中美仿制藥研發(fā)和申報(bào)流程涂家生，Ph.D.中國(guó)藥科大學(xué)藥劑學(xué)教授Telmail:jiashengtu@2011.11鄭州中美仿制藥研發(fā)和申報(bào)流程涂家生，Ph.D.我國(guó)仿制藥申報(bào)、審評(píng)和研發(fā)對(duì)策主要內(nèi)容中美關(guān)于原研藥和仿制藥的背景美國(guó)仿制藥：申報(bào)、基于問(wèn)題的審評(píng)和研發(fā)對(duì)策展望1234我國(guó)仿制藥申報(bào)、審評(píng)和研發(fā)對(duì)策主要內(nèi)容中美關(guān)于原研藥和仿制藥藥物經(jīng)濟(jì)學(xué)催生美國(guó)仿制藥制度美國(guó)社會(huì)安全制度導(dǎo)致政府赤字嚴(yán)重SSA已經(jīng)破產(chǎn)：如何破局？降低醫(yī)療費(fèi)用成為必然Hatch-Waxman法案出臺(tái)美國(guó)FDA藥品注冊(cè)申請(qǐng)：新藥（兩類）、仿制藥和非處方藥申請(qǐng)藥物經(jīng)濟(jì)學(xué)催生美國(guó)仿制藥制度美國(guó)社會(huì)安全制度導(dǎo)致政府赤字嚴(yán)重1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)

“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?

DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)1984年后NewDrugApplicationsAbbNDA的研發(fā)和申報(bào)NDA的研發(fā)和申報(bào)505(b)(1)新藥申報(bào)資料內(nèi)容IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology505(b)(1)新藥申報(bào)資料內(nèi)容Index6.

HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)6.HumanPharmacokineticsand10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification10.Statistical505(b)(2):歷史過(guò)程HatchWaxman法案：1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizen’sPetition(2003)可以降低研發(fā)的費(fèi)用和審評(píng)力量的浪費(fèi)505(b)(2):歷史過(guò)程HatchWaxman法案505(b)(2)的關(guān)鍵:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?505(b)(2)的關(guān)鍵:可靠性Whatis“Reli505(b)(2)的意義介于全創(chuàng)新藥物和仿制藥之間具有專利保護(hù)，且不存在產(chǎn)權(quán)糾紛和仿制藥不同，無(wú)替換的要求

應(yīng)有突破505(b)(2)的意義介于全創(chuàng)新藥物和仿制藥之間505(b)(2)范圍NewChemicalEntity(rarely)：我國(guó)1.1-1.3Newdosageform：我國(guó)5類Newdosingregimen：我國(guó)補(bǔ)充申請(qǐng)Newstrength：我國(guó)補(bǔ)充申請(qǐng)Newrouteofadministration：我國(guó)2類Newindication：我國(guó)1.6505(b)(2)范圍NewChemicalEntity505(b)(2)情形Newactiveingredient(differentsalt,ester,complex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRxOTCswitchNewCombinationProducts“Genericbiologics”505(b)(2)情形Newactiveingredie505(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)NDAsmayalsobeblockedbypatentsonReferenceDrugs505(b)(2)排他性Exclusivitiesavai505(b)(2)新藥的成功例子NCEThalomid?(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine(2000)Guaifenesinextendedrelease(2002)Quininesulfate(2005)NewDosageFormTramadolorallydisintegratingtablets(2005)Ondansetronoralspray(filed2006)505(b)(2)新藥的成功例子NCE505(b)(2)新藥的例子NewDosingRegimenTramadolextendedreleasetablets(2005)NewStrength/FormulationAntara(micronizedfenofibratecaps)(2004)(130mgisBEtoTricor200mg)NewFormulation/InactiveIngredientAvita(tretinoingel)(newemollient)(1998)Abraxane(cremaphor-freepaclitaxel)(2005)Oxy-ADF(oxycodoneformulatedtoreducedrugabuse)(indevelopment)505(b)(2)新藥的例子NewDosingRegim505(b)(2)新藥的例子NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)(2003)NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)RxOTCSwitchAlavert(loratadine)(2002)505(b)(2)新藥的例子NewActiveIngre505(b)(2)新藥的例子“GenericBiologics”O(jiān)mnitrope(rHGH)(2006)Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals2004-05)Fortical(calcitoninsalmonrecombinant)(2005)*Examplesbasedonpubliclyavailableinformation505(b)(2)新藥的例子“GenericBiologiFDANDA審評(píng)過(guò)程FDANDA審評(píng)過(guò)程FDA可以使用已有數(shù)據(jù)用于審評(píng)NDA嗎？Hatch-Waxman之前,國(guó)會(huì)限制FDA在審評(píng)NDAX時(shí)應(yīng)用NDAY的數(shù)據(jù)：“NodatainanNDAcanbeutilizedtosupportanotherNDAwithoutexpresspermissionoftheoriginalNDAholder.”[FDA“FinkelMemorandum”(1978,1981)]Hatch-Waxman解除只適合ANDAs：ANDAprocessallows“genericproducerofthefullytesteddrugtorelyonthesafetyandefficacydataofapriorapplicant....”505(b)(2)doesnotauthorizesuchdatarelianceMerelysetsconditionsforcertainNDAsRequires“fullreportsofinvestigations”establishingsafetyandeffectiveness[21USC§§355(b)(1)(A),(d)(1)]FDA可以使用已有數(shù)據(jù)用于審評(píng)NDA嗎？Hatch-Wax美國(guó)仿制藥

Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.美國(guó)仿制藥Agenericdrugproduct

Genericdrugapplicationsaretermed“abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.GenericdrugapplicationsaFDA審評(píng)仿制藥程序FDA審評(píng)仿制藥程序二、美國(guó)仿制藥的申報(bào)、審評(píng)和研發(fā)對(duì)策由FDA的OGD審評(píng)審評(píng)方式采用QbR申報(bào)資料采用CTD資料內(nèi)容也針對(duì)問(wèn)題二、美國(guó)仿制藥的申報(bào)、審評(píng)和研發(fā)對(duì)策由FDA的OGD審評(píng)中美仿制藥研發(fā)申報(bào)流程課件中美仿制藥研發(fā)申報(bào)流程課件中美仿制藥研發(fā)申報(bào)流程課件OfficeofGenericDrugsOfficeofGenericDrugs如何保證審評(píng)質(zhì)量和效率？StructuredProductLabeling(SPL)MakeslabelingavailableonInternetviaNationalLibraryofMedicine(NLM)ReviewEfficienciesEarlyDMFreviewClusterreviews–productspecialistsSupplementtriagingatteamleaderlevelDBETruncatedReviewQuestionbasedReview(QbR)Willhaveaverypositiveimpact如何保證審評(píng)質(zhì)量和效率？StructuredProductNewresourcesdevelopedDissolutionDatabaseIndividualProductBioequivalenceInformationEncouragedtheuseoftelephoneinreviewprocessIncreasedthenumberof1stcycleapprovalsDecreasedthetotalnumberofreviewcyclesTotaltimetoapprovaldidnotincreaseinspiteofincreasedworkloadNewresourcesdevelopedDissolutionMethodsforDrugProductsNew!!DissolutionMethodsforDrugPbenben中美仿制藥研發(fā)申報(bào)流程課件ThisguidancecontainsanInternetlink

toalistingofdrugproducts,eachlinkedinturntoacorrespondingbioequivalencerecommendation.Clickingonaproductnameinthatlistwillbringupthebioequivalencerecommendationsforthatspecificproduct.Recommendationshavebeendevelopedforseveraldrugsthatarenotyeteligibleforgenericcompetition(i.e.,newlyapprovedproducts)andsomeolderproductsforwhichinformationhaspreviouslybeenprovided.Asadditionalrecommendationsaredeveloped,thosewillbepostedontheWebsite.Whenthisguidanceisfinalized,thelistingwillbeavailablethroughtheAgency’sWebpage.中美仿制藥研發(fā)申報(bào)流程課件OFFICEOFGENERICDRUGSTABLEOFBIOEQUIVALENCERECOMMENDATIONSActiveIngredientPotencyDosageFormRouteofAdministrationDateFinalizedAlmotriptanMalate12.5mgTabletOral5/16/2005Alosetron1mgTabletOral5/31/2005Atazanavir200mgCapsuleOral3/18/2005Atomoxetine60mgCapsuleOral6/13/2005CefditorenPivoxil200mgTabletOral3/18/2005Dutasteride0.5mgCapsuleOral7/5/2005Eplerenone50mgTabletOral3/18/2005FosamprenavirCalcium700mgTabletOral3/18/2005Memantine10mgTabletOral7/8/2005Rosuvastatin40mgTabletOral3/18/2005Tadalafil20mgTabletOral3/18/2005VardenafilHCl20mgTabletOral4/11/2005OFFICEOFGENERICDRUGSTABLEOQbR:從提出到完善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:FullImplementationQbR:從提出到完善QbR的內(nèi)涵Question-basedReviewisageneralframeworkforascienceandrisk-basedassessmentofproductqualityQuestion-basedReviewcontainstheimportantscientificandregulatoryreviewquestionsto關(guān)鍵制備工藝及其質(zhì)控產(chǎn)品的工藝、處方是否有設(shè)計(jì)缺陷強(qiáng)調(diào)QbDQbR的內(nèi)涵Question-basedReviewisANDAsUnderQbR(Continued)FutureGenericApplications

genericsponsorssubmitgenericapplicationsbasedontheformatofICHCTD,preferably,electronicallyModule1:AdministrativeInformationModule2:QualityOverallSummaryandClinicalSummaryModule3:QualityPharmaceuticalDevelopment;QualitybyDesignModule4:NonclinicalModule5:Clinical(Bioequivalence)ANDAsUnderQbR(Continued)Fut新藥申報(bào)（NDA）

和仿制藥申報(bào)（ANDA）的比較1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.AnimalStudies7.ClinicalStudies8.BioavailabilityNDArequirementsANDArequirements1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Bioequivalence新藥申報(bào)（NDA）和仿制藥申報(bào)（ANDA）的比較1.Che美國(guó)仿制藥申報(bào)模塊1包含了管理和處方信息，這個(gè)是區(qū)域特異的。在美國(guó)應(yīng)包括以下信息：①申請(qǐng)書3674；②專利認(rèn)證信息；③原研藥信息，包括NDA號(hào)、藥名和生產(chǎn)商；④仿制藥和原研藥的對(duì)比，包括使用條件、有效成分、非有效成分、給藥途徑、劑型和劑量；⑤環(huán)境影響分析；⑥藥品說(shuō)明書（草稿）。

模塊2模塊2為概論。它包括藥理作用分類，作用模式以及臨床適應(yīng)證。模塊3應(yīng)該包含原料藥和制劑相關(guān)的化學(xué)、生產(chǎn)和質(zhì)量控制信息。FDA仿制藥部（OGD）鼓勵(lì)申請(qǐng)人根據(jù)ICH對(duì)于人用藥物的注冊(cè)技術(shù)要求，即通用技術(shù)文件（CTD）的格式，提交ADNA。包括以下模塊：美國(guó)仿制藥申報(bào)模塊1包含了管理和處方信息，這個(gè)是區(qū)域特異的。模塊4模塊4是關(guān)于動(dòng)物實(shí)驗(yàn)的信息，并不是ANDA要求的。所以，仿制藥申請(qǐng)一般不包含模塊4。

模塊5模塊5是臨床研究報(bào)告。對(duì)于ADNA，生物等效性信息應(yīng)該在這個(gè)部分體現(xiàn)，包括：①生物等效性研究；②體外－體內(nèi)相關(guān)性研究；③生物分析方法開發(fā)。案例報(bào)告，包括不良反應(yīng)事件報(bào)告也應(yīng)包括在此。

模塊4模塊4是關(guān)于動(dòng)物實(shí)驗(yàn)的信息，并不是ANDA要求的。所以

OGDQBR

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

Foreaseofdiscussion,asimpledosageformisdefinedasasolutionoranimmediaterelease(IR)solidoraldosageform.OGDQBR

Theque42QBR: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?QBR:DrugSubstanceDescriptionQBR:DrugProductDescriptionandCompositionWhatarethecomponentsandcompositionofthefinalproduct?Whatisthefunctionofeachexcipient?DoanyexcipientsexceedIIGlimitsinthecontextofmaximumdailydoseandrouteofadministration?IfproductisanNTIdrugoranon-simpledosageformAretheresignificantdifferencesbetweenthisformulationandtheRLDthatpresentpotentialconcernswithrespecttoproductperformance?

ControlofExcipientsWhatarethespecificationsfortheinactiveingredientsandaretheyappropriatepertheirintendedfunction?SimpleDosageForm:EitherasolutionoranIRsolidoraldosageformQBR:DrugProductDescriptionaQBR:DrugProduct(Continued)ManufactureForallproductsDoesthebatchformulaaccuratelyreflectthedrugproductcomposition?Ifnot,whatarethedifferencesandthejustifications(e.g.potencyadjustment,overage,excesscoatingsolution,etc.)?Ifproductisnotasolution

Whatarethekeyunitoperationsinthedrugproductmanufacturingprocess?Arein-processtestsidentifiedbythesponsorappropriate?Whatisthedifferenceinsizebetweencommercialscaleandbiobatchanddotheyusethesameunitoperations?IfproductisanNTIdrugoranon-simpledosageformWhatarethecriticalstepsinthemanufacturingprocess?Whatarethein-processtests/controlsthatensureeachcriticalstepissuccessful?Intheproposedscaleupprocesswhatoperatingconditionswillbeadjustedtoensuretheproductmeetsallin-processandfinalproductspecifications?Whydoyoubelievethesponsorhasdemonstratedareasonableplantoscaleuptheprocess?QBR:DrugProduct(Continued)MQBR:DrugProduct(Continued)ControlofDrugProductIdentityIsthespecificationfortheidentityofthedrugproductappropriate?AssayandUniformityAretheproposeddrugassaylimitsacceptable?Istheassaymethodvalidatedandstability-indicating?Howisthecontentuniformityevaluated?Isitacceptable?Impurities/DegradationProductsArethedegradationproductsandtheiroriginsadequatelydescribed?Whatisthejustificationfortheacceptancelimitsondegradationproducts?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?Dissolution

Whatarethedissolutionmethodsandacceptancecriteriaandhowweretheyselected?Whatisthesignificantroleofdissolutiontestingforthisproduct?AdditionalSpecificationsArethereadditionalspecificationsthatarerequiredtoensuretheproductwillperformaslabeledandwhy?Foreachadditionalspecification:Whatisthejustificationfortheacceptancelimit?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?QBR:DrugProduct(Continued)CQBR:DrugProduct(Continued)ReferenceStandardArethereaqualificationreportandCOAprovidedforthereferencestandardoristhismaterialpurchasedfromanappropriatesource?Container/ClosureSystemHasthecontainer/closuresystembeenusedinapreviouslyapprovedproductorotherwisequalifiedforthisdosageform?Whatspecificcontainer/closureattributesarenecessarytoensureproductperformance?DrugProductStabilityDataWhatstabilitydatahasbeensubmitted?Hasthesponsorprovidedstabilitydataforthedrugproductpackagedintheproposedcontainer/closure?AcceptancelimitsAreallattributesthatcouldchangeovertimeevaluatedinthestabilitytests?Whataretheacceptablelimitsontheseattributes?

Shelf-liferecommendationWhatisthejustificationofshelflife?Isthepost-approvalstabilityprotocolacceptable?QBR:DrugProduct(Continued)RQBR:ProductDevelopmentReportforComplexDosageFormsandNTIDrugsDrugSubstanceWhichpropertiesorphysicalchemicalcharacteristicsofthedrugsubstanceaffectdrugproductperformance?ExcipientsIsthereanyevidenceofincompatibilitybetweentheexcipientsanddrugsubstance?FormulationWhatistheformulationintendedtodo?Whatmechanismdoesitusetoaccomplishthis?Wereanyotherformulationalternativesinvestigatedandhowdidtheseperform?Wereanyformulationoptimizationorsensitivitystudiescarriedoutforvariationsincompositionaroundthefinalformulation?Werethesestudiessufficienttoestablishadesignspaceforformulationcomposition?Istheformulationdesignconsistentwiththedosageformclassificationinthelabel?DrugProductWhatarethecriticalqualityattributesthatensuretheproductwillperformaslabeled?QBR:ProductDevelopmentReporQBR:ProcessDevelopmentReportProcessDescriptionWhywasthismanufacturingprocessselectedforthisdrugproduct?Werealternativeunitoperationsinvestigatedbyprocessdevelopmentstudies?CriticalStepsandScaleUpHowwerethecriticalstepsintheprocessidentified?Whatarethecriticalprocessparametersforeachcriticalstepandhowweretheyidentified,monitoredand/orcontrolled?Wereprocessdevelopmentstudiesthatvariedstartingmaterialsoroperatingparametersconducted?Werethesestudiessufficienttoestablishadesignspaceforprocess?InprocesstestsWhyiseachinprocesstestrequired?Howweretheacceptancelimitschosen?Whywerethein-processtestsidentifiedascriticaltoproductquality?Whatscale-upexperiencedoesthesponsorhavewiththeunitoperationsinthisprocess?QBR:ProcessDevelopmentReporQBR:RiskSummaryNTIdrugClassifiedasanon-NTIdrug,riskscore=+0ClassifiedasanNTIdrug,riskscore=+1DosageFormSimpleDosageForm,riskscore=+0OtherDosageFormsandNTIdrugs,riskscore=+1DevelopmentReportIfthesponsorsubmitsadevelopmentreportthataddressestheFDA’squestions:Riskscore=+0SolutionandIRProducts:ProductDevelopmentReportOtherDosageForms:ProductandProcessDevelopmentReportsInsufficientormissingdevelopmentreport,riskscore=+1IftheapplicationisofhighoverallqualityLessthanorequalto2cycles,riskscore=+0.Greaterthan2cycles,riskscore=+1QBR:RiskSummaryNTIdrugQBR:Risk-BasedConclusionShouldtheapplicationbeapproved?Whatpost-approvalwaivers/commitmentsareappropriateforthisproduct?Ifthetotalriskscoreislessthanorequalto1CBE0andCBE30changesmaybeinannualreportsManyPAStoCBE30Ifthetotalriskscoreisgreaterthan1AllsupplementsshouldbesubmittedasusualQBR:Risk-BasedConclusionShou生物等效性豁免生物等效性豁免是指基于體外數(shù)據(jù)審批的管理程序。固體制劑往往采用溶出度、釋放度作為證據(jù)。生物等效性豁免生物等效性豁免是指基于體外數(shù)據(jù)審批的管理程序。I、基于藥物劑型的生物等效性豁免

只有供試品和參比制劑的原料及其含量一致，輔料一致、用量相當(dāng)，且符合如下規(guī)定時(shí)，可生物等效性豁免：1、注射液；2、口服溶液，含量一致，且不含已知會(huì)影響胃腸道功能和主藥稀釋的輔料；3、氣體；4、溶液散劑；5、耳用或眼用溶液；、6、外用溶液；7、采用同樣裝置使用的吸入劑或鼻噴劑。I、基于藥物劑型的生物等效性豁免

只有供試品和參比制劑的原料II、基于劑型劑量比例的生物等效性豁免當(dāng)最高劑量的BE數(shù)據(jù)具備時(shí)，下列情況可生物等效性豁免：1、 同樣的劑型；2、 主藥和輔料的比例相當(dāng)；3、 對(duì)于緩釋制劑，同樣的釋放機(jī)制；4、 溶出度相似因子符合規(guī)定；5、 比例變化在線性動(dòng)力學(xué)范圍內(nèi)。II、基于劑型劑量比例的生物等效性豁免III、基于BCS分類的生物等效性豁免FDA在其指南中指出：制劑分別在900mlpH1.2、4.5和6.8緩沖液中采用籃法100rpm或漿法50或75rpm下依法測(cè)定，藥物制劑可以分為：（1）極快速溶出：15分鐘內(nèi)溶出量不低于85%；（2）快速溶出：30分鐘內(nèi)溶出量不低于85%；（）緩慢溶出：溶出85%需要30分鐘以上。生物等效性豁免條件：仿制品和參比制劑在上述條件下屬于同一類別，且相似性分析符合規(guī)定，相似性標(biāo)準(zhǔn)如下分類：分類I（FDA和WHO均認(rèn)可）：BCSI類藥物的制劑且符合其中之一：1、在上述三種條件下不超過(guò)30分鐘溶出85%以上，相似因子f2>50；2、參比制劑和受試制劑均為極快速溶出。分類II（WHO認(rèn)可）：BCSII類藥物，但在pH6.8緩沖液中易溶的制劑且符合其中之一：1、在pH6.8條件下為極快速溶出；2、在三種介質(zhì)中的溶出行為與參比制劑相似性符合要求。分類III（WHO認(rèn)可）：BCSIII類藥物：1、參比制劑和受試制劑均為極快速溶出，且不含已知可改變胃腸道運(yùn)動(dòng)或主藥通透性的輔料；2、企業(yè)應(yīng)證明輔料的質(zhì)量與使用目的相符。如使用的為新輔料或使用大量的常用輔料，應(yīng)說(shuō)明其對(duì)生物利用度的影響。III、基于BCS分類的生物等效性豁免FDA在其指南中指出：三、我國(guó)仿制藥的申報(bào)、審評(píng)和研發(fā)對(duì)策新藥新、仿制藥同、新劑型特兩報(bào)兩批豁免生物等效性試驗(yàn)：1、注射液；2、外用制劑；三、我國(guó)仿制藥的申報(bào)、審評(píng)和研發(fā)對(duì)策新藥新、仿制藥同、新劑型CompanyLogo我國(guó)仿制藥申報(bào)流程圖CompanyLogo我國(guó)仿制藥申報(bào)流程圖Technology美國(guó)2009年仿制藥占處方藥市場(chǎng)比例70%以上，處于仿制藥消費(fèi)大國(guó)之首（產(chǎn)品從150個(gè)國(guó)家進(jìn)口）；德國(guó)、英國(guó)的仿制藥也已超過(guò)50%。國(guó)外仿制藥現(xiàn)狀中國(guó)仿制藥產(chǎn)業(yè)發(fā)展的機(jī)遇機(jī)遇與挑戰(zhàn)中國(guó)仿制藥產(chǎn)業(yè)發(fā)展的挑戰(zhàn)國(guó)內(nèi)老齡化，城鎮(zhèn)化加速造成的醫(yī)改和對(duì)仿制藥的要求急劇增加10年內(nèi)專利藥幾種到期造成了仿制藥的戰(zhàn)略機(jī)遇部分企業(yè)已經(jīng)開始國(guó)際標(biāo)準(zhǔn)的注冊(cè)和海外戰(zhàn)略，取得了積極進(jìn)展整體研發(fā)技術(shù)水平低缺乏仿制藥制劑的國(guó)際注冊(cè)經(jīng)驗(yàn)，制劑產(chǎn)品很少進(jìn)入發(fā)達(dá)國(guó)家市場(chǎng)，國(guó)際競(jìng)爭(zhēng)力不強(qiáng)缺乏國(guó)際標(biāo)準(zhǔn)和通行質(zhì)量規(guī)范，質(zhì)量管理的理念和管理水平與國(guó)際水平尚有明顯差距，造成了產(chǎn)品國(guó)際競(jìng)爭(zhēng)能力不足Technology美國(guó)2009年仿制藥占處方藥ThankYou!ThankYou!中美仿制藥研發(fā)和申報(bào)流程涂家生，Ph.D.中國(guó)藥科大學(xué)藥劑學(xué)教授Telmail:jiashengtu@2011.11鄭州中美仿制藥研發(fā)和申報(bào)流程涂家生，Ph.D.我國(guó)仿制藥申報(bào)、審評(píng)和研發(fā)對(duì)策主要內(nèi)容中美關(guān)于原研藥和仿制藥的背景美國(guó)仿制藥：申報(bào)、基于問(wèn)題的審評(píng)和研發(fā)對(duì)策展望1234我國(guó)仿制藥申報(bào)、審評(píng)和研發(fā)對(duì)策主要內(nèi)容中美關(guān)于原研藥和仿制藥藥物經(jīng)濟(jì)學(xué)催生美國(guó)仿制藥制度美國(guó)社會(huì)安全制度導(dǎo)致政府赤字嚴(yán)重SSA已經(jīng)破產(chǎn)：如何破局？降低醫(yī)療費(fèi)用成為必然Hatch-Waxman法案出臺(tái)美國(guó)FDA藥品注冊(cè)申請(qǐng)：新藥（兩類）、仿制藥和非處方藥申請(qǐng)藥物經(jīng)濟(jì)學(xué)催生美國(guó)仿制藥制度美國(guó)社會(huì)安全制度導(dǎo)致政府赤字嚴(yán)重1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)

“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?

DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)1984年后NewDrugApplicationsAbbNDA的研發(fā)和申報(bào)NDA的研發(fā)和申報(bào)505(b)(1)新藥申報(bào)資料內(nèi)容IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology505(b)(1)新藥申報(bào)資料內(nèi)容Index6.

HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)6.HumanPharmacokineticsand10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification10.Statistical505(b)(2):歷史過(guò)程HatchWaxman法案：1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizen’sPetition(2003)可以降低研發(fā)的費(fèi)用和審評(píng)力量的浪費(fèi)505(b)(2):歷史過(guò)程HatchWaxman法案505(b)(2)的關(guān)鍵:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?505(b)(2)的關(guān)鍵:可靠性Whatis“Reli505(b)(2)的意義介于全創(chuàng)新藥物和仿制藥之間具有專利保護(hù)，且不存在產(chǎn)權(quán)糾紛和仿制藥不同，無(wú)替換的要求

應(yīng)有突破505(b)(2)的意義介于全創(chuàng)新藥物和仿制藥之間505(b)(2)范圍NewChemicalEntity(rarely)：我國(guó)1.1-1.3Newdosageform：我國(guó)5類Newdosingregimen：我國(guó)補(bǔ)充申請(qǐng)Newstrength：我國(guó)補(bǔ)充申請(qǐng)Newrouteofadministration：我國(guó)2類Newindication：我國(guó)1.6505(b)(2)范圍NewChemicalEntity505(b)(2)情形Newactiveingredient(differentsalt,ester,complex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRxOTCswitchNewCombinationProducts“Genericbiologics”505(b)(2)情形Newactiveingredie505(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)NDAsmayalsobeblockedbypatentsonReferenceDrugs505(b)(2)排他性Exclusivitiesavai505(b)(2)新藥的成功例子NCEThalomid?(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine(2000)Guaifenesinextendedrelease(2002)Quininesulfate(2005)NewDosageFormTramadolorallydisintegratingtablets(2005)Ondansetronoralspray(filed2006)505(b)(2)新藥的成功例子NCE505(b)(2)新藥的例子NewDosingRegimenTramadolextendedreleasetablets(2005)NewStrength/FormulationAntara(micronizedfenofibratecaps)(2004)(130mgisBEtoTricor200mg)NewFormulation/InactiveIngredientAvita(tretinoingel)(newemollient)(1998)Abraxane(cremaphor-freepaclitaxel)(2005)Oxy-ADF(oxycodoneformulatedtoreducedrugabuse)(indevelopment)505(b)(2)新藥的例子NewDosingRegim505(b)(2)新藥的例子NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)(2003)NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)RxOTCSwitchAlavert(loratadine)(2002)505(b)(2)新藥的例子NewActiveIngre505(b)(2)新藥的例子“GenericBiologics”O(jiān)mnitrope(rHGH)(2006)Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals2004-05)Fortical(calcitoninsalmonrecombinant)(2005)*Examplesbasedonpubliclyavailableinformation505(b)(2)新藥的例子“GenericBiologiFDANDA審評(píng)過(guò)程FDANDA審評(píng)過(guò)程FDA可以使用已有數(shù)據(jù)用于審評(píng)NDA嗎？Hatch-Waxman之前,國(guó)會(huì)限制FDA在審評(píng)NDAX時(shí)應(yīng)用NDAY的數(shù)據(jù)：“NodatainanNDAcanbeutilizedtosupportanotherNDAwithoutexpresspermissionoftheoriginalNDAholder.”[FDA“FinkelMemorandum”(1978,1981)]Hatch-Waxman解除只適合ANDAs：ANDAprocessallows“genericproducerofthefullytesteddrugtorelyonthesafetyandefficacydataofapriorapplicant....”505(b)(2)doesnotauthorizesuchdatarelianceMerelysetsconditionsforcertainNDAsRequires“fullreportsofinvestigations”establishingsafetyandeffectiveness[21USC§§355(b)(1)(A),(d)(1)]FDA可以使用已有數(shù)據(jù)用于審評(píng)NDA嗎？Hatch-Wax美國(guó)仿制藥

Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.美國(guó)仿制藥Agenericdrugproduct

Genericdrugapplicationsaretermed“abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.GenericdrugapplicationsaFDA審評(píng)仿制藥程序FDA審評(píng)仿制藥程序二、美國(guó)仿制藥的申報(bào)、審評(píng)和研發(fā)對(duì)策由FDA的OGD審評(píng)審評(píng)方式采用QbR申報(bào)資料采用CTD資料內(nèi)容也針對(duì)問(wèn)題二、美國(guó)仿制藥的申報(bào)、審評(píng)和研發(fā)對(duì)策由FDA的OGD審評(píng)中美仿制藥研發(fā)申報(bào)流程課件中美仿制藥研發(fā)申報(bào)流程課件中美仿制藥研發(fā)申報(bào)流程課件OfficeofGenericDrugsOfficeofGenericDrugs如何保證審評(píng)質(zhì)量和效率？StructuredProductLabeling(SPL)MakeslabelingavailableonInternetviaNationalLibraryofMedicine(NLM)ReviewEfficienciesEarlyDMFreviewClusterreviews–productspecialistsSupplementtriagingatteamleaderlevelDBETruncatedReviewQuestionbasedReview(QbR)Willhaveaverypositiveimpact如何保證審評(píng)質(zhì)量和效率？StructuredProductNewresourcesdevelopedDissolutionDatabaseIndividualProductBioequivalenceInformationEncouragedtheuseoftelephoneinreviewprocessIncreasedthenumberof1stcycleapprovalsDecreasedthetotalnumberofreviewcyclesTotaltimetoapprovaldidnotincreaseinspiteofincreasedworkloadNewresourcesdevelopedDissolutionMethodsforDrugProductsNew!!DissolutionMethodsforDrugPbenben中美仿制藥研發(fā)申報(bào)流程課件ThisguidancecontainsanInternetlink

toalistingofdrugproducts,eachlinkedinturntoacorrespondingbioequivalencerecommendation.Clickingonaproductnameinthatlistwillbringupthebioequivalencerecommendationsforthatspecificproduct.Recommendationshavebeendevelopedforseveraldrugsthatarenotyeteligibleforgenericcompetition(i.e.,newlyapprovedproducts)andsomeolderproductsforwhichinformationhaspreviouslybeenprovided.Asadditionalrecommendationsaredeveloped,thosewillbepostedontheWebsite.Whenthisguidanceisfinalized,thelistingwillbeavailablethroughtheAgency’sWebpage.中美仿制藥研發(fā)申報(bào)流程課件OFFICEOFGENERICDRUGSTABLEOFBIOEQUIVALENCERECOMMENDATIONSActiveIngredientPotencyDosageFormRouteofAdministrationDateFinalizedAlmotriptanMalate12.5mgTabletOral5/16/2005Alosetron1mgTabletOral5/31/2005Atazanavir200mgCapsuleOral3/18/2005Atomoxetine60mgCapsuleOral6/13/2005CefditorenPivoxil200mgTabletOral3/18/2005Dutasteride0.5mgCapsuleOral7/5/2005Eplerenone50mgTabletOral3/18/2005FosamprenavirCalcium700mgTabletOral3/18/2005Memantine10mgTabletOral7/8/2005Rosuvastat