4 NDA in CTD Formatppt課件

JeffPinkelmanDirector ExecutiveConsultant May16 17 2013 AbbreviatedNewDrugApplication eCTDFormat 2 Discovery 6 5years CMCNonclinicalStudiesIND Clinical 1 000 5 000patients Phase1 1 5years Phase2 2years Phase3 3 5years NDA 1 5years DrugDevelopmentPathway NDAObjectives GoalofdrugcompanyistoobtainapprovalfromFDAtomarketproductinUnitedStatesCompanybeginstomakemoneyandreceivereturnonresearchanddevelopmentinvestmentonceproductisonthemarket10 15yearstogofromresearchbenchtomarketapprovalandmillionsofdollars1drugapproved 5inclinicaltesting 5 000inpreclinicaltesting 3 NDASubmissionineCTDFormat IfsubmittingelectronicallyinUnitedStates needstobeineCTDformatasofJanuary1 2008 PapersubmissioninCTDformatisstillanoption CTDistheidealformatforglobalmarketingofadrugtosubmittechnicalinformationtohealthauthoritiesinmultipleregions 4 GuidanceforIndustryDocumentsforCTD M4 OrganizationoftheCTDProvidingRegulatorySubmissionsinElectronicFormatHumanPharmaceuticalProductApplicationsandRelatedSubmissionsUsingtheeCTDSpecificationsM4Q TheCTD QualityM4S TheCTD SafetyM4S TheCTD SafetyAppendicesM4E TheCTD Efficacy 5 AnOverviewoftheICHCommonTechnicalDocument CTD 6 StructureofaCTD Module1 AdministrativeInformationModule2 SummariesModule3 Quality Chemistry ManufacturingandControls CMC Module4 Safety notrequiredforANDA NonclinicalStudyReportsandLiterature Module5 Efficacy ClinicalStudyReportsandLiterature 7 FolderStructureforeCTDNDA 8 Module1ofeCTDNDA SpecificModuleforU S FDARequirementsforaMarketingApplication 9 Module1AdministrativeInformation Containsregion specificinformationContentsIndexineCTD1 1Forms1 1 2FormFDA356h1 1 3FormFDA33971 2CoverLetterFormFDA36741 3AdministrativeInformation 10 IndexorComprehensiveTableofContents ToincludeacompletelistofalldocumentsprovidedinthesubmissionbymoduleForeCTDsubmissions anindexisgeneratedandlinksdirectlytoNDAsectionsForpapersubmissions atableofcontentsidentifiesthelocationofeachdocumentbyreferringtothemodule volumenumber andtabidentifier 11 SampleeCTDModule1Index 12 SampleeCTDModule1 5Index 13 1 1 2FormFDA356h The356hformissubmittedeverytimeaNDA ANDA BLA amendment orsupplementismadeintoamarketingapplication 14 TypesofNDAs 505 b 1 Newdrugrequiringafullapplicationdemonstratingsafetyandefficacy505 b 2 ApplicationthatreliesuponareferencelisteddrugoravailableliteratureinthepublicdomainforapprovalModificationstoalisteddrugsuchasNewindicationNewdosageform 15 505 j orAbbreviatedNDA ANDA ForgenericdrugsthatarethesameasalisteddrugIdenticalinactiveingredient s dosageform strength routeofadministration andconditionsofuseNote TypesofNDAsarenamedaccordingtoFood Drug andCosmetic FDC Act TypesofNDAs 16 ChangestoNDA AmendmentsInformationsubmittedduringthereviewperiodpriortoapprovaloftheNDAoranunapprovedsupplementAnnualReportsMinorchangeswithminimalpotentialtohaveAEsSubmitannuallyaccordingtoapprovaldate 17 SupplementsInformationsubmittedafterapprovaloftheNDAorsupplementCBE changesbeingeffected MinorchangeswithminimalpotentialtohaveAEsImplementimmediatelyCBE 30 changesbeingeffectedin30days ModeratechangesandpotentialtohaveAEsImplementifFDAdoesnotnotifywithin30daysofreceiptPriorApproval PA MajorchangeswithsubstantialpotentialtohaveAEsExpect4 6monthsreviewperiodforapproval ChangestoNDA 18 1 1 3FormFDA3397 UserFeeCoverSheetRegisteronlineandsubmitelectronicallypriortosubmission 19 1 2CoverLetter ExplainscontentsofsubmissionAdditionaldocumentsincludedinfolderElectronicsubmissioninformationandcontactSponsorcontactinformationFDAForm3674forCertificationofComplianceforClinicalTrials 20 1 3AdministrativeInformation ThefollowingdocumentsshouldbeincludedinSection1 3foraNDA 1 3 2FieldCopyCertification1 3 3DebarmentCertification1 3 4FinancialCertificationandDisclosure1 3 5PatentandExclusivity 21 1 3 2FieldCopyCertification RequeststhatanelectroniccopyoftheQualitySection Module3 oftheapplicationbeprovidedtotheappropriateFDAfieldofficeIfpapersubmission confirmthatthefieldcopyissenttothefieldofficeandthatitisatruecopyoftheQualitySectionofthesubmittedNDATheFDAfieldofficeusestheinformationtoinspectthemanufacturerpriortoapproval 22 1 3 3DebarmentCertification ConfirmsthattheSponsordidnotusetheservicesofanydebarredindividualinconnectionwiththeapplicationOfficeofRegulatoryAffairsprovidesalistofdebarredindividuals 23 DebarmentList 24 1 3 4FinancialCertificationandDisclosure FinancialDisclosureInformation CompleteFormFDA3454 certification orFormFDA3455 disclosure Foreachclinicalinvestigatorwhoconductedthecoveredclinicalstudy ies acertificationand ordisclosureregardingfinancialarrangementsasfollows Disclosureofspecifiedfinancialarrangementsandstepstakentominimizepotentialforbias 25 Certificationthat NofinancialarrangementsweremadewithinvestigatorwherestudyoutcomecouldaffectcompensationTheinvestigatorhadnoproprietaryinterestinthetestedproduct e g patent copyright licenseagreements Theinvestigatordoesnothaveasignificantequityinterestinthesponsorofthestudy e g stockoptions ownership financialinterest Theinvestigatorhasnotreceivedsignificantpayments e g grants equipment retainers honoraria 1 3 4FinancialCertificationandDisclosure 26 1 3 5PatentandExclusivity 1 3 5 1PatentInformationPatentinformationonanypatentthatclaimsadrug Drugsubstance ingredient drugproduct formulationandcomposition ormethodofusepatent andshouldincludepatentnumber expirationdate typeofpatent nameofpatentowner andnameofpatentowneragent ifforeign Declarationstatementforformulation composition ormethodofusepatents orifnorelevantpatentsexist 27 1 3 5 2PatentCertificationPatentCertificationfor505 b 2 NDAandANDAs Certificationincludesthefollowingtypesforeachrelevantpatent PatentinformationnotfiledwithFDAPatentexpiredPatentwillexpireonsuchdatePatentisinvalid unenforceable orwillnotbeinfringed 1 3 5PatentandExclusivity 28 1 3 5 3ExclusivityRequestTypesofexclusivity 7yearsforanorphandrug5yearsofexclusivityfornewchemicalentity3yearsofexclusivityfornewindication6monthsextensionofexclusivityforpediatricindication180daysforpatentchallenge ANDAonly 1 3 5PatentandExclusivity 29 OtherAdministrativeInformation Additionaladministrativedocumentstobeincludedifapplicable 1 4References1 6Meetings1 9PediatricAdministrativeInformation1 12OtherCorrespondence1 14Labeling1 16RiskManagementPlans 30 1 4References 1 4 1LetterofAuthorizationLetterssubmittedbyapplicantallowingothercompaniestoreferencetheirDMFordocuments1 4 2StatementofRighttoReferenceLetterofAuthorizationreceivedbyapplicanttoreferenceanothercompany sDMFordocuments1 4 3ListofAuthorizedPersonstoIncorporatebyReferenceListofcompanies peoplewhoLettersofAuthorizationhavebeenissuedtobyanapplicanttoreferencetheirDMFordocuments 31 1 4 4CrossReferencetoOtherApplicationsReferencestoinformationpreviouslysubmittedbyapplicantorothercompaniesINDsNDAsDMFs 1 4References 32 1 12OtherCorrespondence 1 12 4RequestforCommentsandAdviceFDAcorrespondence1 12 5RequestforaWaiver1 12 11BasisofSubmissionStatement1 12 13RequestforaWaiverforInVivoStudies 33 1 12 14EnvironmentalAnalysisEnvironmentalAssessment orrequestforcategoricalexclusion Provideanassessmentoftheimpactofthedrugtotheenvironmentinaccordancewith21CFR25SubpartDTheEAshouldfocusonenvironmentalissuesrelatedtouseanddisposalofFDA regulatedproducts 34 1 12OtherCorrespondence 1 12 14EnvironmentalAnalysisEnvironmentalAssessment continued Requestforcategoricalexclusionbasedon21CFR25SubpartCExamples DoesnotincreasethecurrentuseoftheactivemoietyIfincreasesuseofactivemoiety buttheestimatedconcentrationenteringtheaquaticenvironmentwillbebelow1partperbillionFornaturallyoccurringsubstanceintheenvironmentwhentheconcentrationordistributionofsubstance metabolites ordegradationproductsarenotaltered1 12 15RequestforaWaiverforInVivoBioavailabilitiesStudies 1 12OtherCorrespondence LabelingRequirements Labelingrequirementsforprescriptionandover the counter OTC drugsareprovidedin21CFR201ThelabelingispreparedfromtheCMC nonclinical andclinicaldataintheNDANewlabelingformatforprescribinginformation physicianslabelingrule PLR wentintoeffectJune30 2006 andmustbesubmittedinstructuredproductlabeling SPL format 36 1 14Labeling 1 14 1DraftLabeling1 14 1 1DraftCartonandContainerLabelsCartons blisters bottles vials patches etc 1 14 1 2AnnotatedDraftLabelingText1 14 1 3DraftLabelingTextPrescribingInformation IncludecopiesofproposedlabelingtextThiscouldconsistofpackageinserts patientleaflets informationsheets medicationguides etc 1 14 2FinalLabeling1 14 3ListedDrugLabeling1 14 5ForeignLabeling 37 1 14 1 2AnnotatedDraftLabeling AnnotatedLabelingText Includeacopyoftheproposedlabelingtextwithannotationsdirectingreviewerstotheinformationinthesummariesandothermodulesthatsupporteachstatementinthelabeling 38 1 14 1 3DraftLabelingText 39 1 14 1 3DraftLabelingText 40 1 14 3ListedDrugLabeling 1 14 3 1AnnotatedComparisonwithListedDrugSide by sidecomparisonsforANDAIncludeaside by sidecomparisonofreferencelisteddrug sapprovedlabelingtotheproposedlabelingdenotingchangesbetweenthetwolabels 41 ElectronicSubmissionofLabeling ThesubmissionofelectroniclabelingappliestoNDAs ANDAs BLAs andAnnualReportstomarketingapplicationsAsofMarch2013 alldraftlabelingmustbesubmittedelectronicallytoFDAinSPL pdf andMSWordfileformats 42 1 16RiskManagementPlans ControlledsubstanceSeriousadverseeventsassociatedwithdrugSpecialmonitoringrequirementsPatientRegistryRiskEvaluationandMitigationStrategies REMS 43 REMSRequirements ElementstoEnsureSafeUseGoalstomitigatespecificseriousriskHealthcareprovidertrainingandcertificationPatientmonitoringandtestingPatientregistryImplementationofsystemstomonitor evaluate andimprovethesystem 44 AdditionalPotentialElementsMedicationGuideorPatientPackageInsertCommunicationPlanforhealthcareprovidersTimetableforSubmissionofAssessments18monthsafterNDAapproval3yearsafterNDAapproval7yearsafterNDAapproval REMSRequirements 45 REMSSupportingDocumentationBackgroundastowhyREMSisnecessaryRationaleforREMSgoalsRationaleforREMSelementsRationaleforassessmentplanOtherrelevantinformationSubmitproposedREMSinNDAoratFDA srequestasaNDAamendmentFinalREMSprovidedwithNDAapprovalletter REMSRequirements 46 Module1ofeCTDNDA 47 Module2 5ofeCTD 48 Module2Summaries Objectives ToprovideasummaryofModule3 Quality CMC Module4 Safety Nonclinical Module5 Efficacy Clinical Tointegratethemostimportantinformationoftheapplicationtofacilitatethereviewoftheapplicationbythecompetentauthority 49 TableofContents2 1TableofContents Modules2 5 paperonly 2 2IntroductiontoSummary2 3QualityOverallSummary2 4NonclinicalOverview2 5ClinicalOverview2 6NonclinicalWrittenandTabulatedSummaries2 7ClinicalSummary Module2Summaries 50 2 2IntroductiontoSummary GeneralintroductiontothepharmaceuticalPharmacologicclassModeofactionProposedclinicaluse indication Note Shouldnotexceedonepage 51 2 3QualityOverallSummary Objectives ProvidethereviewerwithanoverviewofModule3Emphasizecriticalkeyparametersoftheproductrelatedtochemistry manufacturing andcontrolsProvidejustificationsincaseswhereguidelineswerenotfollowedLinktoModule3sections 52 TableofContents 2 3Introduction2 3 SDrugSubstance2 3 PDrugProduct2 3 AAppendices2 3 RRegionalInformation 2 3QualityOverallSummary 53 2 4NonclinicalOverview NotrequiredinanANDAsubmission 54 2 5ClinicalOverview Objectives HighestlevelsummaryandanalysisofclinicaldataandclinicalsectionsoftheapplicationIncludescomparisontoRLDandreferencesRLDforbiopharmaceuticsinformation 55 2 7ClinicalSummary Objectives Provideadetailed factualsummarizationofallclinicalinformationintheCTDTypicallyincludesoneormoreopen label single dose randomized two period two treatmentcrossoverstudyPharmacologicalinformationisgenerallyobtainedfromtheRLDPrescribingInformation 56 TableofContents 2 7 1SummaryofBiopharmaceuticStudiesandAssociatedAnalyticalMethods2 7 2SummaryofClinicalPharmacologyStudies2 7 3SummaryofClinicalEfficacy2 7 4SummaryofClinicalSafety2 7 5LiteratureReferences2 7 6SynopsesofIndividualStudiesNote LinktoReportsandLiteratureinModule5 2 7ClinicalSummary 57 StructureofModule2eCTDFolder 58 Module5ClinicalStudyReports GuidanceforIndustry M4E TheCTD EfficacyGuidancerecommendsaspecificorganizationfortheplacementofclinicalstudyreportsinModule5bytheprimaryobjectiveofthestudy Eachstudyreportshouldappearonlyinonesectionandshouldbecross referencedinallotherapplicablesections 59 TableofContents5 1TableofContentsforModule5 paperonly 5 2TabularListingofAllClinicalStudies5 3ClinicalStudyReportsandRelatedInformation5 4LiteratureReferences Module5ClinicalStudyReports 60 CaseReportForms CRFs andIndividualPatientListings CasereportformsandindividualpatientdatalistingsshouldbeplacedinaCRFfolderwithinthefolderforeachclinicalstudyreportCasereportformsareprovidedforpatientswhoDiedduringthestudyDidnotcompletethestudybecauseofadverseevents whetherbelievedtobedrugrelatedornot includingpatientsreceivingreferencedrugsorplacebo 61 StatisticalDatasets ProvidestatisticaldatabaseforeachstudyasSAS transportfilesPlacedinfoldernamed datasets inModule5witheachstudyinitsownfolderFDAwillconductownstatisticalanalysis 62 5 4LiteratureReferences Copiesofreferenceddocuments includingimportantpublishedarticles officialmeetingminutes orotherregulatoryguidanceoradviceshouldbeprovidedhere ThisalsoincludescopiesofallthereferencescitedinModule2fortheClinicalOverview ClinicalSummary andModule5 Copiesofreferencesthatarenotincludedshouldbemadeavailableuponrequest 63 Module5eCTDFolderStructure 64 GeneralIssuesforNDASubmissions ElectronicSubmissionCompleteNDA PDFfiles Labelingonly MSWordandSPLfiles ClinicalTrialDataSets SAS Transportfiles OnlyonearchivalcopyissubmittedSubmitthroughElectronicSubmissionGateway ESG oronCD RomIncludesignedcopyofcoverletterandforms ifelectronicsignaturesarenotvalidated andindex md5number 65 PaperSubmissionPapersize 8 5 x11 Fontandsize TimesNewRoman 12pointMargins Left handminimumof0 75 Two inchmaximumthicknesspervolumeBindalldocumentsinseparatevolumesorcombineinvolumesifseparatedbytabidentifiers keepallmodulesinseparatevolumes GeneralIssuesforNDASubmissions 66 ReviewercopiesandcolorbindingrequirementsArchival blue isacompletecopyofapplicationReviewcopiesChemistry red Module1 2 3Pharmacology yellow Module1 2 4Pharmacokinetics orange Module1 2 5Microbiology white Module1 2 5 ifrequired Clinical tan Module1 2 5Statistics green Module1 2 5Fieldcopy maroon Module3 submittolocalfieldofficeforFDApre approvalinspection Note Verifynumberofcopiesandmodulesorsectionsofmodulesrequiredforeachreviewerpriortosubmission GeneralIssuesforNDASubmissions 67 eCTDNDASubmissionstoFDA Majorteamworkrequiredtocompleteadministrative CMC nonclinical andclinicaldocuments andsubmitNDA 68 NDAReviewProcessFlowChart 69 ReasonsFDAMayRefusetoFileNDA LackofcompletedapplicationformLackofrequiredinformationLackofcompleteenvironmentalassessmentLackofanaccurateandcompleteEnglishtranslationofforeignlanguageinformationLackofGLPcompliancestatementsorexplanationLackofIRB ICcompliancestatementsAlreadycoveredbyanapprovedNDAorANDA 70 DuringNDAReview SubmitNDAamendmentsatrequestofFDAreviewingdivision 71 FDANDAReviewOutcomes Attheendofthereviewperiod FDAwillsendtheapplicant ApprovalLetterApprovaleffectiveonthedateofissuanceoftheletterApprovableLetterIntentiontoapproveifspecificadditionalinformationormaterialissubmittedorspecificconditionsaremetCompleteResponseLetterNotapprovableduetodeficiencies 72 NDAApproval PostmarketingrequirementsbeginfortheproductReturnoninvestmentbeginswithmarketingoftheproductCelebration 73 Reachultimategoaltohelppatients NDAApproval 74 ReasonsforaCompleteResponseLetter Manufacturingprocessfordrugsubstanceordrugproductinadequatetopreserveidentity strength quality purity stability orbioavailabilityDrugwillbemanufacturedorprocessed inwholeorinpart inanunregisteredfacilityApplicantdoesnotpermitadequateinspectionoffacilities controls orrecordsManufacturingprocessdoesnotcomplywithcGMPsAnessentialnonclinicallaboratorystudywasnotconductedincompliancewithGLPs 75 AnyclinicalinvestigationwasnotconductedincompliancewithIC IRBregulationsProposedlabelingisfalse misleading ordoesnotcomplywithlabelingrequirementsNDAcontainsanuntruestatementofmaterialfactLackofcorrectionofadeficiencyprovidedbyFDAinwriting ReasonsforaCompleteResponseLetter 76 NDAAdministrativeActions CommunicationsbetweenFDAandApplicantFDAreviewersshallmakeeveryreasonableefforttocommunicatepromptlytotheapplicantregardingeasilycorrectabledeficienciesfoundintheapplication theneedformoredataorinformation ortheneedfortechnicalchangestofacilitatethereviewE mailfromFDAprojectmanagerTelephonediscussion teleconferencewithFDAFaxorletterfromFDA 77 CommunicationsbetweenFDAandApplicant continued Atapplicant soption a90 dayconferencemaybeheldtodeterminegeneralprogressandstatus maybebytelephone End of ReviewConference afterconclusionofFDAreviewincaseswhereanapprovableorcompleteresponseletterhasbeenissued todiscussfurtherstepsbeforeapplicationcanbeapproved NDAAdministrativeActions 78 WithdrawalofanUnapprovedApplicationApplicantmayrequestinwritingatanytimebeforeapprovalFailuretorespondwithin10daystoanapprovableorcompleteresponseletterisconsideredbyFDAtobearequestforwithdrawalDecisiontowithdrawwillnotprejudicefutureresubmission NDAAdministrativeActions 79 NDAAnnualReport AnnualReportsForelectronicsubmission Section1 13ineCTDformatForpapersubmissions twocopiesaresubmittedalongwithFormFDA2252Within60daysofapprovalanniversarydateSummarize Newinformation whichmayaffectsafety efficacy orlabelingApplicantactions e g labelingsupplement labelingwarning etc Pediatricuseinformation 80 QuantityofdrugdistributedNDCnumberTotalnumberofdosageunitsofeachstrengthQuantitiesfordomestic foreignuseCMCchangesSampleofcurrentlabeling SPLfile NonclinicallaboratorystudiesClinicaldata NDAAnnualReport 81 Currentstatusofpost marketingstudycommitmentsStatusofotherpost marketingstudiesLogofoutstandingregulatorybusiness NDAAnnualReport 82 WhoMustRegisterTheirEstablishment OwneroroperatorofanestablishmententeringintoManufacture preparation propagation compounding orprocessing re packagingandre labeling ofadrugMustregisterwithin5daysafterbeginningoperationorwithin5daysaftersubmittingadrugapplicationMustrene