中美仿制藥研發(fā)申報(bào)流程課件

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)過程FDANDA審評(píng)過程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-Based