新药开发之临床试验

159ClinicalTrial1.informedconsent1991ICHinternationalconferenceonharmonization(1)goodclinicalpracticeGCP2.Evidence-basedmedicinepathophysiology160signalnoise…./3.1/10GCP161199620002005(5)IIIIIIIVItolerabilityIIIIIIIIIIIVIND(InvestigationalNewDrug)NDA(NewDrugApplication)162clinicaltrialprotocolcasereportform1.IIIIIIpivotaltrialIIlabelingofpackageinsertFoodandDrugAdministrationFDAIIEndofPhaseIIMeeting(1)I“A”(2)II“AX”(3)“AX”2.“”20049VioxxCox-218FDAVioxx8,00014,000(1)163(2)adverseeventIndependentDataSafetyMonitoringCommitteeinterimanalysis(3)IndependentEthicCommitteeIECGCP(4)“”“causalrelationship”“association”tumorresponserate80FlecanideventricularprematurecontractionVPCVPCsuddendeath”CASTStudy”FlecanideVPC4.biasa.RandomizationsimplerandomizationblockrandomizationstratifiedrandomizationdynamicrandomizationABblocksize4AABBABABABBABBAABABABAAB2165interactivevoicerandomizationsystemIVRSb.blindedproceduresingleblindingDoubleblindingevaluatorblindc.confoundingfactorinvestigatorsubjectinclusionexclusion5.powera.effectsize10mmHg2mmHgb.variablescaleintervalscaleordinalscalenominalscale166c.precisiond.variabilitye.f.compliance10090%81100%n12,226.a.primaryhypothesisAsuperiortoBAnon-inferiortoBb.ITTintenttotreatPPperprotocol80%c.167d.e.7.documentationX1.IIMTDmaximaltolerabledose1noobservedadverseeffectlevelNOAELspeciesindividualsafetymargin1/100(2)III1/10LD101/10NOAEL1/6(3)exploratoryINDstudies(4)I2~5XIbiomarker168MTDDLTa:b:2.IIIIIIIdose-responseII1693.IIIIIIa.run-inperiodwashoutperiodbaselineb.paralleldesignAc.cross-overdesignperiodcarry-overeffectmissingdata3.IVIV170FlecanideCASTVioxxAPPROVeB224.a.(5)b.bridgingstudy19973%ethnicgroupICH“”“”1999APECnetworkofpharmaceuticalregulatoryscience60%aggrenoxdipyridamoleaspirin171200225%2005c.III2005d.pharmacogenomicscandidategenepolymorphismpersonalizedmedicineELSIethnicallegalandsocialimplicationELSItargettherapyHerceptin®trastuzumabIressaepidermalgrowthfactorreceptortyrosinekinaseHerceptin®Herceptin®HER-2/neutrastuzumabHER-2/neuHER-2/neuHER-2/neuHER-2/neu172Herceptin®HER-2/neuHER-2/neuHerceptin®1.a.123123456(1)JIRBjointinstitutionalreviewboard(2)CDEcenterfordrugevaluation(3)GCP(948)2.a.GCRCgeneralclinicalresearchcenterb.centerofexcellence2005c.CROcontractresearchorganization174d.SMOsitemanagementorganizatione.1generaltoxicologytestingNOAEL(6)DurationofClinicalTrialsMinimumDurationofRepeatedDoseToxicityStudiesRodentsNon-rodentsSingleDose2Weeks2WeeksUpto2Weeks2Weeks2WeeksUpto1Month1Month2WeeksUpto3Months3Months3MonthsUpto6Months6Months6Months6Months6MonthsChronic1.ICH:173-85(1998).4.GuidanceforIndustry,Investigators,andReviewersExploratoryINDStudiesDRAFTGUIDANCEUSFDA,Apr,2005.5.:=R&now_fod_list_no=6726&class_no=2&level_no=2&divNo=4&divCount=56.MaintenanceoftheICHguidelineonnon-clinicalsafetystudiesfortheconductofhumanclinicaltrialsforpharmaceuticals,ICHguidelineNov,2000.