1、中美仿制药研发和申报流程 涂家生，Ph.D.中国药科大学药剂学教授 Tel:025-83271305 Email: 2011.11 郑州 我国仿制药申报、审评和研发对策 主要内容主要内容 中美关于原研药和仿制药的背景 美国仿制药：申报、基于问题的审评和研发对策 展望 1 2 3 4 Company Logo 3 药物经济学催生美国仿制药制度药物经济学催生美国仿制药制度 美国社会安全制度导致政府赤字严重美国社会安全制度导致政府赤字严重 SSA已经破产：如何破局？已经破产：如何破局？降低医疗费用成为必然降低医疗费用成为必然 Hatch-Waxman法案出台法案出台 美国美国FDA药品注册申请：新药
2、（两类）、仿制药和药品注册申请：新药（两类）、仿制药和非处方药申请非处方药申请 1984年后年后 New Drug Applications(NDAs)Abbreviated New Drug Applications(ANDAs)“Full Reports”of Safety and Efficacy Investigations Applicant has right of reference to essential investigations?Duplicate of an already approved product No safety/efficacy data permit
3、ted(only bioequivalence)YES NO 505(b)(1)505(b)(2)505(j)NDA的研发和申报的研发和申报 505(b)(1)新药申报资料内容新药申报资料内容 1.Index 2.Summary 3.Chemistry,Manufacturing and Control 4.Samples,Methods Validation Package and Labeling 5.Nonclinical Pharmacology and Toxicology 6.Human Pharmacokinetics and Bioavailability 7.Microbio
4、logy(for anti-microbial drugs only)8.Clinical Data 9.Safety Update report(typically submitted 120 days after the NDAs submission)10.Statistical 11.Case Report Tabulations 12.Case Report Forms 13.Patent Information 14.Patent Certification 505(b)(2):历史过程历史过程 Hatch Waxman法案：法案：1984 Parkman Letter Phant
5、om ANDA FDA Draft Guidance for Industry(1999)FDA Response to Citizens Petition(2003)可以降低研发的费用和审评力量的浪费可以降低研发的费用和审评力量的浪费 505(b)(2)的关键的关键:可靠性可靠性 What is“Reliance”By whom?On what?Reliance and Exclusivity Market vs.Data Exclusivity Safety/Efficacy Data vs.CM&C data FDA Process for Determining Reliance Wh
6、o,when and how?505(b)(2)的意义的意义 介于全创新药物和仿制药之间介于全创新药物和仿制药之间 具有专利保护，且不存在产权纠纷具有专利保护，且不存在产权纠纷 和仿制药不同，无替换的要求和仿制药不同，无替换的要求 应有突破应有突破 505(b)(2)范围范围 New Chemical Entity(rarely)：我：我国国1.1-1.3 New dosage form：我国：我国5类类 New dosing regimen：我国补充申：我国补充申请请 New strength：我国补充申请：我国补充申请 New route of administration：我：我国国2类
7、类 New indication：我国：我国1.6 505(b)(2)情形情形 New active ingredient(different salt,ester,complex,chelate,clathrate,racemate,or enantiomer of active moiety)New inactive ingredient that requires more than limited confirmatory studies Rx OTC switch New Combination Products“Generic biologics”505(b)(2)排他性排他性 E
8、xclusivities available for 505(b)(2)products NCE Exclusivity(5 years)New Product Exclusivity(3 years)Orphan Drug Exclusivity(7 years)Pediatric exclusivity extensions(6 months)Patent Issues 505(b)(2)drugs can have Orange Book-listed patents,and enjoy 30-month stay protection against generic competito
9、rs But,505(b)(2)NDAs may also be blocked by patents on Reference Drugs 505(b)(2)新药的成功例子新药的成功例子 NCE Thalomid(thalidomide)(1998)Marketed unapproved drugs Levothyroxine(2000)Guaifenesin extended release(2002)Quinine sulfate(2005)New Dosage Form Tramadol orally disintegrating tablets(2005)Ondansetron or
10、al spray(filed 2006)505(b)(2)新药的例子新药的例子 New Dosing Regimen Tramadol extended release tablets(2005)New Strength/Formulation Antara(micronized fenofibrate caps)(2004)(130 mg is BE to Tricor 200 mg)New Formulation/Inactive Ingredient Avita(tretinoin gel)(new emollient)(1998)Abraxane(cremaphor-free pacl
11、itaxel)(2005)Oxy-ADF(oxycodone formulated to reduce drug abuse)(in development)505(b)(2)新药的例子新药的例子 New Active Ingredient Pexeva(paroxetine mesylate)(new salt)(2003)New Route of Administration Emezine(prochlorperazine)(new buccal/transmucosal delivery)(NDA pending)Oral amphotericin-B(pre-clinical)RxO
12、TC Switch Alavert(loratadine)(2002)505(b)(2)新药的例子新药的例子“Generic Biologics”Omnitrope(rHGH)(2006)Glucagen(glucagon recombinant)(1998)Hyaluronidase(various approvals 2004-05)Fortical(calcitonin salmon recombinant)(2005)*Examples based on publicly available information FDA NDA 审评审评过程过程 FDA 可以使用已有数据用于审评可以
13、使用已有数据用于审评NDA吗？吗？Hatch-Waxman之前之前,国会限制国会限制 FDA在审评在审评 NDA X时应时应用用 NDA Y的数据：的数据：“No data in an NDA can be utilized to support another NDA without express permission of the original NDA holder.”FDA“Finkel Memorandum”(1978,1981)Hatch-Waxman 解除只适合解除只适合 ANDAs：ANDA process allows“generic producer of the fu
14、lly tested drug to rely on the safety and efficacy data of a prior applicant.”505(b)(2)does not authorize such data reliance Merely sets conditions for certain NDAs Requires“full reports of investigations”establishing safety and effectiveness 21 USC 355(b)(1)(A),(d)(1)美国仿制药 A generic drug product is
15、 one that is comparable to an innovator drug product(also known as the reference listed drug(RLD)product as identified in the FDAs list of Approved Drug Products with Therapeutic Equivalence Evaluations)in dosage form,strength,route of administration,quality,performance characteristics and intended
16、use.Generic drug applications are termed“abbreviated”in that they are generally not required to include preclinical(animal)and clinical(human)data to establish safety and effectiveness.These parameters were established upon the approval of the innovator drug product,which is the first version of the drug product approved by the FDA.FDA审评仿制药程序 二、美国仿制药的申报、审评和研发对策二、美国仿制药的申报、审评和研发对策 由由FDA的的OGD审评审评 审评方式采用审评方式采用QbR 申报资料采用申报资料采用CTD 资料内容也针对问题资料内容也针对问题 Comparison of Receipts and Approvals of ANDA Applica