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新药研究中心1新药研发过程2新药研发过程质量规范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4GLP历史–美国WhatpromptedUSFDAtoissueGLPregulations?Inthe1960sand1970s,inadditiontothe“Thalidomide”story,FDAfound:•Selectivelysubmittedfindings•Fabricateddata•Falsifieddata•Discrepanciesinreporting(e.g.,betweenindividualandsummarydata)•Poorlaboratoryrecordkeeping(resultingininabilitytoreconstructstudyperformance)GLP历史–美国Inthe1960sand1970s,FDAalsofound:•Noprotocols,protocolswrittenafterstudyperformance,studynotperformedaccordingtoprotocol•Nooneinchargeofstudies•SloppylaboratorypracticesUSFDAGLP法规1976Congressionalhearings•GLPsproposed1978•GLPsfinalized1979•GLPsbecomeeffectiveUSFDAGLP法规21CFR:CodeofFederalRegulations,Food&DrugAdministration.21CFRPart58:GoodLaboratoryPracticesforNonclinicalLaboratoryStudies21CFRPart11:ElectronicRecords;ElectronicSignaturesUSFDAGLPPart58要求•Describesrequirementsforconductingandreportingnonclinicallaboratorystudies–Intent:providesaframeworkforconductingwell-controlledstudies•assuresqualityandintegrityofthedata•facilitatesstudyreconstruction•providesoverallaccountability•NonclinicalstudiesthatevaluatesafetymustbeGLPcompliantUSFDAGLP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•Developedin1978–USFDAGLPprovidedthebasisforOECD–RevisedOECDprinciplesadoptedin1997•PrimaryobjectivesimilartoUSFDA–Toensurethegenerationofhighqualityandreliabletestdatarelatedtothesafetyofindustrialchemicalsubstancesandpreparationsintheframeworkofharmonisingtestingproceduresforthemutualacceptanceofdata(MAD)OECDMAD（数据互认）•DatageneratedinthetestingofchemicalsinanOECDmembercountryinaccordancewithOECDTestGuidelinesandOECDPrinciplesofGLPshallbeacceptedinotherMembercountriesforpurposesofassessmentandotherusesrelatingtotheprotectionofmanandtheenvironment•OECDMemberCountries–Australia,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标准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•Assuresqualitydataanddataintegrity•Protectsthewell-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TestArticles•theSFDA-/USFDA-regulatedproductbeingtestedGLP规范要素TestSystemsMouse/Rat,GuineaPig,Rabbit,Dog(Beagle),Pig,Monkey,Primate,(Chimpanzee)TheABCofGLPRegulationsDefinitionsPersonIndividualPartnershipGovernmentagencyOrganizationalunitCorporationScientificoracademicestablishmentGLP规范要素RawData•Laboratoryworksheets•Records&document•Memoranda•Notes•Computerprint-outs•Allcommunications(internal/external/sponsors)GLP规范要素OrganizationandPersonnelEducationTrainingExperienceJobdescriptionPersonnelManagementStudyDirectorQAUFollowprotocolDocumentdeviationsArchiveGLP规范要素OrganizationandPersonnelReviewQAUPersonnelStudyDirectorMasterschedulesheetProtocolsInspectionrecordsSOPsManagementStatusreportFinalstudyreportGLP规范要素FacilitiesNonclinicallaboratoryReceiptandstorageMixingGLP现场核查Process-orientedqualitydataasaresultofproperutilizationofandcontroloverfacilities,personnelandproceduresAllowsflexibilityinlaboratoryoperationanduseofscientificjudgmentstudydirectorsmustexertthisjudgmentoverallresponsibilityfortechnicalconduct,interpretationandreporting现场核查要点Step1:InventoryDocuments文件清单•Makesurenecessarydocumentswereincludedinthestudyreport–Protocol–Protocolamendments方案修改–Protocoldeviations方案偏离(withexplanationsonpossibleimpacttostudyinterpretationandvalidity)–Report(withsufficientlydetailedsummaryandindividualanimaldata)现场核查要点Step2:Identifytestarticle供试品•testarticlecodeorname•saltform•formulation•purity•Uniformity均一性•Stability稳定性•lotorbatch#现场核查要点Step3:Theexperimentaldesign试验设计•Studiesarefluid;whatisinaprotocolfrequentlychangesduringthecourseofastudy•Noteimportantdates(experimentaldesignlandmarks)–experimentalordosingstartdate(REPORT)–studyinitiationdate(REPORT)–protocolamendmentdate(s)(AMENDMENTS)–experimentalcompletiondate/necropsydate(REPORT)现场核查要点Step3:Theexperimentaldesign试验设计•Notehowexperimentaldesign/methodschanged–lookatprotocolamendmentsanddeviations–considerifthechangesinvalidatedthestudy’sobjectives–considerifthechangescausedstudytobeinconsistentwithstatedguidelines/methods(andevaluatesi