仿制药研发趋势及中美仿制药申报注册要求对比--课件

1、1,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,2,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。 US FDA：A generic drug is identical - or bioequivalent - to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use.,3,仿制药与新药,4,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,5,新药研发过程,6,新药：高风险高投入高回报,7,Special Tox studies: photosafety, local tolerance, impurity/metabolit

2、e testing,FIH, Ph1,Phase 2,Phase 3,NDA,US FDA Preclinical Requirements,8,Reasons for Attrition (19912000),Ismail Kola & John Landis (2004). Nature Reviews: Drug Discovery 3 : 711 - 715,9,研发费用增加与获批新药不成比例,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),16,医药企业应对策略,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,17,新药生命周期,18,研发成本比较,19,Why Generic？,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,20,FDA 支持仿制药,21,仿制药上市大大降低药价,22,美国仿制药市

3、场（价格）,23,美国仿制药市场（市场）,美国仿制药市场,25,美国仿制药市场,26,美国仿制药市场,27,全球仿制药市场,28,全球领先仿制药公司,29,仿制药研发趋势,品种：市场前景，专利保护，技术难度 时间：Be the first! 18个月专卖权 规模：多品种，规模化,30,FDA 仿制药法规,1984年美国颁布药品价格竞争和专利期恢复法（Drug Price Competition and Patent Term Restoration Act), 通常被称为“Hatch-Waxman修正案”（Hatch-Waxman Amendments）。 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（brandname drug）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（generic versions）能迅速上市，消费者能从中受益。,31,FDA 仿制药法规,“Hatch-Waxman修正案”是对联邦食品、药品和化妆品法（FD&C Act）的修订，设立了第505（j）节。 第5

4、05（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。,32,专利保护期延长,33,“第一个”仿制药,Hatch-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（market exclusivity）作为鼓励。即从仿制药开始商业上市（commercial marketing）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。,34,FDA 仿制药要求,Same active ingredient(s) (Pharmaceutical equivalent) S

5、ame route of administration Same dosage form Same strength Same conditions of use Compared to reference listed drug (RLD) (brand name product - listed in “Orange Book“, www.fda.gov/cder/ob),35,FDA 仿制药相关定义,Pharmaceutical Equivalence Same active drug ingredient; same strength; same dosage form and route of administration; comparable labeling; meets compendial or other applicable standards of strength, quality, purity, and identity. Bioavailability The rate and extent to which the active ingredient

6、 or active moiety is absorbed from a drug product and becomes available at the site of action. Bioequivalence Two pharmaceutical equivalent drug products are bioequivalent if after drug administration, the bioavailabilities (rate and extent of drug availability) provide similar effects with respect to efficacy and safety.,36,FDA 仿制药相关定义,Bioequivalence is established if the in vivo bioavailability of a test drug product (usually the generic product) does not differ significantly (i.e., statistica

7、lly insignificant) in the products rate and extent of drug absorption from that of the reference listed drug (usually the brand name product) when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose.,37,FDA 仿制药相关定义,The RLD is the reference drug product upon which an applicant relies when seeking approval of an abbreviated new drug application (ANDA). The RLD is generally the brand-name drug that has a full new drug a

8、pplication (NDA). FDA designates a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent. FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart. Such variations could result if generic drugs were compared to different reference listed drugs.,38,FDA仿制药指导,39,FDA仿制药指导,40,FDA仿制药指导,41,FDA仿制药指导,42,FDA仿制药指导,43,Bioequivalence Example,44,Possible BE Results (90% CI),45,新药与仿制药申报要求,New Drug Generic Drug

9、 NDA Requirements ANDA Requirements Chemistry 1. Chemistry Manufacturing 2. Manufacturing Controls 3. Controls Labeling 4. Labeling Testing 5. Testing Animal Studies Clinical Studies 6. Bioequivalence Bioavailability,46,仿制药要求,THERAPEUTIC EQUIVALENTS Generic drug products are considered to be therapeutic equivalents only if they meet the following general criteria: * Safe and effective * Pharmaceutical equivalents * Bioequivalent * Adequately labeled * Manufactured in compliance with Current Good Manufacturing Practice (cGMP) regulations. Therapeutic equivalence codes “A” = Substitutable “B” = Inequivalent, NOT Substitutable,47,FDA仿制药批准数,48,FDA仿制药申报数,49,FDA仿制药申报数,50,FDA仿制药申报数,FDA/GPhA Fall Technical Conference,51,GDUFA,“GDUFA” Generic Drug User Fees Only CDER program not supported by user fees Approx. 80% of RXs; estimated $10 billion in savings Backlog of over 2000 Originals; 4000 Supplements FDA receives 800 Originals, 1600 DMFs ann

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