藥學專業(yè)英語視聽說教程 課件 視聽說下篇 lecture 4 Clinical Research

Lecture4ClinicalResearchrelapsebiomarkerfollow-upinformedconsentendpointsubjectblindingprotocolbiasretrospectivetestnewtreatmentsormedicaldevicesinpeopleitisshowntobesafeinpeopleandworkswell20to100participantswithorwithoutthedisease Learnaboutsafety,howthetreatmentworksinthehumanbody,andthebestamounttotake Lessthanayear About300participantswiththedisease Learnmoreaboutsafetybylookingatsideeffectsandotherproblems Afewmonthsto2years Hundredsorthousandsofparticipantswiththedisease Seehowwellthetreatmentworksandlearnmoreaboutsideeffects 1–3years Thousandsofparticipantswiththedisease Continuetolookatthetreatment’sbenefitforpeople Manyyears protectthesafetyof

participants1.Whatisblindinginclinicaltrials?Blindingisaprocedureinwhichoneormorepartiesinatrialarekeptunawareoftreatmentarmallocationofparticipants.2.Whocanbeblindedinclinicaltrials?Dependingonthetypeofthetrialthefollowingcanbeblinded,participantsbeingtreated,clinicalstafforinvestigatoradministeringtreatment,teamcollectingoutcomedataordataanalysts.3.Whatisanopen-labeltrial?Andwhenisitused?Allthepeopleinvolvedinthetrialwillbeawareofthetreatmentgroupassignmentofstudyparticipants.Itisusedwhenethicalconsiderationsdonotpermitblindingandifnocontrolgroupcanbeused.4.Whatisasingle-blindedtrial?Andwhenisitused?Usuallythesubjectreceivingtheinterventionisblinded.Itisusedwhendoubleblindingisnotpossible,andwhentheexperimentalmedicineandcontrolcannotbemanufacturedidentically.5.Whatisadoubleblindedtrial?Andwhenisitused?Usually,theinvestigatorsaswellasthestudyparticipantsareblindedtothetreatmentallocation.Doubleblindingshouldbeusedwheneverpossiblebecauseitisthebestcontroltrialdesignwithdecreasedtenseofobservationalbias.6.Whatisatripleblindedtrial?Andwhatareitsadvantages?Usually,thesubjects,theinvestigators,andtheoutcomeassessorsareblinded.Tripleblindingincreasestheaccuracyandobjectivityofclinicaloutcomes.Ithelpstoavoidbiasintheanalysisofresults.TFTFTTTFTFTFFF1.HowwasthephaseIclinicalstudyofBMS-986393designed?Thephase1studywasamulti-center,open-labelstudywiththetraditionaldoseescalation.Patientswithrelapserefractorymyelomaandreceivingatleast3priorlinesoftherapy,includingaPI,anIMiD,andantibody-CD38,wereselected.Thestartingdosewas25×106CART-cells,thenwentupto75,150,300and450.TheprimaryobjectivesweretoassesssafetyandtolerabilityandtodetermineMTD/RP2D.2.WhatisthetargetofBMS-986393CART-cells,andwhyisthistargetselected?ItisaGPRC5DtargetedchimericantigenreceptorT-celltherapy.BCMAdirectedCART-celltherapieshavedemonstratedunprecedenteddepthanddurationofresponseinthetreatmentofrelapsed/refractorymultiplemyeloma.However,mostpatientsrelapseandadditionaltargetsforCARTT-celltherapyareneeded.3.WhatisthetoxicityprofileofBMS-986393?MostpatientsexperiencedtreatmentemergentAEsandmostofthemwereGrade3or4.IntermsofhematologicTEATs,mostpatientsexperiencedneutropeniaofanygradeandmostwereGrade3or4;40%ofthepatientshadthrombocytopenia,with20Grade3or4.Intermsofnon-hematologicTEATs,cytokinereleasesyndromeisthemostcommontypeandexperiencedby64%ofthepatients,butmostwereGrade1–2,only6%ofthepatientswereatGrade3or4;fatiguepyrexiawasthesecondmostcommontoxicities.Therewasadose-limitingtoxicityofprolongedGrade4neutropeniareportedintwopatientsat25and75CAR-TsbuttheMTDhadnotbeenexceeded.Nodeathrelatedtothestudyhadbeenreported.IntermsofthemostcommonTEAEcytokinereleasesyndrome:-CRSwasseeninalldoselevels;themajorityoftheCRSwasstillGrade1–2,anddidnotseemtoincreasewithincreasingcelldose.Othertoxicities:neurotoxicitywasrarelyseen;cerebraltoxicityhadnotbeenreportedtothetimeofcutoff.dysgeusiaandtastedisorders,aswellasskintoxicityandnailtoxicityhavebeenseen,butwereatverylowlevelsandverytransient.4.WhatistheefficacyprofileofBMS-986393?Intermsofresponserate:theoverallresponserateis89.5%,

withacompleteresponserateof

47.4%;everydoselevelhadresponses;patientswithoutpriorBCMAtherapyhadanoverallresponserateof100%withacompleteresponserateof50%,whereaspatientswithpriorBCMAtherapyhadanoverallresponserateof77.8%andacompleteresponserateof44.4%.Intermsofresponseovertime:Intermsofpharmacodynamicanalyses:5.DothereportedresultswarrantfurtherdevelopmentofBMS-986393?Whyorwhynot?Accordingtotheresultsofphase1study:BMS-986393hasasafetyprofilethatiscomparablewithpriorautologousCAR-Tcelltherapieswithnonewunexpectedtoxicities;Thedose-escalationisongoingandthemaximumtolerateddoseh