中美仿制药研发和申报流程概述

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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:025-83271305Email:2011.11 郑州我国仿制药申报、审评和研发对策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1234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（两类）、仿制药和非药品注册申请：新药（两类）、仿制药和非处方药申请处方药申请19

2、84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 permitted(only bioequivalence)YESNO505(b)(1)505(b

3、)(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.Index2.Summary3.Chemistry,Manufacturing and Control4.Samples,Methods Validation Package and Labeling5.Nonclinical Pharmacology and Toxicology6.Human Pharmacokinetics and Bioavailability7.Microbiology(for anti-microbial drugs only)8.Clinical Data9.S

4、afety Update report(typically submitted 120 days after the NDAs submission)10.Statistical11.Case Report Tabulations12.Case Report Forms13.Patent Information14.Patent Certification505(b)(2):历史过程历史过程vHatch Waxman法案：法案：1984vParkman Letter Phantom ANDAvFDA Draft Guidance for Industry(1999)vFDA Response

5、to Citizens Petition(2003)v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vWhat is“Reliance”By whom?On what?vReliance and Exclusivity Market vs.Data Exclusivity Safety/Efficacy Data vs.CM&C datavFDA Process for Determining Reliance Who,when and how?505(b)(2)的意义的意义v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

6、v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v和仿制药不同，无替换的要求和仿制药不同，无替换的要求 v应有突破应有突破505(b)(2)范围范围vNew Chemical Entity(rarely)：我国：我国1.1-1.3vNew dosage form：我国：我国5类类vNew dosing regimen：我国补充申请：我国补充申请vNew strength：我国补充申请：我国补充申请vNew route of administration：我国：我国2类类vNew indication：我国：我国1.6505(b)(2)情形情形vNew active ingredi

7、ent(different salt,ester,complex,chelate,clathrate,racemate,or enantiomer of active moiety)vNew inactive ingredient that requires more than limited confirmatory studiesvRx OTC switchvNew Combination Productsv“Generic biologics”505(b)(2)排他性排他性Exclusivities available for 505(b)(2)products NCE Exclusiv

8、ity(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 competitors But,505(b)(2)NDAs may also be blocked by patents on Re

9、ference Drugs505(b)(2)新药的成功例子新药的成功例子vNCE Thalomid(thalidomide)(1998)vMarketed unapproved drugs Levothyroxine(2000)Guaifenesin extended release(2002)Quinine sulfate(2005)vNew Dosage Form Tramadol orally disintegrating tablets(2005)Ondansetron oral spray(filed 2006)505(b)(2)新药的例子新药的例子vNew Dosing Regim

10、en Tramadol extended release tablets(2005)vNew Strength/Formulation Antara(micronized fenofibrate caps)(2004)(130 mg is BE to Tricor 200 mg)vNew Formulation/Inactive Ingredient Avita(tretinoin gel)(new emollient)(1998)Abraxane(cremaphor-free paclitaxel)(2005)Oxy-ADF(oxycodone formulated to reduce dr

11、ug abuse)(in development)505(b)(2)新药的例子新药的例子vNew Active Ingredient Pexeva(paroxetine mesylate)(new salt)(2003)vNew Route of Administration Emezine(prochlorperazine)(new buccal/transmucosal delivery)(NDA pending)Oral amphotericin-B(pre-clinical)vRxOTC Switch Alavert(loratadine)(2002)505(b)(2)新药的例子新药的

12、例子v“Generic Biologics”Omnitrope(rHGH)(2006)Glucagen(glucagon recombinant)(1998)Hyaluronidase(various approvals 2004-05)Fortical(calcitonin salmon recombinant)(2005)*Examples based on publicly available informationFDA NDA 审评审评过程过程FDA 可以使用已有数据用于审评可以使用已有数据用于审评NDA吗？吗？v Hatch-Waxman之前之前,国会限制国会限制 FDA在审评在审

13、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)v Hatch-Waxman 解除只适合解除只适合 ANDAs：ANDA process allows“generic producer of the fully tested drug to rely on the safety and efficac

14、y data of a prior applicant.”v 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 one that is comparable to an innovator drug pr

15、oduct(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 use.Generic drug applications are termed“abbrev

16、iated”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

17、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v由由FDA的的OGD审评审评v审评方式采用审评方式采用QbRv申报资料采用申报资料采用CTDv资料内容也针对问题资料内容也针对问题Office of Generic Drugs如何保证审评质量和效率？如何保证审评质量和效率？vStructured Product Labeling(SPL)Makes labeling available on Internet via National Library of Medicine(NLM)vReview Efficiencies Early DMF review Cluster r

18、eviews product specialists Supplement triaging at team leader level DBE Truncated ReviewvQuestion based Review(QbR)Will have a very positive impactvNew resources developed Dissolution Database Individual Product Bioequivalence InformationvEncouraged the use of telephone in review process Increased t

19、he number of 1st cycle approvals Decreased the total number of review cycles Total time to approval did not increase in spite of increased workload Dissolution Methods for Drug ProductsNew!benThis guidance contains an Internet link to a listing of drug products,each linked in turn to a corresponding

20、 bioequivalence recommendation.Clicking on a product name in that list will bring up the bioequivalence recommendations for that specific product.Recommendations have been developed for several drugs that are not yet eligible for generic competition(i.e.,newly approved products)and some older produc

21、ts for which information has previously been provided.As additional recommendations are developed,those will be posted on the Web site.When this guidance is finalized,the listing will be available through the Agencys Web page.OFFICE OF GENERIC DRUGSTABLE OF BIOEQUIVALENCE RECOMMENDATIONSActive Ingre

22、dientPotencyDosage FormRoute of AdministrationDate FinalizedAlmotriptan Malate12.5 mgTabletOral5/16/2005Alosetron1 mgTabletOral5/31/2005Atazanavir200 mgCapsuleOral3/18/2005Atomoxetine60 mgCapsuleOral6/13/2005Cefditoren Pivoxil200 mgTabletOral3/18/2005Dutasteride0.5 mgCapsuleOral7/5/2005Eplerenone50

23、mgTabletOral3/18/2005Fosamprenavir Calcium700 mgTabletOral3/18/2005Memantine10 mgTabletOral7/8/2005Rosuvastatin40 mgTabletOral3/18/2005Tadalafil20 mgTabletOral3/18/2005Vardenafil HCl20 mgTabletOral4/11/2005QbR:从提出到完善从提出到完善 1/2005 2/2005:Question-based Review Drafted 3/2005 4/2005:Division Directors

24、Discussion 5/2005 6/2005:Team Leaders Discussion 7/2005 8/2005:Reviewers Discussion 9/2005 1/2006:Model Pharmaceutical Development Report and Quality Overall Summary 2/2005 12/2005:Discussions with Stakeholders and Upper Management 1/2005 12/2006:Gradual Implementation 1/2007:Full ImplementationQbR的

25、内涵的内涵vQuestion-based Review is a general framework for a science and risk-based assessment of product qualityvQuestion-based Review contains the important scientific and regulatory review questions to 关键制备工艺及其质控 产品的工艺、处方是否有设计缺陷 强调QbDANDAs Under QbR(Continued)v Future Generic Applications generic spo

26、nsors submit generic applications based on the format of ICH CTD,preferably,electronically Module 1:Administrative Information Module 2:Quality Overall Summary and Clinical Summary Module 3:QualityPharmaceutical Development;Quality by Design Module 4:Nonclinical Module 5:Clinical(Bioequivalence)新药申报

27、（新药申报（NDA）和仿制药申报（和仿制药申报（ANDA）的比较）的比较1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Animal Studies7.Clinical Studies8.BioavailabilityNDA requirementsANDA requirements1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Bioequivalence美国仿制药申报美国仿制药申报包含了管理和处方信息，这个是区域特异的。在美国应包括以下信息：申请书3674；专

28、利认证信息；原研药信息，包括NDA号、药名和生产商；仿制药和原研药的对比，包括使用条件、有效成分、非有效成分、给药途径、剂型和剂量；环境影响分析；药品说明书（草稿）。模块2为概论。它包括药理作用分类，作用模式以及临床适应证。应该包含原料药和制剂相关的化学、生产和质量控制信息。FDA仿制药部（OGD）鼓励申请人根据ICH对于人用药物的注册技术要求，即通用技术文件（CTD）的格式，提交ADNA。包括以下模块：模块4是关于动物实验的信息，并不是ANDA要求的。所以，仿制药申请一般不包含模块4。模块5是临床研究报告。对于ADNA，生物等效性信息应该在这个部分体现，包括：生物等效性研究；体外体内相关性研

29、究；生物分析方法开发。案例报告，包括不良反应事件报告也应包括在此。OGD QBR The question based review(QBR)serves as a general framework for the CMC assessment of ANDAs that focuses on critical pharmaceutical attributes of product quality.With justification,deviations or alternate approaches to this framework can be utilize,as necessa

30、ry,to ensure the adequacy of the assessment of product qualityFor ease of discussion,a simple dosage form is defined as a solution or an immediate release(IR)solid oral dosage form.QBR:Drug SubstancevDescription and Characterization What are the nomenclature,molecular structure,molecular formula,and

31、 molecular weight?What are the pKa,aqueous solubility(as function of pH),partition coefficient,polymorphism,hygroscopicity,and melting points?vControl of Drug Substance Appearance and IdentificationAre the specifications for appearance and identification appropriate?AssayIs the proposed drug substan

32、ce assay limit acceptable?Is the analytical method validated and stability-indicating?Impurities and Residual SolventsAre all the possible impurities accounted for?What is the justification for the impurity acceptance limits?Are the analytical methods validated and suitable for their intended functi

33、on?Additional SpecificationsBased on the review of the drug product and manufacturing process are specification(s)required on particle size,solid state form,moisture content,or other properties of the drug substance and why?For each additional specification:What is the justification for the acceptan

34、ce limit?Is it suitable for its intended function?QBR:Drug Productv Description and Composition What are the components and composition of the final product?What is the function of each excipient?Do any excipients exceed IIG limits in the context of maximum daily dose and route of administration?If

35、product is an NTI drug or a non-simple dosage formAre there significant differences between this formulation and the RLD that present potential concerns with respect to product performance?v Control of ExcipientsWhat are the specifications for the inactive ingredients and are they appropriate per th

36、eir intended function?Simple Dosage Form:Either a solution or an IR solid oral dosage formQBR:Drug Product(Continued)v ManufactureFor all productsDoes the batch formula accurately reflect the drug product composition?If not,what are the differences and the justifications(e.g.potency adjustment,overa

37、ge,excess coating solution,etc.)?If product is not a solution What are the key unit operations in the drug product manufacturing process?Are in-process tests identified by the sponsor appropriate?What is the difference in size between commercial scale and biobatch and do they use the same unit opera

38、tions?If product is an NTI drug or a non-simple dosage formWhat are the critical steps in the manufacturing process?What are the in-process tests/controls that ensure each critical step is successful?In the proposed scale up process what operating conditions will be adjusted to ensure the product me

39、ets all in-process and final product specifications?Why do you believe the sponsor has demonstrated a reasonable plan to scale up the process?QBR:Drug Product(Continued)v Control of Drug ProductIdentityIs the specification for the identity of the drug product appropriate?Assay and UniformityAre the

40、proposed drug assay limits acceptable?Is the assay method validated and stability-indicating?How is the content uniformity evaluated?Is it acceptable?Impurities/Degradation ProductsAre the degradation products and their origins adequately described?What is the justification for the acceptance limits

41、 on degradation products?Are the analytical methods validated and suitable for their intended function?Dissolution What are the dissolution methods and acceptance criteria and how were they selected?What is the significant role of dissolution testing for this product?Additional SpecificationsAre the

42、re additional specifications that are required to ensure the product will perform as labeled and why?For each additional specification:What is the justification for the acceptance limit?Are the analytical methods validated and suitable for their intended function?QBR:Drug Product(Continued)vReferenc

43、e StandardAre there a qualification report and COA provided for the reference standard or is this material purchased from an appropriate source?vContainer/Closure System Has the container/closure system been used in a previously approved product or otherwise qualified for this dosage form?What speci

44、fic container/closure attributes are necessary to ensure product performance?vDrug Product StabilityDataWhat stability data has been submitted?Has the sponsor provided stability data for the drug product packaged in the proposed container/closure?Acceptance limitsAre all attributes that could change

45、 over time evaluated in the stability tests?What are the acceptable limits on these attributes?Shelf-life recommendationWhat is the justification of shelf life?Is the post-approval stability protocol acceptable?QBR:Product Development Report for Complex Dosage Forms and NTI DrugsvDrug Substance Whic

46、h properties or physical chemical characteristics of the drug substance affect drug product performance?vExcipients Is there any evidence of incompatibility between the excipients and drug substance?vFormulation What is the formulation intended to do?What mechanism does it use to accomplish this?Wer

47、e any other formulation alternatives investigated and how did these perform?Were any formulation optimization or sensitivity studies carried out for variations in composition around the final formulation?Were these studies sufficient to establish a design space for formulation composition?Is the for

48、mulation design consistent with the dosage form classification in the label?vDrug ProductWhat are the critical quality attributes that ensure the product will perform as labeled?QBR:Process Development ReportvProcess DescriptionWhy was this manufacturing process selected for this drug product?Were a

49、lternative unit operations investigated by process development studies?vCritical Steps and Scale UpHow were the critical steps in the process identified?What are the critical process parameters for each critical step and how were they identified,monitored and/or controlled?Were process development s

50、tudies that varied starting materials or operating parameters conducted?Were these studies sufficient to establish a design space for process?In process testsWhy is each in process test required?How were the acceptance limits chosen?Why were the in-process tests identified as critical to product qua

51、lity?vWhat scale-up experience does the sponsor have with the unit operations in this process?QBR:Risk Summaryv NTI drugClassified as a non-NTI drug,risk score=+0Classified as an NTI drug,risk score=+1v Dosage FormSimple Dosage Form,risk score=+0Other Dosage Forms and NTI drugs,risk score=+1v Develo

52、pment ReportIf the sponsor submits a development report that addresses the FDAs questions:Risk score=+0Solution and IR Products:Product Development ReportOther Dosage Forms:Product and Process Development ReportsInsufficient or missing development report,risk score=+1v If the application is of high

53、overall quality Less than or equal to 2 cycles,risk score=+0.Greater than 2 cycles,risk score=+1QBR:Risk-Based Conclusionv Should the application be approved?v What post-approval waivers/commitments are appropriate for this product?If the total risk score is less than or equal to 1CBE0 and CBE30 cha

54、nges may be in annual reportsMany PAS to CBE 30If the total risk score is greater than 1All supplements should be submitted as usual生物等效性豁免生物等效性豁免v生物等效性豁免是指基于体外数据审批的管理程生物等效性豁免是指基于体外数据审批的管理程序。固体制剂往往采用溶出度、释放度作为证据序。固体制剂往往采用溶出度、释放度作为证据。I、基于药物剂型的生物等效性豁免v只有供试品和参比制剂的原料及其含量一致，辅只有供试品和参比制剂的原料及其含量一致，辅料一致、用量相当，

55、且符合如下规定时，可生物料一致、用量相当，且符合如下规定时，可生物等效性豁免：等效性豁免：1、注射液；、注射液；2、口服溶液，含量一致，且不含已知、口服溶液，含量一致，且不含已知会影响胃肠道功能和主药稀释的辅料；会影响胃肠道功能和主药稀释的辅料；3、气体；、气体；4、溶液散剂；、溶液散剂；5、耳用或眼用溶液；、耳用或眼用溶液；、6、外用溶、外用溶液；液；7、采用同样装置使用的吸入剂或鼻喷剂。、采用同样装置使用的吸入剂或鼻喷剂。II、基于剂型剂量比例的生物等效性豁免、基于剂型剂量比例的生物等效性豁免v当最高剂量的当最高剂量的BE数据具备时，下列情况可生物等数据具备时，下列情况可生物等效性豁免：效

56、性豁免：1、同样的剂型；同样的剂型；2、主药和辅料的比例相当；主药和辅料的比例相当；3、对于缓释制剂，同样的释放机制；对于缓释制剂，同样的释放机制；4、溶出度相似因子符合规定；溶出度相似因子符合规定；5、比例变化在线性动力学范围内。比例变化在线性动力学范围内。III、基于BCS分类的生物等效性豁免FDA在其指南中指出：制剂分别在在其指南中指出：制剂分别在900ml pH1.2、4.5和和6.8缓冲液中采用篮缓冲液中采用篮法法100rpm或浆法或浆法50或或75rpm下依法测定，药物制剂可以分为：（下依法测定，药物制剂可以分为：（1）极）极快速溶出：快速溶出：15分钟内溶出量不低于分钟内溶出量不

57、低于85%；（；（2）快速溶出：）快速溶出：30分钟内溶分钟内溶出量不低于出量不低于85%；（）缓慢溶出：溶出；（）缓慢溶出：溶出85%需要需要30分钟以上。分钟以上。生物等效性豁免条件：仿制品和参比制剂在上述条件下属于同一类别，生物等效性豁免条件：仿制品和参比制剂在上述条件下属于同一类别，且相似性分析符合规定，相似性标准如下分类：且相似性分析符合规定，相似性标准如下分类：v 分类分类I（FDA和和WHO均认可）：均认可）：BCS I类药物的制剂且符合其中之一：类药物的制剂且符合其中之一：1、在上述三种条件下不超过、在上述三种条件下不超过30分钟溶出分钟溶出85%以上，相似因子以上，相似因子f

58、250；2、参比制剂和受试制剂均为极快速溶出。参比制剂和受试制剂均为极快速溶出。v 分类分类II（WHO认可）：认可）：BCS II类药物，但在类药物，但在pH6.8缓冲液中易溶的制剂缓冲液中易溶的制剂且符合其中之一：且符合其中之一：1、在、在pH6.8条件下为极快速溶出；条件下为极快速溶出；2、在三种介质中、在三种介质中的溶出行为与参比制剂相似性符合要求。的溶出行为与参比制剂相似性符合要求。v 分类分类III（WHO认可）：认可）：BCS III类药物：类药物：1、参比制剂和受试制剂均为极、参比制剂和受试制剂均为极快速溶出，且不含已知可改变胃肠道运动或主药通透性的辅料；快速溶出，且不含已知可

59、改变胃肠道运动或主药通透性的辅料；2、企、企业应证明辅料的质量与使用目的相符。如使用的为新辅料或使用大量业应证明辅料的质量与使用目的相符。如使用的为新辅料或使用大量的常用辅料，应说明其对生物利用度的影响。的常用辅料，应说明其对生物利用度的影响。三、我国仿制药的申报、审评和研发对策三、我国仿制药的申报、审评和研发对策v新药新、仿制药同、新剂型特新药新、仿制药同、新剂型特v两报两批两报两批v豁免生物等效性试验：豁免生物等效性试验：1、注射液；、注射液；2、外用制剂、外用制剂；Company Logov我国仿制药申报流程图我国仿制药申报流程图Technology 美国2009年仿制药占处方药市场比例

60、70%以上，处于仿制药消费大国之首（产品从150个国家进口）；德国、英国的仿制药也已超过50%。国外仿制药现状国外仿制药现状中国仿制药产业发展的机遇中国仿制药产业发展的机遇中国仿制药产业发展的挑战中国仿制药产业发展的挑战v 国内老龄化，城镇化加速造成的医改和对仿制药的要求急剧增加v 10年内专利药几种到期造成了仿制药的战略机遇v 部分企业已经开始国际标准的注册和海外战略，取得了积极进展v 整体研发技术水平低v 缺乏仿制药制剂的国际注册经验，制剂产品很少进入发达国家市场，国际竞争力不强v 缺乏国际标准和通行质量规范，质量管理的理念和管理水平与国际水平尚有明显差距，造成了产品国际竞争能力不足谢谢观看/欢迎下载BY FAITH I MEAN A VISION OF GOOD ONE CHERISHES AND THE ENTHUSIASM THAT PUSHES ONE TO SEEK ITS FULFILLMENT REGARDLESS OF OBSTACLES.BY FAITH I BY FAITH