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: jiashengtuyahoo.com.cn2011.11 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1234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 SSA已经破产：如何破局？ 降低医疗费用成为必然 Hatch-Waxman法案出台 美国FDA药品注册申请：新药（两类）、仿制药 和非处方药申请3Ceryak1984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)(2)505(j)NDA的研发和申报505(b)(1) 新药申报资料内容IndexSummaryChemistry, Manufacturing and ControlSamples, Methods Validation Package and LabelingNonclinical Pharmacology and Toxicology6. Human Pharmacokinetics and Bioavailability7. Microbiology ( for anti-microbial drugs only)8. Clinical Data9. Safety 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 Patent Certification505(b)(2): 历史过程vHatch Waxman法案：1984 vParkman Letter Phantom ANDA vFDA Draft Guidance for Industry (1999) vFDA Response to Citizens Petition (2003) v可以降低研发的费用和审评力量的浪费505(b)(2)的关键: 可靠性vWhat is “Reliance” By whom? On what?vReliance and Exclusivity Market vs. Data Exclusivity Safety/Efficacy Data vs. CM Quality by Design Module 4: Nonclinical Module 5: Clinical (Bioequivalence)新药申报（NDA） 和仿制药申报（ANDA）的比较1.Chemistry 2.Manufacturing 3.Controls 4.Labeling 5.Testing 6.Animal Studies 7.Clinical Studies 8.BioavailabilityNDA requirementsANDA requirements1.Chemistry 2.Manufacturing 3.Controls 4.Labeling 5.Testing6.Bioequivalence美国仿制药申报模块模块1 1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）。模块模块2 2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。模块模块3 3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：模块模块4 4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。模块模块5 5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 necessary, 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 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 Identification Are the specifications for appearance and identification appropriate? Assay Is the proposed drug substance assay limit acceptable? Is the analytical method validated and stability-indicating? Impurities and Residual Solvents Are 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 function? Additional Specifications Based 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 acceptance limit? Is it suitable for its intended function?QBR: Drug ProductvDescription 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 product is an NTI drug or a non-simple dosage form Are there significant differences between this formulation and the RLD that present potential concerns with respect to product performance? vControl of Excipients What are the specifications for the inactive ingredients and are they appropriate per their intended function?Simple Dosage Form: Either a solution or an IR solid oral dosage formQBR: Drug Product (Continued)vManufacture For all products Does the batch formula accurately reflect the drug product composition? If not, what are the differences and the justifications (e.g. potency adjustment, overage, 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 operations? If product is an NTI drug or a non-simple dosage form What are the cr