ChineseJournalofNewDrugs2010,19(10)

情况下,偏差浮动可适当放宽至25%以内;如超过

25%的限度,则可能影响到产品的体内行为,建议进行生物等效性试验,验证上下限之间生物等效。根据 口服缓释制剂:体内外相关性的创建、评价和应用 ,拥有IVIVC模型后可能会允许设定较宽的释放度质量标准,其取决于IVIVC模型的预测能力(即,采用卷积分或其他适当的建模计算方法绘制血药浓度 时间曲线,并确定在试验中,比较采用释放度标准所能允许的最快和最慢释放速率的批次分别预测得到的Cmax和AUC,两者的最大差异是否不超过20%)。

4 小结

按我国目前的药品注册法规要求,在开发口服缓控释制剂时,如果仍按照凭经验的研发模式,风险必然加大,因此必须引入新的思路和方法,以适应当前的药品注册要求。IVIVC作为一种预测模型,能够在优化处方工艺、辅助设定体外释放度质量标准和支持生物等效性豁免方面发挥重要作用,有助于降低研发口服缓控释制剂的风险,节省研发成本和

注册时间,希望我国药品研发者和注册申请人重视

IVIVC并积极开展相关研究工作。

[ 参 考 文 献

]

[1] 国家食品药品监督管理局. 口服缓控释制剂药学研究技术指

导原则 [S].2007.9.

[2] USP30 NF25.Generalcharpters:<1088>invitroandinvivoe

valuationofdosageforms[S].2007.

[3] FDA.Guidanceforindustry:extendedreleaseoraldosageforms:de

velopment,evaluation,andapplicationofinvitro/invivocorrela tions[EB/OL].(1997-09).http://www.fda.gov/cder/guid ance/1306fn.lpd.f

[4] 国家食品药品监督管理局. 药品注册管理办法 [S].2007.7.[5] 黄钦,马玉楠.从技术审评角度看药品的体内外相关性研究

[J].中国临床药理学与治疗学,2007,12(9):961-964.[6] FDA.Guidanceforindustry:scaleupandpostapprovalchanges

modifiedrelease(SUPAC MR)[EB/OL].(1997-10).http://www.fda.gov/cder/guidance/1214fn.lpd.f

编辑:王宇梅/接受日期:2010-02-22

(上接第826页)

[4] OLSSONULF.Themethodofminimizationproposedbypocock

andsimon propertieswithregardstobalanceandinferentialvalid ity[D].Uppsalauniversitydepartmentofinformationscience,statistics.2004.

[5] BEGGC,IGLEWICZB.Atreatmentallocationprocedureforse

quentialclinicaltrials[J].Biometrics,1980,36(1):81-90.[6] KLOTZJ.Maximumentropyconstrainedbalancerandomization

forclinicaltrial[J].Biometrics,1978,34(2):283-287.[7] TITTERINGTOND.Onconstrainedbalancerandomizationfor

clinicaltrials[J].Biometrics,1983,39(4):1083-1086.[8] HOFMEIJERJ,ANEMAPC,vanderTWEELI.Newalgorithm

fortreatmentallocationreducedselectionbiasandlossofpowerinsmalltrials[J].JClinEpidemiol,2008,61(2):119-124.[9] VICKERSA.Howtorandomize[J].JSocIntOncol,2006,4

(4):194-198.

[10] SCOTTN,MCPHERSONG,RAMSAYC,etal.Themethodof

minimizationforallocationtoclinicaltrials:areview[J].ControlClinTrials,2002,23(6):662-674.

[11] TREASURET,MACRAEK.Minimisationismuchbetterthan

therandomisedblockdesignincertaincases[J].BMJ,1999,318(7195):1420.

[12] HAGINOA,HAMADAC,YOSHIMURAI,etal.Statistical

comparisonofrandomallocationmethodsincancerclinicaltrials[J].ControlClinTrials,2004,25(6):572-584.

[13] 闫世艳,姚晨,夏结来.简单随机化、中心分层区组随机化和

最小化法的均衡性比较[J].中国循证医学杂志,2006,6

(5):376-379.

[14] VERBERKW,KROONA,KESSELSA,parisonof

randomizationtechniquesforclinicaltrialswithdatafromtheHO MERUS trial[J].BloodPress,2005,14(5):306-314.

[15] CPMP(TheCommitteeonProprietaryMedicinalProducts).

Pointstoconsideronadjustmentforbaselinecovariates(CPMP/EWP/908/99)[S].EMEA:London,2002.

[16] InternationalConferenceonHarmonisationofTechnicalRequire

mentsforRegistrationofPharmaceuticalsforHumanUse.icalTrials[J].BrJClinPharmacol,1994,37(5):401-404.

[17] BUYSEM,MCENTEGARTD.Achievingbalanceinclinicaltri

als:anunbalancedviewfromEUregulators[EB/OL].(2004-05-01).

/

appliedclinicaltrials/article/articleDetai.ljsp?id=92957.

[18] ALTMAND,SCHULZKF,MOHERD,etal.CONSORTGroup

(ConsolidatedStandardsofReportingTrials).TherevisedCON SORTstatementforreportingrandomisedtrials:explanationandelaboration[J].AnnIntMed,2001,134(8):663-694.

[19] BUYSEM.Centralizedtreatmentallocationincomparativeclini

caltrials[J].ApplClinTrials,2000,9(6):32-37.

[20] GREENH,MCENTEGARTDJ,BYROMB,etal.Minimization

incrossovertrialswithnon prognosticstrata:theoryandpracticalapplication[J].JClinPharmTher,2001,26(2):121-128.

编辑:王宇梅/接受日期:2010-02-25

ICH

HarmonisedTripartiteGuideline.E9:StatisticalPrinciplesforClin