高变异药物生物等效性评价中多组试验的设计及统计分析_张煊

◇◇CN34-1206/ＲISSN1009-2501http//．cjcpt．com2015Oct20101115－11212015-03-072015-06-15“”2014ZX09201002。[e-mail]111211170042110179。90%SAS。90%84．79%～104．17%82．46%。。Ｒ969．1A1009-2501201510-1115-071。、groupsequentialdesignSABE2。。1CmaxAUCintrasubjectCV%30%3。18～24418～24power30%5%3880%40%6850%1061。2×4TＲTＲＲTＲT42。FDAEMACmax69．84%～143．19%AUC80．00%～125．00%5。。·5111·2。two-stagedesignEMA5。I6I。FDAEMASABE7-824。1。。。25～50。50%106。53。2、。。3。FDAmultiplegroups9。、。50%106336427。。add-on80%。3。EMA10。FDA911。FDAGLM9、、、、。t90%12。TmaxWilcoxonTmax。1－2α%·6111·ChinJClinPharmacolTher2015Oct2010100×eXT－XＲ±t0．1df×DiffSEXT－XＲedfDiffSE。Intra-subjectCV=100×es2槡－1S2eMSE612。PowerSchuirmannt613xdftncx～tdfncxCDFtdfnc=Prx≤t1－β=CDFt1－αdfdfnc1－CDFt1－αdfdfnc2nc1=XT－XＲ－Ln0．8DiffSEnc2=XT－XＲ－Ln1．25DiffSEt1－αdfdft1001－α%。1GLMSubjectSequence*Groupn－4Sequence1PeriodGroup2Treatment1Groupm－1Sequence*Groupm－1Group*Treatmentm－1Ｒesidualerrorn－3m+2Total2n－1mmn。45%80%55～62。663432。66643430。2AUCCmax264AUC1TＲ11832．805580．6235ＲT27503．323989．162ＲT12769．863271．7736ＲT24245．575665．913ＲT112220．9611917．7037ＲT211836．2414108．114ＲT12568．313141．5038TＲ22062．434775．085TＲ110352．139351．0039ＲT25532．144665．236TＲ13899．112589．4441TＲ26689．1511326．467TＲ14521．354208．7842ＲT25502．757906．578ＲT13054．003509．7743TＲ26811．3912872．089TＲ15659．742792．7644TＲ28951．169674．1310ＲT16154．714652．0745ＲT26623．956695．2211TＲ15790．114246．7946TＲ24627．723019．02·7111·2015Oct201012ＲT16859．943726．2847ＲT26133．617616．2613TＲ15001．028259．3748ＲT26267．676382．6914TＲ113071．724112．5249TＲ29102．965105．2115ＲT14566．484921．6750ＲT24079．713409．7916TＲ14286．763665．3451TＲ28359．119202．9417ＲT14920．062518．5252ＲT23100．234478．1018ＲT16475．773091．9853TＲ25768．583994．9619TＲ111453．944999．5354ＲT27461．885995．2020ＲT16114．093883．1755ＲT27201．1211398．6621ＲT111715．508251．2056TＲ24532．756858．7922ＲT12127．312783．8857ＲT23489．742940．5323TＲ11131．491869．4659ＲT25038．404091．9424TＲ13021．984067．8860TＲ24368．884107．7325ＲT16208．248434．5861TＲ24653．662289．3226TＲ12498．418877．4862ＲT25819．429910．6827ＲT15777．815760．0563ＲT25468．944991．3528ＲT114638．516509．9764TＲ24244．253325．8229TＲ19602．913766．5865TＲ23620．122862．7430TＲ17725．979386．6366ＲT25855．179213．2731ＲT112755．625613．3432TＲ13957．732704．2033TＲ19191．688459．8934TＲ14141．442806．12564-1。345。164-x±sn=64611。。EMA10。。11。14。。group·8111·ChinJClinPharmacolTher2015Oct2010stage。groupcenter。EMA1012。。。。。3Subject6412345678910111213141516171819202122232425262728293031323334353637383941424344454647484950515253545556575960616263646566Sequence2ＲTTＲGroup212Period212Treatment2ＲTNumberofObservations128。4SourceDFSSMeanSquareFValuePr＞FModel6724．61000．36733．07＜．0001Error607．18140．1197CorrectedTotal12731．7914Group10．41530．41533．470．0674Sequence10．31530．31532．630．1098Sequence*Group10．00340．00340．030．8669SubjectSequence*Group6023．27280．38793．24＜．0001PeriodGroup20．09560．04780．400．6726Treatment10．12140．12141．010．3179Group*Treatment10．29370．29372．450．1225NumberofObservations128。5AUC%90%%%LogAUC5091．815417．8193．9884．79～104．1735．6682．4690%80%～125%AUC80%。7SASdataBioequivalence/*Bioequiv-alence*/inputSubjectSequence$GroupTreatment$PeriodAUClogAUC=logAUC/*AUC*/datalines1TＲ1Ｒ21832．801TＲ1T15580．62……66ＲT2Ｒ15855．1766ＲT2T29213．27/*、、、*/procglmdata=Bioequivalenceoutstat=Tano-va/*GLMTanova*/·9111·2015Oct2010classSubjectSequenceGroupPeriodTreat-mentmodellogAUC=GroupSequenceGroup*Se-quenceSubjectGroup*SequencePeriodGroupTreatmentGroup*Treatment/ss3solutionprandomSubjectGroup*Sequence/testoutputout=predp=yhatr=residstudent=stresidlsmeansTreatment/stderrpdiffalpha=0．10clout=lsmean/*lsmean*/procprintdata=tanovaprocprintdata=lsmeanprocsortdata=BioequivalencebySequencegroupsubjectTreatment/*、、*/procprintdata=Bioequivalence/**/procmeansndata=BioequivalencebySe-quenceGroupvarAUCoutputout=non=ndataerrorsettanovaif_SOUＲCE_=＇EＲ-ＲOＲ＇/**/MSE=ss/dfsse=ssid=1keepidmsessedfprocsortdata=errorbyiddataSubSeqsettanovaif_SOUＲCE_=＇Sub-jecSequen*Group＇and_TYPE_=＇SS3＇MSB=ss/dfssb=ssid=1keepidMSBssbdfprocsortdata=SubSeqbyiddatano1rtsetnoifGroup=1andsequence=＇ＲT＇n1rt=n/2id=1keepn1rtidprocsortdata=no1rtbyiddatano2rtsetnoifGroup=2andsequence=＇ＲT＇n2rt=n/2id=1keepn2rtidprocsortdata=no2rtbyiddatano1trsetnoifGroup=1andsequence=＇TＲ＇n1tr=n/2id=1keepn1tridprocsortdata=no1trbyiddatano2trsetnoifGroup=2andsequence=＇TＲ＇n2tr=n/2id=1keepn2tridprocsortdata=no2trbyiddatalsmeanＲsetlsmeanifTreatment=＇Ｒ＇/*ＲefLSM*/ＲefLSM=lsmeanid=1keepidＲefLSMprocsortdata=lsmeanＲbyiddatalsmeanTsetlsmeanifTreatment=＇T＇/*TestLSM*/TestLSM=lsmeanid=1keepidTestLSMprocsortdata=lsmeanTbyiddataTwosidemergelsmeanＲlsmeanTno1rtno2rtno1trno2trerrorSubSeqbyidn1=n1rt+n2rtn2=n1tr+n2trspool=MSE*1/n1tr+1/n2tr+1/n1rt+1/n2rt*0．125DiffSE=sqrtspoolIntraSubjectCV=100*sqrtexpMSE－1/**/InterSubjectCV=100*sqrtexpMSB－MSE/2－1/**/ＲefGeoLSM=EXPＲefLSMTestGeoLSM=EXPTestLSMDifference=TestLSM－Ｒe-fLSMＲatio=100*EXPDifference/**/t=TestLSM－ＲefLSM/DiffSEt1=TestLSM－ＲefLSM－LOG0．8/DiffSEt2=TestLSM－ＲefLSM－LOG1．25/DiffSE/*t*/ct90=tinv0．95dfabsct90=absct90lower90=TestLSM－ＲefLSM－absct90*DiffSEupper90=TestLSM－ＲefLSM+ab-sct90*DiffSECI90_lower=EXP