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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,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。 US FDA：A generic drug is identical - or bioequivalent - to a brand name drug in dosage form, safety, strength, route of administration, quality, performanc
2、e characteristics and intended use.,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,6,Special Tox studies: photosafety, local tolerance, impurity/metabolite testing,FIH, Ph1,Phase 2,Phase 3,NDA,US FDA Preclinical Requirements,7,Reasons for Attrition (19912
3、000),Ismail Kola 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 or active moiety is absorbed from a drug pr
4、oduct 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.,FDA 仿制药相关定义,36,Bioeq
5、uivalence is established if the in vivo bioavailability of a test drug product (usually the generic product) does not differ significantly (i.e., statistically insignificant) in the products rate and extent of drug absorption from that of the reference listed drug (usually the brand name product) wh
6、en administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose.,FDA 仿制药相关定义,37,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
7、generally the brand-name drug that has a full new drug application (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 counter
8、part. Such variations could result if generic drugs were compared to different reference listed drugs.,FDA仿制药指导,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,42,43,Bioequivalence Example,44,Possible BE Results (90% CI),新药与仿制药申报要求,45,New DrugGeneric Drug NDA RequirementsANDA Requirements Chemistry1
9、. Chemistry Manufacturing2. Manufacturing Controls3. Controls Labeling4. Labeling Testing5. Testing Animal Studies Clinical Studies6. Bioequivalence Bioavailability,仿制药要求,THERAPEUTIC EQUIVALENTS Generic drug products are considered to be therapeutic equivalents only if they meet the following genera
10、l 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,46,FDA仿制药批准数,47,FDA仿制药申
11、报数,48,FDA仿制药申报数,49,FDA仿制药申报数,50,FDA/GPhA Fall Technical Conference,51,GDUFA,“GDUFA” GenericDrugUserFees OnlyCDERprogramnotsupportedbyuserfees Approx.80%ofRXs;estimated$10billioninsavings Backlogofover2000Originals;4000Supplements FDAreceives800Originals,1600DMFsannually ImpactsallofCDER Review Inspe
12、ction Petitions Medical/clinicalconsults Postmarketingsafety GDUFAStatus Secondattempttonegotiate;firstin2007 Publicmeetingheldin3rd Quarter2010 Expecttoenternegotiationin1st Quarter2011,仿制药批准标准 - US FDA,contain the same active ingredients as the innovator drug (inactive ingredients may vary) be ide
13、ntical in strength, dosage form, and route of administration have the same use indications be bioequivalent meet the same batch requirements for identity, strength, purity, and quality be manufactured under the same strict standards of FDAs good manufacturing practice regulations required for innova
14、tor products,53,仿制药申报程序,54,55,Simplified Application 21 CFR 314.94 Do Not Prove Safe and Effective Prove Bioequivalent to the Reference Listed Drug 21 CFR Part 320 Bioequivalence based on Cmax AUC (area under the time-concentration curve),ANDA 申报,56,Need a Reference “Listed Drug” 21 CFR 314.92 Same
15、Active Ingredients Same Route of Administration Same Dosage Form Same Strength Same Indication/Conditions for Use Some Changes Allowed Suitability Petition (Patents go to marketing, not approvability),ANDA 申报,57,1984年的HatchWaxman法案提出了四种可 能状态声明： 1)：专利尚未申请 2)：专利已经过期 3)：专利将会过期 4)：专利无效或不存在侵权 对于1）和2）两种情形
16、，只要其它部分符合条件，该ANDA可马上被批准。 对于3), ANDA可能在专利届满之日（patent expiration date）被批准。 对于4), 法院决定是否侵犯专利。,ANDA 申报,58,IV：专利无效或不存在侵权 仿制药申请者必须首先通知专利的所有者。而专利的所有者可以在收到该通知的45天内提出专利侵权的诉讼。 如原研药厂家以第状态声明为基础起诉仿制药厂家，FDA则在3O个月内不能批准该药，除非法庭在此之前判决原研药专利无效或侵权不存在。如果在3O个月内，法庭判定原研药专利无效或侵权不存在，FDA可立即批准仿制药申请。如果在30个月内，法庭判定原研药专利有效而且侵权存在，FDA就必须等到该药专利过期后才能批准仿制药申请,ANDA 申报,59,ANDA 申报侵权诉讼,Generic Drug Review,Much the same as new, brand name drug review 8 major parts,Generic Drug Review,FDA-approved generic drugs must have s
