药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙

药品研究中GLP实验室实验原始记录审核技术要求龚兆龙博士资深副总裁兼首席技术官昭衍新药研究中心1新药研发过程2新药研发过程质量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的要求案例内容提要4GLP历史–美国WhatpromptedUSFDAtoissueGLPregulations? Inthe1960sand1970s,inadditiontothe“Thalidomide”story,FDAfound:SelectivelysubmittedfindingsFabricateddataFalsifieddataDiscrepanciesinreporting(e.g.,betweenindividualandsummarydata)Poorlaboratoryrecordkeeping(resultingininabilitytoreconstructstudyperformance)GLP历史–美国Inthe1960sand1970s,FDAalsofound:Noprotocols,protocolswrittenafterstudyperformance,studynotperformedaccordingtoprotocolNooneinchargeofstudiesSloppylaboratorypracticesUSFDAGLP法规1976CongressionalhearingsGLPsproposed1978GLPsfinalized1979GLPsbecomeeffectiveUSFDAGLP法规21CFR:CodeofFederalRegulations,Food&DrugAdministration.21CFRPart58:GoodLaboratoryPracticesforNonclinicalLaboratoryStudies21CFRPart11:ElectronicRecords;ElectronicSignaturesUSFDAGLPPart58要求DescribesrequirementsforconductingandreportingnonclinicallaboratorystudiesIntent:providesaframeworkforconductingwell-controlledstudiesassuresqualityandintegrityofthedatafacilitatesstudyreconstructionprovidesoverallaccountabilityNonclinicalstudiesthatevaluatesafetymustbeGLPcompliantUSFDAGLP检查FDAGLP检查过的美国国内实验室 200余家,CRO,药厂USFDAGLP检查FDAGLP检查过的美国境外实验室 40余家,CRO,药厂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。OECDGLP规范Developedin1978USFDAGLPprovidedthebasisforOECDRevisedOECDprinciplesadoptedin1997PrimaryobjectivesimilartoUSFDAToensurethegenerationofhighqualityandreliabletestdatarelatedtothesafetyofindustrialchemicalsubstancesandpreparationsintheframeworkofharmonisingtestingproceduresforthemutualacceptanceofdata(MAD)OECDMAD（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GLP2009年7月–3家在中国的GLP实验室接受美国FDA检查中国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280条药品注册现场核查管理规定 7章、59条、5个附件 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。GLP规范要素Whatisanonclinicallaboratory? IntheSFDAorUSFDAregulatoryworld,alaboratoriesthatconductnonclinicalstudiesinvolvingtestarticlestodevelopdatathatwillbesubmittedtotheagencyinsupportofanapplicationandmarketingapprovalGLP规范要素TestArticlestheSFDA-/USFDA-regulatedproductbeingtestedGLP规范要素TestSystemsMouse/Rat,GuineaPig,Rabbit,Dog(Beagle),Pig,Monkey,Primate,(Chimpanzee)TheABCofGLPRegulationsDefinitionsPersonGLP规范要素RawDataLaboratoryworksheetsRecords&documentMemorandaNotesComputerprint-outsAllcommunications(internal/external/sponsors)GLP规范要素OrganizationandPersonnelEducationTrainingExperienceJobdescriptionFollowprotocolDocumentdeviationsArchiveGLP规范要素OrganizationandPersonnelReviewMasterschedulesheetProtocolsInspectionrecordsSOPsGLP规范要素FacilitiesReceiptandstorageMixingGLP现场核查Process-oriented qualitydataasaresultofproperutilizationofandcontroloverfacilities,personnelandproceduresAllowsflexibilityinlaboratoryoperationanduseofscientificjudgmentstudydirectorsmustexertthisjudgmentoverallresponsibilityfortechnicalconduct,interpretationandreporting现场核查要点Step1:InventoryDocuments文件清单MakesurenecessarydocumentswereincludedinthestudyreportProtocolProtocolamendments修改Protocoldeviations方案偏离 (withexplanationsonpossibleimpacttostudyinterpretationandvalidity)Report (withsufficientlydetailedsummaryandindividualanimaldata)现场核查要点Step2:Identifytestarticle供试品testarticlecodeornamesaltformformulationpurityUniformity均一性Stability稳定性lotorbatch#现场核查要点Step3:Theexperimentaldesign试验Studiesarefluid;whatisinaprotocolfrequentlychangesduringthecourseofastudyNoteimportantdates(experimentaldesignlandmarks)experimentalordosingstartdate(REPORT)studyinitiationdate(REPORT)protocolamendmentdate(s)(AMENDMENTS)experimentalcompletiondate/necropsydate(REPORT)现场核查要点Step3:Theexperimentaldesign试验设计Notehowexperimentaldesign/methodschangedlookatprotocolamendmentsanddeviationsconsiderifthechangesinvalidatedthestudy’sobjectivesconsiderifthechangescausedstudytobeinconsistentwithstatedguidelines/methods(andevaluatesignificance)Makesureyouunderstandexperimentaldesign(asperformed)andchronologyperamendmentsanddocumenteddeviations现场核查要点Step4:Comparedocumentsforconsistency 一致性DoreportscomplywithGLPrequirementsonreportingfortestarticlecharacteristicstestingofdosingformulationsforpuritystabilityuniformity现场核查要点 Step4:ComparedocumentsforconsistencyMakesurethatdataandtheirassociateddocumentsareconsistentwithoneanother.现场核查要点Step4:ComparedocumentsforconsistencyAreprotocol-specifiedevaluationsofdataapplied?statisticaltestscriteriaforacceptablestudy,positivefinding(e.g.,genotoxicitytests)Doesselectionofhighestdosecomplywithprotocol?Withreferencedguideline?现场核查要点Step4:ComparedocumentsforconsistencyArefindingsforallprotocol-specifiedevaluationsreportedbodyweightclinicalchemistryhistopathologyforallprotocol-specifieddosegroupstoxicokinetics现场核查要点Step5:Dodataseemcredible?ReportRawdata/Reality现场核查要点Step6:Evaluationofsignificanceoflapses 失误的评估Thebigquestions–Didproblemsinstudydocumentsresultinyourinabilitytodrawmeaningfulconclusionsfromthestudy(withrespecttostudy’sstatedobjective)?Didinconsistenciesinthispartofthesubmission,relativetootherpartsofthesubmission,makeyouhavelessfaithintheintegrityofotherportionsofthesubmission?Intheconclusionsofotherstudies?现场核查要点 NotalllapsesprecludedrawingconclusionsfromastudymistakescanhappeninperformingastudyindescribingfactsometimesfactisnotconvenientTheevaluationofmistakesrequiresanevalutionoftheirmagnitudeandnature.Areerrorswidespread?Limited?Doerrorsoccurinreportingofendpointsthatarecriticaltoscientificinterpretation?Doerrorsspeakforareport-specificproblemorsomethingthatisasystemicproblem ?现场核查要点：职责TESTINGFACILITYMANAGEMENT:Overalllaboratorymanagementandadministrativefunctionsdesignatesstudydirectorbeforestudyisinitiatedreplacesstudydirector(promptly),ifnecessaryassuresthereisaqualityassuranceunit(QAU)assurestestandcontrolarticleshavebeenappropriatelyevaluatedforidentity,strength,purity,stabilityanduniformity(asapplicable)现场核查要点：职责TESTINGFACILITYMANAGEMENT:(cont’d)assuresappropriatestaffing,facilities,equipmentandmaterialsareavailableforscheduledtestsassuresthatstaffunderstandsthefunctionstheyaretoperformassuresdeviationsreportedbyQAUarepromptlyreportedtostudydirector现场核查要点：职责STUDYDIRECTORSinglepointofstudycontrolhasoverallresponsibilityfor:ProtocolpreparationtechnicalconductofstudyinterpretationofresultsanalysisofresultsdocumentationofresultsreportingofresultsArchiving现场核查要点：职责STUDYDIRECTOR:(cont’d)Protocolpreparation现场核查要点：职责STUDYDIRECTOR:(cont’d)ContributorsOphthalmologyCardiologyImmunologyAnalyticalFormulationanalysisBioanalyticalStatisticalanalysisSpecialists/Consultants Antibodies Bonemarrowdifferentialcounts Specializedclinicalpathology SpermAnalysis现场核查要点：职责STUDYDIRECTOR:(cont’d)SpecialProceduresConsiderationsArethereSOPsinplace?Arethestaffappropriatelytrained? Isthistrainingdocumented?Areliteraturesearchesnecessary? IACUCimplications?Doyouneedtouseaconsultant/PIforthework?现场核查要点：职责STUDYDIRECTOR:(cont’d)Multi-SiteStudies*Work(i.e.phaseofaGLPstudy)performedatageographicallydistinctsite(NotaFDAGLPterm)AssignaPItoensurecompliancewithGLPsWillsignan"AcceptanceofResponsibilities"formWillsignastatementtothisfactuponcompletionoftheworkStudydirectorremainsthesinglepointofcontrolandmaintainsresponsibilityforoverallconductQualityassuranceofthetestsite*OECDrequirement现场核查要点：职责STUDYDIRECTOR:(cont’d)StudySchedulingConsiderationsTestarticleavailabilityAnimalavailability/orderingHousingTrainedstaffAnalyticalchemistryClinicalpathologyNecropsyReports现场核查要点：职责STUDYDIRECTOR:(cont’d)TestArticleCalculations-Howmuchwillyouneed?Whenisitavailable?Finaldoses?AnalyticalConfirmationStorage/handlingconditionsCertificateofAnalysis(COA),MSDS,purity,stabilityIsthereadoseformulation?现场核查要点：职责STUDYDIRECTOR:(cont’d)Protocol–Review&ApprovalManagementSDSponsor(ifdonebyCRO)ScientificcontributorsandlaboratorystaffReportpreparationstaffQAUIACUC现场核查要点：职责STUDYDIRECTOR:(cont’d)OvetsightofStudyConductObserveanimalsandproceduresReviewdataCommunicatewithscientificcontributorsandtechnicalstaffQAaudits–internalandexternalInteractionswithcontributors/PIsSubmissionofsamplesReceipt/reviewofreportRespondtounexpectedevents现场核查要点：职责STUDYDIRECTOR:(cont’d)OversightofStudyConductProtocolamendments-aplannedchangeProtocoldeviations–notplanned;impactonstudymustbedeterminedSOPdeviations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现场核查要点：职责STUDYDIRECTOR:(cont’d)ReportPreparation现场核查要点：职责STUDYDIRECTOR:(cont’d)ArchivingProtocol/amendmentsRawdataDocumentationSpecimensFinalreport现场核查要点：职责STUDYDIRECTOR:(cont’d)SDResponsibilitiesforaFinalReportDatainterpretationPreliminarydraft–audited?unaudited?Integrationoftoxicology,pathology,TKandothersupportivedataContributingScientist/PIreportsStopped/suspendedprogramsGLPcomplianceDeviationsandimpactondata现场核查要点：职责STUDYDIRECTOR:(cont’d)assuresthat:protocol,includinganychanges,isapprovedasspecifiedinGLPs,andisfollowedallexperimentaldata,includingobservationsofunanticipatedresponsesofthetestsystem,areaccuratelyrecordedandverifiedunforeseencircumstances,thatmayaffectthequalityandintegrityofthestudy,arenotedwhentheyoccur,andthatcorrectiveactionistakenanddocumented现场核查要点：职责QUALITYASSURANCEUNIT(QAU):OverseesGLPComplianceinlaboratoryresponsibleformonitoringeachstudyforGLPcomplianceorganizationally,QAUreportstotestfacilitymanagementindependentofthepersonnelengagedinthedirectionandconductofindividualstudiesassuresthatfacilities,equipment,personnel,methods,practices,records,andcontrolsareinconformancewiththeGLPs现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)OverseesGLPcomplianceinlaboratorykeepsup-to-daterecordsofallstudiesscheduled/performedwithmasterscheduleatlabmaintainscopiesofallstudyprotocols现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)Inspectsstudiesatintervalsadequatetoassuretheintegrityofthestudymaintainswrittenandproperlysignedrecordsateachinspectionidentifyingdateofinspectionthestudyinspectedphaseorsegmentofstudyinspectedpersonperforminginspection现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)maintainswrittenandproperlysignedrecords ateachinspectionidentifyingfindingsandproblemsobservedduringinspectionscheduleddateforreinspection,ifapplicableproblemsmustimmediatelybebroughttoattentionofstudydirectorandmanagement现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)submitsperiodicstatusreportsoneachstudytomanagementandstudydirectornotesproblemsnotescorrectiveactionstakendeterminesthatnodeviationfromapprovedprotocolsorstandardsoperatingproceduresweremadewithoutproperauthorizationanddocumentation现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)Reviewsfinalstudyreporttoassurethat:reportaccuratelydescribesmethodsandstandardoperatingproceduresreportedresultsaccuratelyreflectthestudy’srawdataPreparesandsignsstatementstobeincludedwiththefinalreportspecifyingdetailsoninspections现场核查要点：职责FacilityOperationsStandardoperatingprocedures(SOP)CompleteandcomprehensiveUptodateSoundscienceandpracticalReagentsandsolutionsIdentity,titer/concentration,storagerequirements,andexpirationdateAnimalcareandIACUCMajorissuesofdataauditWhatdowelookforwhileauditingaGLPlabStudyDirectorFacilityManagementQualityAssuranceChemistryPathology(Clinicalandanatomical)TechnicalStaffReportwritingSponsorAccountingSubcontractors非临床实验室常见错误StudydirectorFailuretofollowprotocol Mostcommonbecauseeverythingisdrivenbyprotocol.Examples:TAStabilitydeterminationEnvironmentalconditionsExposuretotestarticle(dosing)非临床实验室常见错误Studydirector(cont’d)FinalReport Commonlyseefailurestoaddressissuesthatoccurredduringstudythatcouldaffectoutcomes非临床实验室常见错误Studydirector(cont’d)Failuretorecordalldataandverify Formulation Dosing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.非临床实验室常见错误InconsistencieswithinaprotocolorbetweenprotocolandSOPOmissionofnecessaryinformationfromprotocolLateentriesinstudybooksNonGLPcorrectionsFailuretosignanddateentriesExpiredreagents非临床实验室常见错误FailuretoissuetimelyprotocolamendmentsanddeviationreportsPaperworkmissingfromstudybookInconsistenciesbetweenprotocolandreportorrawdataandreport.非临床实验室常见错误QAUfailstoauthorizedeviationDeviationsnotdetectedbytheQAU,butshouldhavebeen非临床实验室常见错误 Transferofdata,specimens,recordstoarchivesAtcompletionofstudyNotallrecordstransferred非临床实验室常见错误DidnotfollowSOPsforrequiredauditingInappropriatetrainingrecordkeepingEquipmentcalibrationissuesSanitation–cage/roomdisinfectantsWatersystemattachedtocagerackGLPornotGLPSafetyPharmacologystudies,Core/GLP,followupstudiesdependingonthedesign/nonGLPPrimaryPharmacodynamic/non-GLP,SecondaryPD/nonGLPunlesscontributetothesafetyevaluationBridgingstudies,GLPQTstudies,Guidance/GLP,datanotrequiredforregulatorysubmission/nonGLPInVitro,ifpivotal,genotox/GLP,efficacy,MOA,metabolism/nonGLPGLPornotGLP StudiesthatarenotwithinthescopeofGLPregulationsInclude(USdomesticonly):EfficacyChemicalassaysforqualitycontrolStabilitytestsConformancepharmacopeiastandardsPharmacologyandeffectivenessNewmethodologyfortoxicologyexperimentationExploratorystudiesonvirusesandcellbiologyModeofaction,synthesis,analysisStudiescoveredbyGMPsGLPornotGLPDiseaseModelBiologicSystems,Pharmacology,Transgenicanimals,efficacy/nonGLP,Carc/GLPAnimalRule,Efficacy/GLPImmunotoxicitystudies,GuidancedoesnotmentionGLP,notpivotalforsafetyandmosttestsroutinelynotconductedaccordingtoGLPExcipients,GLPGLPornotGLP TheStandardisGLP…WhenisFDA“morelikely”toacceptnonGLP(USdomesticonly)?Oncology(safetydataisfrompublishedliterature)Biologics(smallcompanies,university,NIH,NCI)tissuecrossreactivitystudiesAIDSDrugs(earlydays,studiesdonebyAcademicians)BotanicalsubmissionsKnownclassofdrugsOlddrugs,changeofrouteofadministrationtoalesshazardousexposure(bridgingstudies)Drugsmarketedoverseas,toxstudiesperformedinUSbutnotGLPs(antimalarial,parasiticdrugs)GLPornotGLP However,forstudiessubmittedfromoverseasinsupportofsafetyassessment,theFDAmostlikelyacceptonlyGLPcompliantdata:ShouldbeGLP,OECDguidelinesacceptedJapaneseGLPOrcountrieswithOECDMutualAcceptanceofData(MAD)GLPornotGLPIffromoverseasandnotGLPUsuallymorestrictStudiesfromnon-traditionalsources,nonICHcountries,requestinspectionMOU,memorandumofunderstandingwithdifferentcountriesRequestpermissiontodoinspectionfromtheentitydoingthestudyCountriesacceptinspectionbyDSIormightnotAcceptanceofthesestudiesisuptothereviewer/DivisioninCDER案例分析(1)RCC：Findingsinaratreprotoxstudyaudited:Onlyoneabnormality/variation/developmentaldelay,etc.inthoracicandabdominalvisceraoffetusesfromcontrolortreatedanimalsinthreestudies •Possiblyfewerthanexpecteda/v/ddinskeletons •Almostnoviscerala/v/ddinhistoricalcontrols,butskeletalratesreasonableQuestion: Wereobservationthresholdssufficientlysensitive?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)案例分析(1)Q:whatisthedeficiencyofthisGLPreprotoxstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?案例分析(1)A:whatisthedeficiencyofthisGLPreprotoxstudyauditedvsregulations?人员资质培训Isdataacceptableforsupportingsafetyevaluation?NO！！案例分析(2)InspectionatABCCompanyFindings:Thefinalstudyreportdidnotincludethesignedanddatedreportsoftheindividualscientistsorotherprofessionalsinvolvedinthestudy:studydirectordidnotreceivecontributingscientists'reportsforevaluationandinclusioninfinalreports案例分析(2)StudydirectordidnotreceiveTKresultsforstudiesX,Y,ZantibodytestingresultsforstudiesQ,R,SInstead,sponsorrewrotethe“finalreports”attachedthestudydirector’sreportplusseparateTKandantibodytestingreportsdatanotacceptablestudydirectorsinglepointofstudycontrol,responsibleforevaluatingallfindings案例分析(2)Notallchangesin,orrevisionsof,anapprovedprotocolandthereasonsthereforeweredocumented,signedbythestudydirector,dated,andmaintainedwiththeprotocolprotocolamendmentnotcontemporaneouswithstudyeventsignedbythestudydirector1½monthsafterthefactpossiblyimmune-sensitizedmalestransferredfrom107to113,replacedwithnaïvemalesprotocolviolatedduringthistimeperiod案例分析(2)ThefinalstudyreportdidnotincludeadescriptionofallcircumstancesthatmayhaveaffectedthequalityorintegrityofthedatafinalreportsforstudiesXandYdidnotdiscusspotentialimmunesensitizationofmaleandfemaleguineapigsintherespectivestudiesascircumstancesthatmayhaveaffecteddataqualityandintegrity案例分析(2)Q:whatisthedeficiencyofthisGLPstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?案例分析(2)whatisthedeficiencyofthisGLPstudyauditedvsregulations?SD试验记录试验报告QAIsdataacceptableforsupportingsafetyevaluation?NO！！案例分析(3)InspectionatDEFLabsFindings:protocolcalledforweeklyweights,butstudyreportedbiweeklyweights.formanyoftheweights,thebiweeklyweightslookedverypeculiar.bodywtdatadiscrepancies案例分析(3)thefounder/president/studydirectorclaimedhepersonallyrecordedthebodywtanddeniedfalsificationbyduplicationoraddingdigitstheSponsorattemptedtopursuadethestudydirectorandthehistopathologisttochangethestudyresults(unrelatedtobodywt).案例分析(3)Q:whatisthedeficiencyofthisGLPstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?案例分析(3)whatisthedeficiencyofthisGLPtoxstudyauditedvsregulations?方案SD试验记录试验报告Isdataacceptableforsupportingsafetyevaluation?NO！！案例分析(4)AuditfindingsatGHIlabs:Studydirectordidn’talwaysknowiftheintendeddosewastheactualdoseadministeredtestarticlecharacteristicsandresultsofdosingformulationtestingnotprovidedtostudydirector案例分析(4)Contributingscientistreportssubmittedseparatelystudydirectornotgiventheopportunitytoevaluatethedata/conclusionsAbsenceofintactcontributingscientistreportsunclearifstudydirector’stextisattributedtoorreflectiveofcontributingscientistconclusions案例分析(4)Q:whatisthedeficiencyofthisGLPstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?案例分析(4)whatisthedeficiencyofthisGLPtoxstudyauditedvsregulations?SD试验报告Isdataacceptableforsupportingsafetyevaluation?NO！！案例分析(5)FindingsofinspectionatJKLlabsStudyincompletewhensafetysummarywrittenrecoverygroupnotyetsacrificedhistopathologicfindingsnotavailablememousedtopreparetheintegratedsafetysummarynotmaintained案例分析(