中美仿制藥研發(fā)和申報(bào)流程涂家生，Ph.D.中國藥科大學(xué)藥劑學(xué)教授Telmail:jiashengtu@2011.11鄭州我國仿制藥申報(bào)、審評和研發(fā)對策主要內(nèi)容中美關(guān)于原研藥和仿制藥的背景美國仿制藥：申報(bào)、基于問題的審評和研發(fā)對策展望1234藥物經(jīng)濟(jì)學(xué)催生美國仿制藥制度美國社會安全制度導(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法案出臺美國FDA藥品注冊申請：新藥（兩類）、仿制藥和非處方藥申請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):歷史過程HatchWaxman法案：1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizen’sPetition(2003)可以降低研發(fā)的費(fèi)用和審評力量的浪費(fèi)505(b)(2)的關(guān)鍵:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?505(b)(2)的意意義義介于于全全創(chuàng)創(chuàng)新新藥藥物物和和仿仿制制藥藥之之間間具有有專專利利保保護(hù)護(hù)，，且且不不存存在在產(chǎn)產(chǎn)權(quán)權(quán)糾糾紛紛和仿仿制制藥藥不不同同，，無無替替換換的的要要求求應(yīng)有有突突破破505(b)(2)范圍圍NewChemicalEntity(rarely)：我我國國1.1-1.3Newdosageform：我我國國5類Newdosingregimen：我國補(bǔ)充充申請Newstrength：我國補(bǔ)充充申請Newrouteofadministration：我國2類Newindication：我國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)新藥的成功功例子NCEThalomid??(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine(2000)Guaifenesinextendedrelease(2002)Quininesulfate(2005)NewDosageFormTramadolorallydisintegratingtablets(2005)Ondansetronoralspray(filed2006)505(b)(2)新藥的例子子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)新藥的例子子“GenericBiologics”O(jiān)mnitrope(rHGH)(2006)Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals2004-05)Fortical(calcitoninsalmonrecombinant)(2005)*ExamplesbasedonpubliclyavailableinformationFDANDA審評過程FDA可以使用已已有數(shù)據(jù)用用于審評NDA嗎？Hatch-Waxman之前,國會限制FDA在審評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)]美國仿制藥Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.Genericdrugapplicationsaretermed“abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.FDA審評仿制藥程程序二、美國仿制制藥的申報(bào)、、審評和研發(fā)發(fā)對策由FDA的OGD審評審評方式采用用QbR申報(bào)資料采用用CTD資料內(nèi)容也針針對問題OfficeofGenericDrugs如何保證審評評質(zhì)量和效率率？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:從提出到完善善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Question-basedReviewisageneralframeworkforascienceandrisk-basedassessmentofproductqualityQuestion-basedReviewcontainstheimportantscientificandregulatoryreviewquestionsto關(guān)鍵制備工藝藝及其質(zhì)控產(chǎn)品的工藝、、處方是否有有設(shè)計(jì)缺陷強(qiáng)調(diào)QbDANDAsUnderQbR(Continued)FutureGenericApplicationsgenericsponsorssubmitgenericapplicationsbasedontheformatofICHCTD,preferably,electronicallyModule1:AdministrativeInformationModule2:QualityOverallSummaryandClinicalSummaryModule3:QualityPharmaceuticalDevelopment;QualitybyDesignModule4:NonclinicalModule5:Clinical(Bioequivalence)新藥申報(bào)（NDA）和仿制藥申報(bào)報(bào)（ANDA）的比較1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.AnimalStudies7.ClinicalStudies8.BioavailabilityNDArequirementsANDArequirements1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Bioequivalence美國國仿仿制制藥藥申申報(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。在美國應(yīng)包括以下信息：①申請書3674；②專利認(rèn)證信息；③原研藥信息，包括NDA號、藥名和生產(chǎn)商；④仿制藥和原研藥的對比，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仿制制藥藥部部（（OGD）鼓鼓勵(lì)勵(lì)申申請請人人根根據(jù)據(jù)ICH對于于人人用用藥藥物物的的注注冊冊技技術(shù)術(shù)要要求求，，即即通通用用技技術(shù)術(shù)文文件件（（CTD）的的格格式式，，提提交交ADNA。包包括括以以下下模模塊塊：：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，仿制藥申請一般不包含模塊4。

模塊5模塊5是臨床研究報(bào)告。對于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。

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；2、口服溶液，，含量一致，，且不含已知知會影響胃腸腸道功能和主主藥稀釋的輔輔料；3、氣體；4、溶液散劑；；5、耳用或眼用用溶液；、6、外用溶液；；7、采用同樣裝裝置使用的吸吸入劑或鼻噴噴劑。II、基于劑型劑劑量比例的生生物等效性豁豁免當(dāng)最高劑量的的BE數(shù)據(jù)具備時(shí)，，下列情況可可生物等效性性豁免：1、 同樣的劑劑型；2、 主藥和輔輔料的比例相相當(dāng)；3、 對于緩釋釋制劑，同樣樣的釋放機(jī)制制；4、 溶出度相相似因子符合合規(guī)定；5、 比例變化化在線性動(dòng)力力學(xué)范圍內(nèi)。。III、基于BCS分類的生物等等效性豁免FDA在其指南中指指出：制劑分分別在900mlpH1.2、4.5和6