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(lèi)）、仿制藥和非處方藥申請(qǐng)1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)

“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?

DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)NDA的研發(fā)和申報(bào)505(b)(1)新藥申報(bào)資料內(nèi)容IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology6.

HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification505(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)的關(guān)鍵:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?505(b)(2)的意義介于全創(chuàng)創(chuàng)新藥物物和仿制制藥之間間具有專(zhuān)利利保護(hù)，，且不存存在產(chǎn)權(quán)權(quán)糾紛和仿制藥藥不同，，無(wú)替換換的要求求應(yīng)有突破破505(b)(2)范圍NewChemicalEntity(rarely)：我國(guó)1.1-1.3Newdosageform：我國(guó)5類(lèi)Newdosingregimen：我國(guó)補(bǔ)補(bǔ)充申請(qǐng)請(qǐng)Newstrength：我國(guó)補(bǔ)補(bǔ)充申請(qǐng)請(qǐng)Newrouteofadministration：我國(guó)2類(lèi)Newindication：我國(guó)1.6505(b)(2)情形Newactiveingredient(differentsalt,ester,complex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRxOTCswitchNewCombinationProducts“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)NDAsmayalsobeblockedbypatentsonReferenceDrugs505(b)(2)新藥的成功例例子NCEThalomid?(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine(2000)Guaifenesinextendedrelease(2002)Quininesulfate(2005)NewDosageFormTramadolorallydisintegratingtablets(2005)Ondansetronoralspray(filed2006)505(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NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)(2003)NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)RxOTCSwitchAlavert(loratadine)(2002)505(b)(2)新藥的例子“GenericBiologics”O(jiān)mnitrope(rHGH)(2006)Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals2004-05)Fortical(calcitoninsalmonrecombinant)(2005)*ExamplesbasedonpubliclyavailableinformationFDANDA審評(píng)過(guò)程FDA可以使用已有有數(shù)據(jù)用于審審評(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解除只適合合ANDAs：ANDAprocessallows“genericproducerofthefullytesteddrugtorelyonthesafetyandefficacydataofapriorapplicant....”505(b)(2)doesnotauthorizesuchdatarelianceMerelysetsconditionsforcertainNDAsRequires““fullreportsofinvestigations””establishingsafetyandeffectiveness[21USC§§§355(b)(1)(A),(d)(1)]美國(guó)仿制藥藥Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.Genericdrugapplicationsaretermed““abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.FDA審評(píng)評(píng)仿仿制制藥藥程程序序二、、美美國(guó)國(guó)仿仿制制藥藥的的申申報(bào)報(bào)、、審審評(píng)評(píng)和和研研發(fā)發(fā)對(duì)對(duì)策策由FDA的OGD審評(píng)審評(píng)方方式采采用QbR申報(bào)資資料采采用CTD資料內(nèi)內(nèi)容也也針對(duì)對(duì)問(wèn)題題OfficeofGenericDrugs如何保保證審審評(píng)質(zhì)質(zhì)量和和效率率？StructuredProductLabeling(SPL)MakeslabelingavailableonInternetviaNationalLibraryofMedicine(NLM)ReviewEfficienciesEarlyDMFreviewClusterreviews––productspecialistsSupplementtriagingatteamleaderlevelDBETruncatedReviewQuestionbasedReview(QbR)WillhaveaverypositiveimpactNewresourcesdevelopedDissolutionDatabaseIndividualProductBioequivalenceInformationEncouragedtheuseoftelephoneinreviewprocessIncreasedthenumberof1stcycleapprovalsDecreasedthetotalnumberofreviewcyclesTotaltimetoapprovaldidnotincreaseinspiteofincreasedworkloadDissolutionMethodsforDrugProductsNew!!benThisguidancecontainsanInternetlinktoalistingofdrugproducts,eachlinkedinturntoacorrespondingbioequivalencerecommendation.Clickingonaproductnameinthatlistwillbringupthebioequivalencerecommendationsforthatspecificproduct.Recommendationshavebeendevelopedforseveraldrugsthatarenotyeteligibleforgenericcompetition(i.e.,newlyapprovedproducts)andsomeolderproductsforwhichinformationhaspreviouslybeenprovided.Asadditionalrecommendationsaredeveloped,thosewillbepostedontheWebsite.Whenthisguidanceisfinalized,thelistingwillbeavailablethroughtheAgency’’sWebpage.OFFICEOFGENERICDRUGSTABLEOFBIOEQUIVALENCERECOMMENDATIONSActiveIngredientPotencyDosageFormRouteofAdministrationDateFinalizedAlmotriptanMalate12.5mgTabletOral5/16/2005Alosetron1mgTabletOral5/31/2005Atazanavir200mgCapsuleOral3/18/2005Atomoxetine60mgCapsuleOral6/13/2005CefditorenPivoxil200mgTabletOral3/18/2005Dutasteride0.5mgCapsuleOral7/5/2005Eplerenone50mgTabletOral3/18/2005FosamprenavirCalcium700mgTabletOral3/18/2005Memantine10mgTabletOral7/8/2005Rosuvastatin40mgTabletOral3/18/2005Tadalafil20mgTabletOral3/18/2005VardenafilHCl20mgTabletOral4/11/2005QbR:從提出出到完完善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:FullImplementationQbR的內(nèi)涵涵Question-basedReviewisageneralframeworkforascienceandrisk-basedassessmentofproductqualityQuestion-basedReviewcontainstheimportantscientificandregulatoryreviewquestionsto關(guān)鍵制制備工工藝及及其質(zhì)質(zhì)控產(chǎn)品的的工藝藝、處處方是是否有有設(shè)計(jì)計(jì)缺陷陷強(qiáng)調(diào)QbDANDAsUnderQbR(Continued)FutureGenericApplicationsgenericsponsorssubmitgenericapplicationsbasedontheformatofICHCTD,preferably,electronicallyModule1:AdministrativeInformationModule2:QualityOverallSummaryandClinicalSummaryModule3:QualityPharmaceuticalDevelopment;QualitybyDesignModule4:NonclinicalModule5:Clinical(Bioequivalence)新藥申申報(bào)（（NDA）和仿制制藥申申報(bào)（（ANDA）的比比較1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.AnimalStudies7.ClinicalStudies8.BioavailabilityNDArequirementsANDArequirements1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Bioequivalence美國(guó)仿仿制藥藥申報(bào)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(shū)3674；②專(zhuān)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(shū)（草稿）。

模塊2模塊2為概論。它包括藥理作用分類(lèi)，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仿制藥藥部（（OGD）鼓勵(lì)勵(lì)申請(qǐng)請(qǐng)人根根據(jù)ICH對(duì)于人人用藥藥物的的注冊(cè)冊(cè)技術(shù)術(shù)要求求，即即通用用技術(shù)術(shù)文件件（CTD）的格格式，，提交交ADNA。包括括以下下模塊塊：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(kāi)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。

OGDQBRThequestionbasedreview(QBR)servesasageneralframeworkfortheCMCassessmentofANDAsthatfocusesoncriticalpharmaceuticalattributesofproductquality.Withjustification,deviationsoralternateapproachestothisframeworkcanbeutilize,asnecessary,toensuretheadequacyoftheassessmentofproductqualityForeaseofdiscussion,asimpledosageformisdefinedasasolutionoranimmediaterelease(IR)solidoraldosageform.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?QBR:DrugProductDescriptionandCompositionWhatarethecomponentsandcompositionofthefinalproduct?Whatisthefunctionofeachexcipient?DoanyexcipientsexceedIIGlimitsinthecontextofmaximumdailydoseandrouteofadministration?IfproductisanNTIdrugoranon-simpledosageformAretheresignificantdifferencesbetweenthisformulationandtheRLDthatpresentpotentialconcernswithrespecttoproductperformance?ControlofExcipientsWhatarethespecificationsfortheinactiveingredientsandaretheyappropriatepertheirintendedfunction?SimpleDosageForm:EitherasolutionoranIRsolidoraldosageformQBR: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:ProductDevelopmentReportforComplexDosageFormsandNTIDrugsDrugSubstanceWhichpropertiesorphysicalchemicalcharacteristicsofthedrugsubstanceaffectdrugproductperformance?ExcipientsIsthereanyevidenceofincompatibilitybetweentheexcipientsanddrugsubstance?FormulationWhatistheformulationintendedtodo?Whatmechanismdoesitusetoaccomplishthis?Wereanyotherformulationalternativesinvestigatedandhowdidtheseperform?Wereanyformulationoptimizationorsensitivitystudiescarriedoutforvariationsincompositionaroundthefinalformulation?Werethesestudiessufficienttoestablishadesignspaceforformulationcomposition?Istheformulationdesignconsistentwiththedosageformclassificationinthelabel?DrugProductWhatarethecriticalqualityattributesthatensuretheproductwillperformaslabeled?QBR:ProcessDevelopmentReportProcessDescriptionWhywasthismanufacturingprocessselectedforthisdrugproduct?Werealternativeunitoperationsinvestigatedbyprocessdevelopmentstudies?CriticalStepsandScaleUpHowwerethecriticalstepsintheprocessidentified?Whatarethecriticalprocessparametersforeachcriticalstepandhowweretheyidentified,monitoredand/orcontrolled?Wereprocessdevelopmentstudiesthatvariedstartingmaterialsoroperatingparametersconducted?Werethesestudiessufficienttoestablishadesignspaceforprocess?InprocesstestsWhyiseachinprocesstestrequired?Howweretheacceptancelimitschosen?Whywerethein-processtestsidentifiedascriticaltoproductquality?Whatscale-upexperiencedoesthesponsorhavewiththeunitoperationsinthisprocess?QBR:RiskSummaryNTIdrugClassifiedasanon-NTIdrug,riskscore=+0ClassifiedasanNTIdrug,riskscore=+1DosageFormSimpleDosageForm,riskscore=+0OtherDosageFormsandNTIdrugs,riskscore=+1DevelopmentReportIfthesponsorsubmitsadevelopmentreportthataddressestheFDA’squestions:Riskscore=+0SolutionandIRProducts:ProductDevelopmentReportOtherDosageForms:ProductandProcessDevelopmentReportsInsufficientormissingdevelopmentreport,riskscore=+1IftheapplicationisofhighoverallqualityLessthanorequalto2cycles,riskscore=+0.Greaterthan2cycles,riskscore=+1QBR:Risk-BasedConclusionShouldtheapplicationbeapproved?Whatpost-approvalwaivers/commitmentsareappropriateforthisproduct?Ifthetotalriskscoreislessthanorequalto1CBE0andCBE30changesmaybeinannualreportsManyPAStoCBE30Ifthetotalriskscoreisgreaterthan1Allsupplementsshouldbesubmittedasusual生物等效性豁豁免生物等效性豁豁免是指基于于體外數(shù)據(jù)審審批的管理程程序。固體制制劑往往采用用溶出度、釋釋放度作為證證據(jù)。I、基于藥物劑型型的生物等效效性豁免只有供試品和和參比制劑的的原料及其含含量一致，輔輔料一致、用用量相當(dāng)，且且符合如下規(guī)規(guī)定時(shí)，可生生物等效性豁豁免：1、注射液液；2、口服溶溶液，含含量一致致，且不不含已知知會(huì)影響響胃腸道道功能和和主藥稀稀釋的輔輔料；3、氣體；；4、溶液散散劑；5、耳用或或眼用溶溶液；、、6、外用溶溶液；7、采用同同樣裝置置使用的的吸入劑劑或鼻噴噴劑。II、基于劑劑型劑量量比例的的生物等等效性豁豁免當(dāng)最高劑劑量的BE數(shù)據(jù)具備備時(shí)，下下列情況況可生物物等效性性豁免：：1、 同樣樣的劑型型；2、 主藥藥和輔