上海CMC培訓(xùn)美國仿制藥申報和當(dāng)前的挑戰(zhàn)從研發(fā)到注冊上市課件

JimHuang,PhDAAPS/CPAWorkshopShanghai,June28-29,2010

GenericDrugApplicationsandCurrentChallenge:FromDevelopmenttoMarketintheU.S.

美國仿制藥申報和當(dāng)前的挑戰(zhàn):從研發(fā)到注冊上市TableofContents藥物品種選擇

ProductSelection研發(fā)過程

DevelopmentProcess仿制藥申報文件提交

ANDAfiling商業(yè)化

CommercializationTableofContents藥物品種選擇ProductSelection研發(fā)過程DevelopmentProcess仿制藥申報文件提交ANDAfiling商業(yè)化CommercializationSelectionProcessPortfolioDevelopmentBrandSale(IMSdata)NewProductValue(NPV)–projectionProductIndication–competitionBusinesscaseforapprovalIPEvaluationTechnicalEvaluationCommerciallaunch(baseandbestcase)KeyPatents(Orangebook&published)FTF(PIV)orFTMopportunityExclusivityexpiry/PediatricexclusivityFormulationchallenge(difficulttoreplicate)AnalyticalIssues(reversedengineering)CompetitiveintelligentMarketformation(forecast)ANDAApproval(estimate)Launch(projection)SODIRTraditionalChewableODTSODERPelletsMatrix/CoatedMatrix/BarrierOsmoticOthertechnologiesInjectableFastactingDepoTopicalw/clinicalCorticosteroidsTopicalsolutionsOralLiquidLiquidSuspensionStrategy

bybalancingportfolioProductCategoriesDifficulttoReplicate(DTR)

SODIRTraditionalChewableODTSODERPellets(ERandDR)Matrix/CoatedMatrix/BarrierOsmoticundefinedFirsttoFile(FTF)NCE(newchemicalentities)ERversionsofIRCombinationproductsNewdosageformsNewstrengthsNewproductsOrphanDrug505b(2)

Paragraph4Filing

vs.Para3FilingWhenapplyingtoenterthemarketwithagenericformofareferenceproduct,agenericcompanyfilesanANDAandcertifiesagainstapatentlistedintheOrangeBook.Thecertificationstatesthateither(a)FDAshouldapproveofitsgenericversionafterthepatentexpires[a“Paragraph3”filing]or(b)thatitsgenericproductdoesnotinfringeonthelistedpatentorthatthepatentisnotenforceable[a“Paragraph4”filing]FTFandParagraph4

……

FIRSTtoFILEaParaIVFilingBeingthefirsttofileaParaIVANDAentitlesthegenericsponsorto180daysofmarketingexclusivityuponlaunchofaproduct,priortoFDAapprovingotherapplications.BenefitofFTF…..Ona$500milliondollarbrandproduct…FirstNotFirst(limitedcompetition)NotFirst(hyper-competition)Competitors:2-51stWave:22ndWave:3othersCompetitors:5-enter6mnthsafterMFCompetitors:10-enter6mnthsafterMFMarketShare:50%(1st6months)MarketShare:11%MarketShare:6%Price:42%ofBrand(1st6months)Price:11%ofBrandPrice:1.5%ofBrandFirstYearSales:$61.3MFirstYearSales:$6.6MFirstYearSales:$0.5MSalesvalueforaFTFisworth

10-130times

anon-FTFProcessoffilingaParaIV,approvalandlaunchSubmitANDAOGDAcceptsANDANotifyPatentHolder(Brand)BrandResponds(suesornot)TentativeApprovalLaunchAcceptanceistakinglonger,upto6monthsBrandhas45daystorespondtothecertificationofnon-infringementApplicanthas30monthsfromdateoffilingtoreceiveTentativeApprovalOtherwiseFDAwilldeemtheapplicant’sexclusivityforfeitedIfBrandsues,Hatch-WaxmanpreventstheFDAfromapprovingtheANDAfora30monthperiodrunningfromthedateofnoticeunlessthecourtrulesinfavoroftheANDAapplicantbeforetheperiodexpiresDevelopmentPhasesPre-formulationLiteraturesearch(FDACDER,compendia)Patentevaluation(OrangeGuide,issuedpatent)ActiveSourcing(IPposition,evaluatesupplier)Brandproductevaluation(reversedengineering,characterization,profiling)FormulationdesignapprovedbylegalProto-typeformulationwithexcipientscompatibilitystudyFormulationExcipientselectionContainerclosuresystemManufacturingprocess(simplified)AnalyticaldevelopmentandtestingSpecificationsandcontrolProcureactiveandexcipientsforclinicalandexhibitbatchesDevelopmentPhases

(continued)ProcessOptimizationGranulationoptimizationFluidbedparametersBlendingeffects(BU,CU)Compression(hardness,friability,dissolution)Coatingefficiency/optimizationExhibitbatchGMPproductionfacilityFeasibilityandconfirmationbatchesBatchdocument(masterformulaorprotocol)ReviewandapprovalbyR&D,QA-QC,RAorproductionExecutionandproperdocumentationAnalyticaltestingFinalreleaseandreportDevelopmentPhases

(continued)BioequivalentstudyIn-vitroprofilingmatchwithbrandfrommulti-mediaandapparatusClinicalstudydesign(2-or3-waycrossoversingledosefedandfast)DoseTestvs.RLD(highestorloweststrengthdependingonsafetyandtolerance)–pilot(POC)orpivotalBio-waiverformulti-strengthsotherthanRLDwithin-vitrodissolutiontestinginmulti-mediaPerformSimilarityTest[f2test]toshowbio-waiverPre-submissionChecklistMethodvalidationreportBio-studyreportreadinessStabilitystudyandreportAllGMPrecordreviewedandapprovedANDARegulatoryplaceHighQualityANDAElectronicsubmission(eCTD)(efficiency)Clean,completeandhighqualityfilingisveryimportant(reduceapprovaltime)PharmaceuticalDevelopmentReport(developmenthistory)QualityOverviewSummary(QOS,Qbr)StabilityData(degradationandtrending)ClinicalSummaryandStudyReport(no“outlier”or“clinicalrepeat”)HowtofileanANDAAbbreviatedNewDrugApplication(ANDA):GenericsrugsareDevelopedandApproved/ApprovalApplications/AbbreviatdNewDrugApplicationANDAGenerics/default.htmElectronicRegulatorySubmissionandReview:rugsareDevelopedandApproved/ApprovalApplications/AbbreviatdNewDrugApplicationANDAGenerics/ucm154163.htm#ANDAANDAChecklistforCompletenessandAcceptability:wDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNeDrugApplicationANDAGenerics/UCM154150.pdfFDAwebsiteforANDAsubmissionTableofContents藥物品種選擇ProductSelection研發(fā)過程DevelopmentProcess仿制藥申報文件提交AND