释制剂，同样的释放机制；4、 溶出度相似因子符合规定；5、 比例变化在线性动力学范围内。中美仿制药研发申报流程共59页，您现在浏览的是第29页!三、我国仿制药的申报、审评和研发对策新药新、仿制药同、新剂型特两报两批豁免生物等效性试验：1、注射液；2、外用制剂；中美仿制药研发申报流程共59页，您现在浏览的是第30页!Technology美国2009年仿制药占处方药市场比例70%以上，处于仿制药消费大国之首（产品从150个国家进口）；德国、英国的仿制药也已超过50%。国外仿制药现状中国仿制药产业发展的机遇机遇与挑战中国仿制药产业发展的挑战国内老龄化，城镇化加速造成的医改和对仿制药的要求急剧增加10年内专利药几种到期造成了仿制药的战略机遇部分企业已经开始国际标准的注册和海外战略，取得了积极进展整体研发技术水平低缺乏仿制药制剂的国际注册经验，制剂产品很少进入发达国家市场，国际竞争力不强缺乏国际标准和通行质量规范，质量管理的理念和管理水平与国际水平尚有明显差距，造成了产品国际竞争能力不足中美仿制药研发申报流程共59页，您现在浏览的是第31页!NDA的研发和申报中美仿制药研发申报流程共59页，您现在浏览的是第32页!6.

HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)中美仿制药研发申报流程共59页，您现在浏览的是第33页!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中美仿制药研发申报流程共59页，您现在浏览的是第34页!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

应有突破中美仿制药研发申报流程共59页，您现在浏览的是第35页!505(b)(2)情形Newactiveingredient(differentsalt,ester,plex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRxOTCswitchNewCombinationProducts“Genericbiologics”中美仿制药研发申报流程共59页，您现在浏览的是第36页!505(b)(2)新药的成功例子NCEThalomid®(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine(2000)Guaifenesinextendedrelease(2002)Quininesulfate(2005)NewDosageFormTramadolorallydisintegratingtablets(2005)Ondansetronoralspray(filed2006)中美仿制药研发申报流程共59页，您现在浏览的是第37页!505(b)(2)新药的例子NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)(2003)NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)RxOTCSwitchAlavert(loratadine)(2002)中美仿制药研发申报流程共59页，您现在浏览的是第38页!FDANDA审评过程中美仿制药研发申报流程共59页，您现在浏览的是第39页!美国仿制药

Agenericdrugproductisonethatisparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.中美仿制药研发申报流程共59页，您现在浏览的是第40页!FDA审评仿制药程序中美仿制药研发申报流程共59页，您现在浏览的是第41页!中美仿制药研发申报流程共59页，您现在浏览的是第42页!中美仿制药研发申报流程共59页，您现在浏览的是第43页!如何保证审评质量和效率？StructuredProductLabeling(SPL)MakeslabelingavailableonInternetviaNationalLibraryofMedicine(NLM)ReviewEfficienciesEarlyDMFreviewClusterreviews–productspecialistsSupplementtriagingatteamleaderlevelDBETruncatedReviewQuestionbasedReview(QbR)Willhaveaverypositiveimpact中美仿制药研发申报流程共59页，您现在浏览的是第44页!DissolutionMethodsforDrugProductsNew!!中美仿制药研发申报流程共59页，您现在浏览的是第45页!中美仿制药研发申报流程共59页，您现在浏览的是第46页!OFFICEOFGENERICDRUGSTABLEOFBIOEQUIVALENCERECOMMENDATIONSActiveIngredientPotencyDosageFormRouteofAdministrationDateFinalizedAlmotriptanMalate12.5mgTabletOral5/16/2005Alosetron1mgTabletOral5/31/2005Atazanavir200mgCapsuleOral3/18/2005Atomoxetine60mgCapsuleOral6/13/2005CefditorenPivoxil200mgTabletOral3/18/2005Dutasteride0.5mgCapsuleOral7/5/2005Eplerenone50mgTabletOral3/18/2005FosamprenavirCalcium700mgTabletOral3/18/2005Memantine10mgTabletOral7/8/2005Rosuvastatin40mgTabletOral3/18/2005Tadalafil20mgTabletOral3/18/2005VardenafilHCl20mgTabletOral4/11/2005中美仿制药研发申报流程共59页，您现在浏览的是第47页!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中美仿制药研发申报流程共59页，您现在浏览的是第48页!新药申报（NDA）

和仿制药申报（ANDA）的比较1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.AnimalStudies7.ClinicalStudies8.BioavailabilityNDArequirementsANDArequirements1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Bioequivalence中美仿制药研发申报流程共59页，您现在浏览的是第49页!模块4模块4是关于动物实验的信息，并不是ANDA要求的。所以，仿制药申请一般不包含模块4。

模块5模块5是临床研究报告。对于ADNA，生物等效性信息应该在这个部分体现，包括：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。案例报告，包括不良反应事件报告也应包括在此。

中美仿制药研发申报流程共59页，您现在浏览的是第50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?中美仿制药研发申报流程共59页，您现在浏览的是第51页!QBR:DrugProduct(Continued)ManufactureForallproductsDoesthebatchformulaaccuratelyreflectthedrugproductposition?Ifnot,whatarethedifferencesandthejustifications(e.g.potencyadjustment,overage,excesscoatingsolution,etc.)?Ifproductisnotasolution

Whatarethekeyunitoperationsinthedrugproductmanufacturingprocess?Arein-processtestsidentifiedbythesponsorappropriate?Whatisthedifferenceinsizebetweenmercialscaleandbiobatchanddotheyusethesameunitoperations?IfproductisanNTIdrugoranon-simpledosageformWhatarethecriticalstepsinthemanufacturingprocess?Whatarethein-processtests/controlsthatensureeachcriticalstepissuccessful?Intheproposedscaleupprocesswhatoperatingconditionswillbeadjustedtoensuretheproductmeetsallin-processandfinalproductspecifications?Whydoyoubelievethesponsorhasdemonstratedareasonableplantoscaleuptheprocess?中美仿制药研发申报流程共59页，您现在浏览的是第52页!QBR:DrugProduct(Continued)ReferenceStandardArethereaqualificationreportandCOAprovidedforthereferencestandardoristhismaterialpurchasedfromanappropriatesource?Container/ClosureSystemHasthecontainer/closuresystembeenusedinapreviouslyapprovedproductorotherwisequalifiedforthisdosageform?Whatspecificcontainer/closureattributesarenecessarytoensureproductperformance?DrugProductStabilityDataWhatstabilitydatahasbeensubmitted?Hasthesponsorprovidedstabilitydataforthedrugproductpackagedintheproposedcontainer/closure?AcceptancelimitsAreallattributesthatcouldchangeovertimeevaluatedinthestabilitytests?Whataretheacceptablelimitsontheseattributes?

Shelf-liferemendationWhatisthejustificationofshelflife?Isthepost-approvalstabilityprotocolacceptable?中美仿制药研发申报流程共59页，您现在浏览的是第53页!QBR:ProcessDevelopmentReportProcessDescriptionWhywasthismanufacturingprocessselectedforthisdrugproduct?Werealternativeunitoperationsinvestigatedbyprocessdevelopmentstudies?