品研究实验原始记录审核技术要求

品研究实验原始记录审核技术要求第1页/共109页新药研发过程质量规范第2页/共109页GLP历史沿革

遵从GLP的意义GLP规范基本要求原始数据核查要点

非临床实验室常见错误法规对GLP或非GLP的要求案例分析内容提要3第3页/共109页GLP历史–美国WhatpromptedUSFDAtoissueGLPregulations?

Inthe1960sand1970s,inadditiontothe“Thalidomide”story,FDAfound:SelectivelysubmittedfindingsFabricateddataFalsifieddataDiscrepanciesinreporting(e.g.,betweenindividualandsummarydata)Poorlaboratoryrecordkeeping(resultingininabilitytoreconstructstudyperformance)第4页/共109页GLP历史–美国Inthe1960sand1970s,FDAalsofound:Noprotocols,protocolswrittenafterstudyperformance,studynotperformedaccordingtoprotocolNooneinchargeofstudiesSloppylaboratorypractices第5页/共109页USFDAGLP法规1976CongressionalhearingsGLPsproposed1978GLPsfinalized1979GLPsbecomeeffective第6页/共109页USFDAGLP法规

21CFR:CodeofFederalRegulations,Food&DrugAdministration.

21CFRPart58:GoodLaboratoryPracticesforNonclinicalLaboratoryStudies

21

CFRPart11:ElectronicRecords;ElectronicSignatures第7页/共109页USFDAGLPPart

58要求DescribesrequirementsforconductingandreportingnonclinicallaboratorystudiesIntent:providesaframeworkforconductingwell-controlledstudiesassuresqualityandintegrityofthedatafacilitatesstudyreconstructionprovidesoverallaccountabilityNonclinicalstudiesthatevaluatesafetymustbeGLPcompliant第8页/共109页USFDAGLP检查FDAGLP检查过的美国国内实验室 200余家,CRO,药厂第9页/共109页USFDAGLP检查FDAGLP检查过的美国境外实验室 40余家,CRO,药厂第10页/共109页USFDAGLP检查：MOU8个国家日本法国德国加拿大意大利瑞典瑞士荷兰第11页/共109页USFDAGLP检查：中国GLP实验室

2009年7月检查了三家GLP实验室

国家安评中心(NCSED)昭衍（JOINN)

Bridge(康龙化成)昭衍提交的试验报告获得美国FDA 认可,用于支持美国的临床试验。第12页/共109页OECDGLP规范Developedin1978USFDAGLPprovidedthebasisforOECDRevisedOECDprinciplesadoptedin1997PrimaryobjectivesimilartoUSFDAToensurethegenerationofhighqualityandreliabletestdatarelatedtothesafetyofindustrialchemicalsubstancesandpreparationsintheframeworkofharmonisingtestingproceduresforthemutualacceptanceofdata(MAD)第13页/共109页OECD

MAD（数据互认）DatageneratedinthetestingofchemicalsinanOECDmembercountryinaccordancewithOECDTestGuidelinesandOECDPrinciplesofGLPshallbeacceptedinotherMembercountriesforpurposesofassessmentandotherusesrelatingtotheprotectionofmanandtheenvironmentOECDMemberCountriesAustralia,Austria,Belgium,Canada,CzechRepublic,Denmark,Finland,France,Germany,Greece,Hungary,Iceland,Ireland,Italy,Japan,Korea,Luxembourg,Mexico,Netherlands,NewZealand,Norway,Poland,Portugal,SlovakRepublic,Spain,Sweden,Switzerland,Turkey,UnitedKingdom,UnitedStates第14页/共109页中国GLP发展历史

1993年12月，国家科委发布了GLP（试行）

1999年10月，SDA发布GLP（试行）

2001年中国修订《中华人民共和国药品管理法》、《药品法实施条例》，将GLP明确为法定要求

2003年9月,SFDA颁布实施GLP（二号令）280条,开展GLP认证检查

2007年1月–法规毒理实验强制要求GLP

2009年7月–3家在中国的GLP实验室接受美国FDA检查第15页/共109页中国GLP管理规范

药物非临床研究质量管理规范（局令第2号） 2003年9自2003年9月1日起施行

共九章45条非临床研究质量管理规范认证标准280条

药品注册现场核查管理规定 7章、59条、5个附件

第16页/共109页遵从GLP的意义AssuresqualitydataanddataintegrityProtectsthewell-beingofsubjectsinclinicaltrialsmanyofwhomarehealthyvolunteers(humansafety)Ensuresthatastudycanbecompletelyreconstructedfromarchivedrecords对中国CRO来说，研究报告可以得到国际认可。第17页/共109页GLP规范要素

Whatisanonclinicallaboratory? IntheSFDAorUSFDAregulatoryworld,a

laboratoriesthatconductnonclinicalstudiesinvolvingtestarticlestodevelopdatathatwillbesubmittedtotheagencyinsupportofanapplicationandmarketingapproval第18页/共109页

GLP规范要素

TestArticlestheSFDA-/USFDA-regulatedproductbeingtested第19页/共109页GLP规范要素TestSystemsMouse/Rat,GuineaPig,Rabbit,Dog(Beagle),Pig,Monkey,Primate,(Chimpanzee)第20页/共109页TheABCofGLPRegulations

DefinitionsPersonIndividualPartnershipGovernmentagencyOrganizationalunitCorporationScientificoracademicestablishment第21页/共109页GLP规范要素

RawDataLaboratoryworksheetsRecords&documentMemorandaNotesComputerprint-outsAllcommunications(internal/external/sponsors)第22页/共109页GLP规范要素

OrganizationandPersonnelEducationTrainingExperienceJobdescriptionPersonnelRecordPersonnelManagementStudyDirectorQAUFollowprotocolDocumentdeviationsArchive第23页/共109页GLP规范要素

OrganizationandPersonnelReviewQAUPersonnelStudyDirectorMasterschedulesheetProtocolsInspectionrecordsSOPsManagementStatusreportFinalstudyreport第24页/共109页GLP规范要素

Facilities

NonclinicallaboratoryReceiptandstorageMixing第25页/共109页GLP现场核查Process-oriented

qualitydataasaresultofproperutilizationofandcontroloverfacilities,personnelandproceduresAllowsflexibilityinlaboratoryoperationanduseofscientificjudgment

studydirectorsmustexertthisjudgment

overallresponsibilityfortechnicalconduct,interpretationandreporting第26页/共109页现场核查要点Step1:InventoryDocuments文件清单MakesurenecessarydocumentswereincludedinthestudyreportProtocolProtocolamendments方案修改Protocoldeviations方案偏离 (withexplanationsonpossibleimpacttostudyinterpretationandvalidity)Report (withsufficientlydetailedsummaryandindividualanimaldata)第27页/共109页现场核查要点Step2:Identifytestarticle供试品testarticlecodeornamesaltformformulationpurityUniformity均一性Stability稳定性lotorbatch#第28页/共109页现场核查要点Step3:Theexperimentaldesign试验设计Studiesarefluid;whatisinaprotocolfrequentlychangesduringthecourseofastudyNoteimportantdates(experimentaldesignlandmarks)experimentalordosingstartdate(REPORT)studyinitiationdate(REPORT)protocolamendmentdate(s)(AMENDMENTS)experimentalcompletiondate/necropsydate(REPORT)第29页/共109页现场核查要点Step3:Theexperimentaldesign试验设计Notehowexperimentaldesign/methodschangedlookatprotocolamendmentsanddeviationsconsiderifthechangesinvalidatedthestudy’sobjectivesconsiderifthechangescausedstudytobeinconsistentwithstatedguidelines/methods(andevaluatesignificance)Makesureyouunderstandexperimentaldesign(asperformed)andchronologyperamendmentsanddocumenteddeviations第30页/共109页现场核查要点Step4:Comparedocumentsforconsistency

一致性DoreportscomplywithGLPrequirementsonreportingfortestarticlecharacteristicstestingofdosingformulationsforpuritystabilityuniformity第31页/共109页现场核查要点 Step4:

ComparedocumentsforconsistencyMakesurethatdataandtheirassociateddocumentsareconsistentwithoneanother.第32页/共109页现场核查要点Step4:Comparedocumentsforconsistency

Areprotocol-specifiedevaluationsofdataapplied?statisticaltestscriteriaforacceptablestudy,positivefinding(e.g.,genotoxicitytests)Doesselectionofhighestdosecomplywithprotocol?Withreferencedguideline?第33页/共109页现场核查要点Step4:ComparedocumentsforconsistencyArefindingsforallprotocol-specifiedevaluationsreportedbodyweightclinicalchemistryhistopathologyforallprotocol-specifieddosegroupstoxicokinetics第34页/共109页现场核查要点

Step5:Dodataseemcredible?

ReportRawdata/Reality第35页/共109页现场核查要点Step6:Evaluationofsignificanceoflapses

失误的评估Thebigquestions–Didproblemsinstudydocumentsresultinyourinabilitytodrawmeaningfulconclusionsfromthestudy(withrespecttostudy’sstatedobjective)?Didinconsistenciesinthispartofthesubmission,relativetootherpartsofthesubmission,makeyouhavelessfaithintheintegrityofotherportionsofthesubmission?Intheconclusionsofotherstudies?第36页/共109页现场核查要点 NotalllapsesprecludedrawingconclusionsfromastudymistakescanhappeninperformingastudyindescribingfactsometimesfactisnotconvenientTheevaluationofmistakesrequiresanevalutionoftheirmagnitudeandnature.Areerrorswidespread?Limited?Doerrorsoccurinreportingofendpointsthatarecriticaltoscientificinterpretation?Doerrorsspeakforareport-specificproblemorsomethingthatisasystemicproblem

?第37页/共109页

现场核查要点：职责

TESTINGFACILITYMANAGEMENT:Overalllaboratorymanagementandadministrativefunctionsdesignatesstudydirectorbeforestudyisinitiatedreplacesstudydirector(promptly),ifnecessaryassuresthereisaqualityassuranceunit(QAU)assurestestandcontrolarticleshavebeenappropriatelyevaluatedforidentity,strength,purity,stabilityanduniformity(asapplicable)第38页/共109页现场核查要点：职责TESTINGFACILITYMANAGEMENT:(cont’d)assuresappropriatestaffing,facilities,equipmentandmaterialsareavailableforscheduledtestsassuresthatstaffunderstandsthefunctionstheyaretoperformassuresdeviationsreportedbyQAUarepromptlyreportedtostudydirector第39页/共109页现场核查要点：职责STUDYDIRECTOR

Singlepointofstudycontrolhasoverallresponsibilityfor:ProtocolpreparationtechnicalconductofstudyinterpretationofresultsanalysisofresultsdocumentationofresultsreportingofresultsArchiving第40页/共109页现场核查要点：职责STUDYDIRECTOR:

(cont’d)Protocolpreparation第41页/共109页现场核查要点：职责

STUDYDIRECTOR:

(cont’d)ContributorsOphthalmologyCardiologyImmunologyAnalyticalFormulationanalysisBioanalyticalStatisticalanalysisSpecialists/Consultants Antibodies Bonemarrowdifferentialcounts Specializedclinicalpathology SpermAnalysis第42页/共109页现场核查要点：职责

STUDYDIRECTOR:

(cont’d)SpecialProceduresConsiderationsArethereSOPsinplace?Arethestaffappropriatelytrained? Isthistrainingdocumented?Areliteraturesearchesnecessary? IACUCimplications?Doyouneedtouseaconsultant/PIforthework?第43页/共109页现场核查要点：职责

STUDYDIRECTOR:

(cont’d)Multi-SiteStudies*

Work(i.e.phaseofaGLPstudy)performedatageographicallydistinctsite(NotaFDAGLPterm)AssignaPItoensurecompliancewithGLPsWillsignan"AcceptanceofResponsibilities"formWillsignastatementtothisfactuponcompletionoftheworkStudydirectorremainsthesinglepointofcontrolandmaintainsresponsibilityforoverallconductQualityassuranceofthetestsite*OECDrequirement第44页/共109页现场核查要点：职责

STUDYDIRECTOR:

(cont’d)StudySchedulingConsiderationsTestarticleavailabilityAnimalavailability/orderingHousingTrainedstaffAnalyticalchemistryClinicalpathologyNecropsyReports第45页/共109页现场核查要点：职责

STUDYDIRECTOR:

(cont’d)TestArticleCalculations-Howmuchwillyouneed?Whenisitavailable?Finaldoses?AnalyticalConfirmationStorage/handlingconditionsCertificateofAnalysis(COA),MSDS,purity,stabilityIsthereadoseformulation?第46页/共109页现场核查要点：职责

STUDYDIRECTOR:

(cont’d)Protocol–Review&ApprovalManagementSDSponsor(ifdonebyCRO)ScientificcontributorsandlaboratorystaffReportpreparationstaffQAUIACUC第47页/共109页现场核查要点：职责STUDYDIRECTOR:

(cont’d)OvetsightofStudyConductObserveanimalsandproceduresReviewdataCommunicatewithscientificcontributorsandtechnicalstaffQAaudits–internalandexternalInteractionswithcontributors/PIsSubmissionofsamplesReceipt/reviewofreportRespondtounexpectedevents第48页/共109页现场核查要点：职责STUDYDIRECTOR:

(cont’d)OversightofStudyConductProtocolamendments-aplannedchangeProtocoldeviations–notplanned;impactonstudymustbedeterminedSOPdeviations第49页/共109页现场核查要点：职责STUDYDIRECTOR:

(cont’d)ExampleofDocumentationProtocol/protocolamendmentProtocol/SOPdeviationsAnimalorderTestarticlereceipt/informationTestarticlepreparationprocedureDoseaccountability(outofrange?)StudyfilenotesVeterinaryrequests/approvaloftreatmentEnvironmentaldeviations(e.g.light/darkcycleandhumidity)observationsofanimals/proceduresDatareviewCorrespondenceemail,fax,letter,telephonecallsReports第50页/共109页现场核查要点：职责STUDYDIRECTOR:

(cont’d)ReportPreparation第51页/共109页现场核查要点：职责STUDYDIRECTOR:

(cont’d)ArchivingProtocol/amendmentsRawdataDocumentationSpecimensFinalreport第52页/共109页现场核查要点：职责STUDYDIRECTOR:

(cont’d)SDResponsibilitiesforaFinalReportDatainterpretationPreliminarydraft–audited?unaudited?Integrationoftoxicology,pathology,TKandothersupportivedataContributingScientist/PIreportsStopped/suspendedprogramsGLPcomplianceDeviationsandimpactondata第53页/共109页现场核查要点：职责STUDYDIRECTOR:

(cont’d)

assuresthat:protocol,includinganychanges,isapprovedasspecifiedinGLPs,andisfollowedallexperimentaldata,includingobservationsofunanticipatedresponsesofthetestsystem,areaccuratelyrecordedandverifiedunforeseencircumstances,thatmayaffectthequalityandintegrityofthestudy,arenotedwhentheyoccur,andthatcorrectiveactionistakenanddocumented第54页/共109页现场核查要点：职责QUALITYASSURANCEUNIT(QAU):OverseesGLP

ComplianceinlaboratoryresponsibleformonitoringeachstudyforGLPcomplianceorganizationally,QAUreportstotestfacilitymanagementindependentofthepersonnelengagedinthedirectionandconductofindividualstudiesassuresthatfacilities,equipment,personnel,methods,practices,records,andcontrolsareinconformancewiththeGLPs第55页/共109页现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)OverseesGLPcomplianceinlaboratorykeepsup-to-daterecordsofallstudiesscheduled/performedwithmasterscheduleatlabmaintainscopiesofallstudyprotocols第56页/共109页现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)

Inspectsstudiesatintervalsadequatetoassuretheintegrityofthestudymaintainswrittenandproperlysignedrecordsateachinspectionidentifyingdateofinspectionthestudyinspectedphaseorsegmentofstudyinspectedpersonperforminginspection第57页/共109页现场核查要点：职责QUALITYASSURANCEUNIT(QAU):

(cont’d)maintainswrittenandproperlysignedrecords ateachinspectionidentifyingfindingsandproblemsobservedduringinspectionscheduleddateforreinspection,ifapplicableproblemsmustimmediatelybebroughttoattentionofstudydirectorandmanagement第58页/共109页现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)submitsperiodicstatusreportsoneachstudytomanagementandstudydirectornotesproblemsnotescorrectiveactionstakendeterminesthatnodeviationfromapprovedprotocolsorstandardsoperatingproceduresweremadewithoutproperauthorizationanddocumentation第59页/共109页现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)Reviewsfinalstudyreporttoassurethat:reportaccuratelydescribesmethodsandstandardoperatingproceduresreportedresultsaccuratelyreflectthestudy’srawdataPreparesandsignsstatementstobeincludedwiththefinalreportspecifyingdetailsoninspections第60页/共109页现场核查要点：职责FacilityOperationsStandardoperatingprocedures(SOP)CompleteandcomprehensiveUptodateSoundscienceandpracticalReagentsandsolutionsIdentity,titer/concentration,storagerequirements,andexpirationdateAnimalcareandIACUC第61页/共109页Majorissuesofdataaudit

WhatdowelookforwhileauditingaGLPlabStudyDirectorFacilityManagementQualityAssuranceChemistryPathology(Clinicalandanatomical)TechnicalStaffReportwritingSponsorAccountingSubcontractors第62页/共109页非临床实验室常见错误StudydirectorFailuretofollowprotocol Mostcommonbecauseeverythingisdrivenbyprotocol.Examples:TAStabilitydeterminationEnvironmentalconditionsExposuretotestarticle(dosing)第63页/共109页非临床实验室常见错误Studydirector(cont’d)

FinalReport Commonlyseefailurestoaddressissuesthatoccurredduringstudythatcouldaffectoutcomes第64页/共109页非临床实验室常见错误Studydirector(cont’d)

Failuretorecordalldataandverify Formulation Dosing第65页/共109页非临床实验室常见错误Studydirector(cont’d)DocumentationissuesBestway,protocolamendment.Mustbedonebeforeaction(signedbySDandalsoQA,managementandsponsor).Secondbest,deviationreport(deviationfromprotocolorSOP).Completedafter-the-factbypersonmakingtheobservation(signedbySDandalsoQAandmanagement).Deviationisnotedinstudyreportalongwithdescriptionoftheimpactthedeviationhasonstudyintegrity.第66页/共109页非临床实验室常见错误InconsistencieswithinaprotocolorbetweenprotocolandSOPOmissionofnecessaryinformationfromprotocolLateentriesinstudybooksNonGLPcorrectionsFailuretosignanddateentriesExpiredreagents第67页/共109页非临床实验室常见错误FailuretoissuetimelyprotocolamendmentsanddeviationreportsPaperworkmissingfromstudybookInconsistenciesbetweenprotocolandreportorrawdataandreport.第68页/共109页非临床实验室常见错误QAUfailstoauthorizedeviationDeviationsnotdetectedbytheQAU,butshouldhavebeen第69页/共109页非临床实验室常见错误 Transferofdata,specimens,recordstoarchivesAtcompletionofstudyNotallrecordstransferred第70页/共109页非临床实验室常见错误DidnotfollowSOPsforrequiredauditingInappropriatetrainingrecordkeepingEquipmentcalibrationissuesSanitation–cage/roomdisinfectantsWatersystemattachedtocagerack第71页/共109页GLPornotGLPSafetyPharmacologystudies,Core/GLP,followupstudiesdependingonthedesign/nonGLPPrimaryPharmacodynamic/non-GLP,SecondaryPD/nonGLPunlesscontributetothesafetyevaluationBridgingstudies,GLPQTstudies,Guidance/GLP,datanotrequiredforregulatorysubmission/nonGLPInVitro,ifpivotal,genotox/GLP,efficacy,MOA,metabolism/nonGLP第72页/共109页GLPornotGLP

StudiesthatarenotwithinthescopeofGLPregulationsInclude(USdomesticonly):EfficacyChemicalassaysforqualitycontrolStabilitytestsConformancepharmacopeiastandardsPharmacologyandeffectivenessNewmethodologyfortoxicologyexperimentationExploratorystudiesonvirusesandcellbiologyModeofaction,synthesis,analysisStudiescoveredbyGMPs第73页/共109页GLPornotGLPDiseaseModelBiologicSystems,Pharmacology,Transgenicanimals,efficacy/nonGLP,Carc/GLPAnimalRule,Efficacy/GLPImmunotoxicitystudies,GuidancedoesnotmentionGLP,notpivotalforsafetyandmosttestsroutinelynotconductedaccordingtoGLPExcipients,GLP第74页/共109页GLPornotGLP TheStandardisGLP…WhenisFDA“morelikely”toacceptnonGLP(USdomesticonly)?Oncology(safetydataisfrompublishedliterature)Biologics(smallcompanies,university,NIH,NCI)tissuecrossreactivitystudiesAIDSDrugs(earlydays,studiesdonebyAcademicians)BotanicalsubmissionsKnownclassofdrugsOlddrugs,changeofrouteofadministrationtoalesshazardousexposure(bridgingstudies)Drugsmarketedoverseas,toxstudiesperformedinUSbutnotGLPs(antimalarial,parasiticdrugs)第75页/共109页GLPornotGLP

However,forstudiessubmittedfromoverseasinsupportofsafetyassessment,theFDAmostlikelyacceptonlyGLPcompliantdata:ShouldbeGLP,OECDguidelinesacceptedJapaneseGLPOrcountrieswithOECDMutualAcceptanceofData(MAD)第76页/共109页GLPornotGLPIffromoverseasandnotGLPUsuallymorestrictStudiesfromnon-traditionalsources,nonICHcountries,requestinspectionMOU,memorandumofunderstandingwithdifferentcountriesRequestpermissiontodoinspectionfromtheentitydoingthestudyCountriesacceptinspectionbyDSIormightnotAcceptanceofthesestudiesisuptothereviewer/DivisioninCDER第77页/共109页案例分析(1)RCC：Findingsinaratreprotoxstudyaudited:Onlyoneabnormality/variation/developmentaldelay,horacicandabdominalvisceraoffetusesfromcontrolortreatedanimalsinthreestudies •Possiblyfewerthanexpecteda/v/ddinskeletons •Almostnoviscerala/v/ddinhistoricalcontrols,butskeletalratesreasonableQuestion: Wereobservationthresholdssufficientlysensitive?第78页/共109页Inspectionalfindings TheStudyDirectorandheadofthereprotoxdepartmenthadonlyahighschooldiplomaandafewmonthsofon-the-jobtraining,mostlyforskeletalevaluations.Theleadtechnicianhadlessthanelementaryschooleducation.BeforecomingtoRCC,hisbutcherbusinesshadfailed.Technicianhadon-the-jobtrainingatRCC.SOPswereOKforcranial/skeletal,weakforvisceral.Recordedcranial/skeletaldatafairlyrepresentedthespecimens.Externalfindingswerereasonable,comparableto literature. NosatisfactoryexplanationforthelowratesINSOFTTISSUES案例分析(1)第79页/共109页案例分析(1)Q:whatisthedeficiencyofthisGLPreprotoxstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?第80页/共109页案例分析(1)A:whatisthedeficiencyofthisGLPreprotoxstudyauditedvsregulations?人员资质培训Isdataacceptableforsupportingsafetyevaluation?NO！！

第81页/共109页案例分析(2)InspectionatABCCompanyFindings:Thefinalstudyreportdidnotincludethesignedanddatedreportsoftheindividualscientistsorotherprofessionalsinvolvedinthestudy:studydirectordidnotreceivecontributingscientists'reportsforevaluationandinclusioninfinalreports第82页/共109页案例分析(2)Studydirectordidnotreceive

TKresultsforstudiesX,Y,ZantibodytestingresultsforstudiesQ,R,SInstead,sponsorrewrotethe“finalreports”attachedthestudydirector’sreportplusseparateTKandantibodytestingreportsdatanotacceptablestudydirectorsinglepointofstudycontrol,responsibleforevaluatingallfindings第83页/共109页案例分析(2)Notallchangesin,orrevisionsof,anapprovedprotocolandthereasonsthereforeweredocumented,signedbythestudydirector,dated,andmaintainedwiththeprotocolprotocolamendmentnotcontemporaneouswithstudyeventsignedbythestudydirector1½monthsafterthefactpossiblyimmune-sensitizedmalestransferredfrom107to113,replacedwithnaïvemalesprotocolviolatedduringthistimeperiod第84页/共109页案例分析(2)ThefinalstudyreportdidnotincludeadescriptionofallcircumstancesthatmayhaveaffectedthequalityorintegrityofthedatafinalreportsforstudiesXandYdidnotdiscusspotentialimmunesensitizationofmaleandfemaleguineapigsintherespectivestudiesascircumstancesthatmayhaveaffecteddataqualityandintegrity第85页/共109页案例分析(2)Q:whatisthedeficiencyofthisGLPstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?第86页/共109页案例分析(2)whatisthedeficiencyofthisGLPstudyauditedvsregulations?SD试验记录试验报告QAIsdataacceptableforsupportingsafetyevaluation?NO！！

第87页/共109页案例分析(3)InspectionatDEFLabsFindings:protocolcalledforweeklyweights,butstudyreportedbiweeklyweights.formanyoftheweights,thebiweeklyweightslookedverypeculiar.bodywtdatadiscrepancies第88页/共109页案例分析(3)thefounder/president/studydirectorclaimedhepersonallyrecordedthebodywtanddeniedfalsificationbyduplicationoraddingdigitstheSponsorattemptedtopursuadethestudydirectorandthehistopathologisttochangethestudyresults(unrelatedtobodywt).第89页/共109页案例分析(3)Q:whatisthedeficiencyofthisGLPstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?第90页/共109页案例分析(3)whatisthedeficiencyofthisGLPtoxstudyauditedvsregulations?方案SD试验记录试验报告Isdataacceptableforsupportingsafetyevaluation?NO！！

第91页/共109页案例分析(4)AuditfindingsatGHIlabs:Studydirectordidn’talwaysknowiftheintendeddosewastheactualdoseadministered

testarticlecharacteristicsandresultsofdosingformulationtestingnotprovidedtostudydirector第92页/共109页案例分析(4)Contributingscientistreportssubmittedseparatelystudydirectornotgiventheopportunitytoevaluatethedata/conclusionsAbsenceofintactcontributingscientistreportsunclearifstudydirector’stextisattributedtoorreflectiveofcontributingscientistconclusions第93页/共109页案例分析(4)Q:whatisthedeficiencyofthisGLPstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?第94页/共109页案例分析(4)whatisthedeficiencyofthisGLPtoxstudyauditedvsregulations?SD试验报告Isdataacceptableforsupportingsafetyevaluation?NO！！

第95页/共109页案例分析(5)FindingsofinspectionatJKLlabsStudyincompletewhensafetysummarywrittenrecoverygroupnotyetsacrificedhistopathologicfindingsnotavailablememousedtopreparetheintegratedsafetysummarynotmaintained第96页/共109页案例分析(5)Q:whatisthedeficiencyofthisGLPstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?第97页/共109页案例分析(5)whatisthedeficiencyofthisGLP