中美仿制藥研發(fā)和申報(bào)流程概述專家講座

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)于原研藥和仿制藥背景美國(guó)仿制藥：申報(bào)、基于問(wèn)題審評(píng)和研發(fā)對(duì)策展望1234中美仿制藥研發(fā)和申報(bào)流程概述專家講座第1頁(yè)藥品經(jīng)濟(jì)學(xué)催生美國(guó)仿制藥制度美國(guó)社會(huì)安全制度造成政府赤字嚴(yán)重SSA已經(jīng)破產(chǎn)：怎樣破局？降低醫(yī)療費(fèi)用成為必定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)2Ceryak中美仿制藥研發(fā)和申報(bào)流程概述專家講座第2頁(yè)1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)

“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?

DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第3頁(yè)NDA研發(fā)和申報(bào)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第4頁(yè)505(b)(1)新藥申報(bào)資料內(nèi)容IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology中美仿制藥研發(fā)和申報(bào)流程概述專家講座第5頁(yè)6.HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第6頁(yè)10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification中美仿制藥研發(fā)和申報(bào)流程概述專家講座第7頁(yè)505(b)(2):歷史過(guò)程HatchWaxman法案:1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizen’sPetition()能夠降低研發(fā)費(fèi)用和審評(píng)力量浪費(fèi)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第8頁(yè)505(b)(2)關(guān)鍵:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?中美仿制藥研發(fā)和申報(bào)流程概述專家講座第9頁(yè)505(b)(2)意義介于全創(chuàng)新藥品和仿制藥之間含有專利保護(hù),且不存在產(chǎn)權(quán)糾紛和仿制藥不一樣,無(wú)替換要求應(yīng)有突破中美仿制藥研發(fā)和申報(bào)流程概述專家講座第10頁(yè)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)1.6中美仿制藥研發(fā)和申報(bào)流程概述專家講座第11頁(yè)505(b)(2)情形Newactiveingredient(differentsalt,ester,complex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRx

OTCswitchNewCombinationProducts“Genericbiologics”中美仿制藥研發(fā)和申報(bào)流程概述專家講座第12頁(yè)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)NDAsmayalsobeblockedbypatentsonReferenceDrugs中美仿制藥研發(fā)和申報(bào)流程概述專家講座第13頁(yè)505(b)(2)新藥成功例子NCEThalomid?(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine()Guaifenesinextendedrelease()Quininesulfate()NewDosageFormTramadolorallydisintegratingtablets()Ondansetronoralspray(filed)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第14頁(yè)505(b)(2)新藥例子NewDosingRegimenTramadolextendedreleasetablets()NewStrength/FormulationAntara(micronizedfenofibratecaps)()(130mgisBEtoTricor200mg)NewFormulation/InactiveIngredientAvita(tretinoingel)(newemollient)(1998)Abraxane(cremaphor-freepaclitaxel)()Oxy-ADF(oxycodoneformulatedtoreducedrugabuse)(indevelopment)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第15頁(yè)505(b)(2)新藥例子NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)()NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)Rx

OTCSwitchAlavert(loratadine)()中美仿制藥研發(fā)和申報(bào)流程概述專家講座第16頁(yè)505(b)(2)新藥例子“GenericBiologics”O(jiān)mnitrope(rHGH)()Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals-05)Fortical(calcitoninsalmonrecombinant)()*Examplesbasedonpubliclyavailableinformation中美仿制藥研發(fā)和申報(bào)流程概述專家講座第17頁(yè)FDANDA審評(píng)過(guò)程中美仿制藥研發(fā)和申報(bào)流程概述專家講座第18頁(yè)FDA能夠使用已經(jīng)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)]中美仿制藥研發(fā)和申報(bào)流程概述專家講座第19頁(yè)美國(guó)仿制藥

Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.中美仿制藥研發(fā)和申報(bào)流程概述專家講座第20頁(yè)

Genericdrugapplicationsaretermed“abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.中美仿制藥研發(fā)和申報(bào)流程概述專家講座第21頁(yè)FDA審評(píng)仿制藥程序中美仿制藥研發(fā)和申報(bào)流程概述專家講座第22頁(yè)二、美國(guó)仿制藥申報(bào)、審評(píng)和研發(fā)對(duì)策由FDAOGD審評(píng)審評(píng)方式采取QbR申報(bào)資料采取CTD資料內(nèi)容也針對(duì)問(wèn)題中美仿制藥研發(fā)和申報(bào)流程概述專家講座第23頁(yè)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第24頁(yè)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第25頁(yè)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第26頁(yè)OfficeofGenericDrugs中美仿制藥研發(fā)和申報(bào)流程概述專家講座第27頁(yè)怎樣確保審評(píng)質(zhì)量和效率？StructuredProductLabeling(SPL)MakeslabelingavailableonInternetviaNationalLibraryofMedicine(NLM)ReviewEfficienciesEarlyDMFreviewClusterreviews–productspecialistsSupplementtriagingatteamleaderlevelDBETruncatedReviewQuestionbasedReview(QbR)Willhaveaverypositiveimpact中美仿制藥研發(fā)和申報(bào)流程概述專家講座第28頁(yè)NewresourcesdevelopedDissolutionDatabaseIndividualProductBioequivalenceInformationEncouragedtheuseoftelephoneinreviewprocessIncreasedthenumberof1stcycleapprovalsDecreasedthetotalnumberofreviewcyclesTotaltimetoapprovaldidnotincreaseinspiteofincreasedworkload中美仿制藥研發(fā)和申報(bào)流程概述專家講座第29頁(yè)DissolutionMethodsforDrugProductsNew!!中美仿制藥研發(fā)和申報(bào)流程概述專家講座第30頁(yè)ben中美仿制藥研發(fā)和申報(bào)流程概述專家講座第31頁(yè)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第32頁(yè)ThisguidancecontainsanInternetlinktoalistingofdrugproducts,eachlinkedinturntoacorrespondingbioequivalencerecommendation.Clickingonaproductnameinthatlistwillbringupthebioequivalencerecommendationsforthatspecificproduct.Recommendationshavebeendevelopedforseveraldrugsthatarenotyeteligibleforgenericcompetition(i.e.,newlyapprovedproducts)andsomeolderproductsforwhichinformationhaspreviouslybeenprovided.Asadditionalrecommendationsaredeveloped,thosewillbepostedontheWebsite.Whenthisguidanceisfinalized,thelistingwillbeavailablethroughtheAgency’sWebpage.中美仿制藥研發(fā)和申報(bào)流程概述專家講座第33頁(yè)OFFICEOFGENERICDRUGSTABLEOFBIOEQUIVALENCERECOMMENDATIONSActiveIngredientPotencyDosageFormRouteofAdministrationDateFinalizedAlmotriptanMalate12.5mgTabletOral5/16/Alosetron1mgTabletOral5/31/Atazanavir200mgCapsuleOral3/18/Atomoxetine60mgCapsuleOral6/13/CefditorenPivoxil200mgTabletOral3/18/Dutasteride0.5mgCapsuleOral7/5/Eplerenone50mgTabletOral3/18/FosamprenavirCalcium700mgTabletOral3/18/Memantine10mgTabletOral7/8/Rosuvastatin40mgTabletOral3/18/Tadalafil20mgTabletOral3/18/VardenafilHCl20mgTabletOral4/11/中美仿制藥研發(fā)和申報(bào)流程概述專家講座第34頁(yè)QbR:從提出到完善1/–2/:Question-basedReviewDrafted3/–4/:DivisionDirectorsDiscussion5/–6/:TeamLeadersDiscussion7/–8/:ReviewersDiscussion9/–1/:ModelPharmaceuticalDevelopmentReportandQualityOverallSummary2/–12/:DiscussionswithStakeholdersandUpperManagement1/–12/:Gradual Implementation1/:FullImplementation中美仿制藥研發(fā)和申報(bào)流程概述專家講座第35頁(yè)QbR內(nèi)涵Question-basedReviewisageneralframeworkforascienceandrisk-basedassessmentofproductqualityQuestion-basedReviewcontainstheimportantscientificandregulatoryreviewquestionsto關(guān)鍵制備工藝及其質(zhì)控產(chǎn)品工藝、處方是否有設(shè)計(jì)缺點(diǎn)強(qiáng)調(diào)QbD中美仿制藥研發(fā)和申報(bào)流程概述專家講座第36頁(yè)ANDAsUnderQbR(Continued)FutureGenericApplications

genericsponsorssubmitgenericapplicationsbasedontheformatofICHCTD,preferably,electronicallyModule1:AdministrativeInformationModule2:QualityOverallSummaryandClinicalSummaryModule3:QualityPharmaceuticalDevelopment;QualitybyDesignModule4:NonclinicalModule5:Clinical(Bioequivalence)中美仿制藥研發(fā)和申報(bào)流程概述專家講座第37頁(yè)新藥申報(bào)（NDA）

和仿制藥申報(bào)（ANDA）比較1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.AnimalStudies7.ClinicalStudies8.BioavailabilityNDArequirementsANDArequirements1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Bioequivalence中美仿制藥研發(fā)和申報(bào)流程概述專家講座第38頁(yè)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。在美國(guó)應(yīng)包含以下信息：①申請(qǐng)書3674；②專利認(rèn)證信息；③原研藥信息，包含NDA號(hào)、藥名和生產(chǎn)商；④仿制藥和原研藥對(duì)比，包含使用條件、有效成份、非有效成份、給藥路徑、劑型和劑量；⑤環(huán)境影響分析；⑥藥品說(shuō)明書（初稿）。

模塊2模塊2為概論。它包含藥理作用分類，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)化學(xué)、生產(chǎn)和質(zhì)量控制信息。FDA仿制藥部（OGD）勉勵(lì)申請(qǐng)人依據(jù)ICH對(duì)于人用藥品注冊(cè)技術(shù)要求，即通用技術(shù)文件（CTD）格式，提交ADNA。包含以下模塊:中美仿制藥研發(fā)和申報(bào)流程概述專家講座第39頁(yè)模塊4模塊4是關(guān)于動(dòng)物試驗(yàn)信息，并不是ANDA要求。所以，仿制藥申請(qǐng)普通不包含模塊4。

模塊5模塊5是臨床研究匯報(bào)。對(duì)于ADNA，生物等效性信息應(yīng)該在這個(gè)部分表達(dá)，包含：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)。案例匯報(bào)，包含不良反應(yīng)事件匯報(bào)也應(yīng)包含在此。

中美仿制藥研發(fā)和申報(bào)流程概述專家講座第40頁(yè)OGDQBR

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

Foreaseofdiscussion,asimpledosageformisdefinedasasolutionoranimmediaterelease(IR)solidoraldosageform.中美仿制藥研發(fā)和申報(bào)流程概述專家講座第41頁(yè)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?中美仿制藥研發(fā)和申報(bào)流程概述專家講座第42頁(yè)QBR:DrugProductDescriptionandCompositionWhatarethecomponentsandcompositionofthefinalproduct?Whatisthefunctionofeachexcipient?DoanyexcipientsexceedIIGlimitsinthecontextofmaximumdailydoseandrouteofadministration?IfproductisanNTIdrugoranon-simpledosageformAretheresignificantdifferencesbetweenthisformulationandtheRLDthatpresentpotentialconcernswithrespecttoproductperformance?

ControlofExcipientsWhatarethespecificationsfortheinactiveingredientsandaretheyappropriatepertheirintendedfunction?SimpleDosageForm:EitherasolutionoranIRsolidoraldosageform中美仿制藥研發(fā)和申報(bào)流程概述專家講座第43頁(yè)QBR:DrugProduct(Continued)ManufactureForallproductsDoesthebatchformulaaccuratelyreflectthedrugproductcomposition?Ifnot,whatarethedifferencesandthejustifications(e.g.potencyadjustment,overage,excesscoatingsolution,etc.)?IfproductisnotasolutionWhatarethekeyunitoperationsinthedrugproductmanufacturingprocess?Arein-processtestsidentifiedbythesponsorappropriate?Whatisthedifferenceinsizebetweencommercialscaleandbiobatchanddotheyusethesameunitoperations?IfproductisanNTIdrugoranon-simpledosageformWhatarethecriticalstepsinthemanufacturingprocess?Whatarethein-processtests/controlsthatensureeachcriticalstepissuccessful?Intheproposedscaleupprocesswhatoperatingconditionswillbeadjustedtoensuretheproductmeetsallin-processandfinalproductspecifications?Whydoyoubelievethesponsorhasdemonstratedareasonableplantoscaleuptheprocess?中美仿制藥研發(fā)和申報(bào)流程概述專家講座第44頁(yè)QBR:DrugProduct(Continued)ControlofDrugProductIdentityIsthespecificationfortheidentityofthedrugproductappropriate?AssayandUniformityAretheproposeddrugassaylimitsacceptable?Istheassaymethodvalidatedandstability-indicating?Howisthecontentuniformityevaluated?Isitacceptable?Impurities/DegradationProductsArethedegradationproductsandtheiroriginsadequatelydescribed?Whatisthejustificationfortheacceptancelimitsondegradationproducts?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?Dissolution

Whatarethedissolutionmethodsandacceptancecriteriaandhowweretheyselected?Whatisthesignificantroleofdissolutiontestingforthisproduct?AdditionalSpecificationsArethereadditionalspecificationsthatarerequiredtoensuretheproductwillperformaslabeledandwhy?Foreachadditionalspecification:Whatisthejustificationfortheacceptancelimit?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?中美仿制藥研發(fā)和申報(bào)流程概述專家講座第45頁(yè)QBR:DrugProduct(Continued)ReferenceStandardArethereaqualificationreportandCOAprovidedforthereferencestandardoristhismaterialpurchasedfromanappropriatesource?Container/ClosureSystemHasthecontainer/closuresystembeenusedinapreviouslyapprovedproductorotherwisequalifiedforthisdosageform?Whatspecificcontainer/closureattributesarenecessarytoensureproductperformance?DrugProductStabilityDataWhatstabilitydatahasbeensubmitted?Hasthesponsorprovidedstabilitydataforthedrugproductpackagedintheproposedcontainer/closure?AcceptancelimitsAreallattributesthatcouldchangeovertimeevaluatedinthestabilitytests?Whataretheacceptablelimitsontheseattributes?

Shelf-liferecommendationWhatisthejustificationofshelflife?Isthepost-approvalstabilityprotocolacceptable?中美仿制藥研發(fā)和申報(bào)流程概述專家講座第46頁(yè)QBR:ProductDevelopmentReportforComplexDosageFormsandNTIDrugsDrugSubstanceWhichpropertiesorphysicalchemicalcharacteristicsofthedrugsubstanceaffectdrugproductperformance?ExcipientsIsthereanyevidenceofincompatibilitybetweentheexcipientsanddrugsubstance?FormulationWhatistheformulationintendedtodo?Whatmechanismdoesitusetoaccomplishthis?Wereanyotherformulationalternativesinvestigatedandhowdidtheseperform?Wereanyformulationoptimizationorsensitivitystudiescarriedoutforvariationsincompositionaroundthefinalformulation?Werethesestudiessufficienttoestablishadesignspaceforformulationcomposition?Istheformulationdesignconsistentwiththedosageformclassificationinthelabel?DrugProductWhatarethecriticalqualityattributesthatensuretheproductwillperformaslabeled?中美仿制藥研發(fā)和申報(bào)流程概述專家講座第47頁(yè)QBR:ProcessDevelopmentReportProcessDescriptionWhywasthismanufacturingprocessselectedforthisdrugproduct?Werealternativeunitoperationsinvestigatedbyprocessdevelopmentstudies?CriticalStepsandScaleUpHowwerethecriticalstepsintheprocessidentified?Whatarethecriticalprocessparametersforeachcriticalstepandhowweretheyidentified,monitoredand/orcontrolled?Wereprocessdevelopmentstudiesthatvariedstartingmaterialsoroperatingparametersconducted?Werethesestudiessufficienttoestablishadesignspaceforprocess?InprocesstestsWhyiseachinprocesstestrequired?Howweretheacceptancelimitschosen?Whywerethein-processtestsidentifiedascriticaltoproductquality?Whatscale-upexperiencedoesthesponsorhavewiththeunitoperationsinthisprocess?中美仿制藥研發(fā)和申報(bào)流程概述專家講座第48頁(yè)QBR:RiskSummaryNTIdrugClassifiedasanon-NTIdrug,riskscore=+0ClassifiedasanNTIdrug,riskscore=+1DosageFormSimpleDosageForm,riskscore=+0OtherDosageFormsandNTIdrugs,riskscore=+1DevelopmentReportIfthesponsorsubmitsadevelopmentreportthataddressestheFDA’squestions:Riskscore=+0SolutionandIRProducts:ProductDevelopmentReportOtherDosageForms:ProductandProcessDevelopmentReportsInsufficientormissingdevelopmentreport,riskscore=+1IftheapplicationisofhighoverallqualityLessthanorequalto2cycles,riskscore=+0.