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仿制药研发趋势及中美仿制药申报注册要求对比龚兆龙博士副总裁兼首席技术官北京昭衍新药研究中心有限公司1仿制药定义SFDA:仿制药应当与被仿制药具有同样的活性成份、给药途径、剂型、规格和相同的治疗作用。已有多家企业生产的品种,应当参照有关技术指导原则选择被仿制药进行对照研究。USFDA:Agenericdrugisidentical--orbioequivalent--toabrandnamedrugindosageform,safety,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.2仿制药与新药3新药与仿制药仿制药研发趋势美国FDA仿制药注册要求中国SFDA仿制药注册要求中美仿制药注册要求比较目录4新药研发过程5新药:高风险高投入高回报6SpecialToxstudies:photosafety,localtolerance,impurity/metabolitetestingFIH,Ph1Phase2Phase3NDAChronictoxicologyCompletionofgenetictoxbatteryCarciSXprotocols(ifneeded)ReproToxStudies(Segs1,2,(3))ADMEPharmacologySafetyPharmacologyAcuteToxicologySubchronicToxicologyGeneticToxicologyADMECarcinogenicityStudies(Seg3reprotox)IntegrationofallstudiesUSFDAPreclinicalRequirements7ReasonsforAttrition(1991–2000)IsmailKola&JohnLandis(2004).NatureReviews:DrugDiscovery3:711-7158研发费用增加与获批新药不成比例9015304560196319681973197819831988199319982003NCEApprovals02040R&DExpenditures(Billionsof2000$)FDA批准新药(平均20个/年)2007年全球十大医药企业(垄断,只有少数挣钱)十大药厂前5位药品销售市场份额2007年全球十大生物制药企业2007年全球十大生物医药治疗领域大药企市值下降(新的不出,旧的将过期)$287$203$213$75$173$155$143$51$104$66$90$72$85$60$83$31$76$76$0$320BillionsofUS$PFEMRKGSKBMYLLYAZNWYESGPABTMarketCapon12-31-00MarketCapon4-29-05医药企业应对策略16鼓励创新–新药机构重组,资源整合节省开支开发仿制药化学仿制药生物仿制药新药生命周期1703006009001234567891011121314151617181920YearsofMarketingMillionsof2000$Anesth/AnalgAntiinfectiveAllCardiovascularNeuropharm研发成本比较18WhyGeneric?19安全性、有效性、质量:仿制药==原研药政府支持:合理利用资源药厂兴趣:市场利益驱使消费者需求:节省开支FDA支持仿制药20仿制药上市大大降低药价21美国仿制药市场(价格)22美国仿制药市场(市场)23美国仿制药市场美国仿制药市场25美国仿制药市场26全球仿制药市场27全球领先仿制药公司28仿制药研发趋势品种:市场前景,专利保护,技术难度时间:Bethefirst!18个月专卖权规模:多品种,规模化29FDA仿制药法规30•1984年美国颁布《药品价格竞争和专利期恢复法》(DrugPriceCompetitionandPatentTermRestorationAct),通常被称为“Hatch-Waxman修正案”(Hatch-WaxmanAmendments)。•该修正案规定了仿制药的批准过程,被视为现代仿制药工业的里程碑。•保证品牌药(brandnamedrug)生产厂家得到切实可行的市场保护,以鼓励他们开发有价值的新药。•一旦这些药的法定专利保护期和市场专卖期届满,其仿制品(genericversions)能迅速上市,消费者能从中受益。FDA仿制药法规31•“Hatch-Waxman修正案”是对《联邦食品、药品和化妆品法》(FD&CAct)的修订,设立了第505(j)节。•第505(j)节建立了简化新药申请(ANDA)的批准程序,即仿制药无需提交完整的新药申请,参考以前批准的NDA,并依靠FDA对该药品的安全性和有效性的资料,就可获得批准。专利保护期延长32“第一个”仿制药33Hatch-Waxman修正案中Roche-Bolar条款允许仿制药商在专利药到期前提出申请。即一旦药品的专利到期,其他药品生产企业的同类仿制药商就可以立即上市。“第一个”仿制申请者拥有180天的市场专卖权(marketexclusivity)作为鼓励。即从仿制药开始商业上市(commercialmarketing)之日起或者从法院判决认定该专利无效、不可实施(unenforceable)或不被侵权之日起,无论何者为先,有资格拥有180天的市场专营权。许多仿制药商不再仅仅满足于等到专利到期前才开始申报。他们瞄准一些还有数年才到期的重量级药物,包括抗抑郁药Lexapro、抗精神病药奥氮平(Zyprexa)等,试图推出“第一个”仿制药。FDA仿制药要求34•Sameactiveingredient(s)(Pharmaceuticalequivalent)•Samerouteofadministration•Samedosageform•Samestrength•Sameconditionsofuse•Comparedtoreferencelisteddrug(RLD)–•(brandnameproduct-listedinOrangeBook,)FDA仿制药相关定义35•PharmaceuticalEquivalenceSameactivedrugingredient;samestrength;samedosageformandrouteofadministration;comparablelabeling;meetscompendialorotherapplicablestandardsofstrength,quality,purity,andidentity.•BioavailabilityTherateandextenttowhichtheactiveingredientoractivemoietyisabsorbedfromadrugproductandbecomesavailableatthesiteofaction.•BioequivalenceTwopharmaceuticalequivalentdrugproductsarebioequivalentifafterdrugadministration,thebioavailabilities(rateandextentofdrugavailability)providesimilareffectswithrespecttoefficacyandsafety.FDA仿制药相关定义36•Bioequivalenceisestablishediftheinvivobioavailabilityofatestdrugproduct(usuallythegenericproduct)doesnotdiffersignificantly(i.e.,statisticallyinsignificant)intheproduct‘srateandextentofdrugabsorptionfromthatofthereferencelisteddrug(usuallythebrandnameproduct)whenadministeredatthesamemolardoseoftheactivemoietyundersimilarexperimentalconditions,eithersingledoseormultipledose.FDA仿制药相关定义37•TheRLDisthereferencedrugproductuponwhichanapplicantrelieswhenseekingapprovalofanabbreviatednewdrugapplication(ANDA).•TheRLDisgenerallythebrand-namedrugthathasafullnewdrugapplication(NDA).•FDAdesignatesasinglereferencelisteddrugasthestandardtowhichallgenericversionsmustbeshowntobebioequivalent.•FDAhopestoavoidpossiblesignificantvariationsamonggenericdrugsandtheirbrandnamecounterpart.Suchvariationscouldresultifgenericdrugswerecomparedtodifferentreferencelisteddrugs.FDA仿制药指导38FDA仿制药指导39FDA仿制药指导40FDA仿制药指导41FDA仿制药指导4243BioequivalenceExample612182430364248012345678Test/GenericReference/BrandT/R(%)80%125%44PossibleBEResults(90%CI)新药与仿制药申报要求45NewDrugGenericDrugNDARequirementsANDARequirements1.Chemistry1.Chemistry2.Manufacturing2.Manufacturing3.Controls3.Controls4.Labeling4.Labeling5.Testing5.Testing6.AnimalStudies7.ClinicalStudies6.Bioequivalence8.Bioavailability仿制药要求THERAPEUTICEQUIVALENTSGenericdrugproductsareconsideredtobetherapeuticequivalentsonlyiftheymeetthefollowinggeneralcriteria:*Safeandeffective*Pharmaceuticalequivalents*Bioequivalent*Adequatelylabeled*ManufacturedincompliancewithCurrentGoodManufacturingPractice(cGMP)regulations.Therapeuticequivalencecodes“A”=Substitutable“B”=Inequivalent,NOTSubstitutable46FDA仿制药批准数47FDA仿制药申报数48FDA仿制药申报数49FDA仿制药申报数50FDA/GPhAFallTechnicalConference5128.224.719.618.717.318.918.418.317.316.316.305101520253019951996199719981999200020012002200320042005MonthsFiscalYearMEDIANApprovalTimesANDA
本文标题:仿制药研发趋势及中美仿制药申报注册要求对比--
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