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本帖最后由 flydengfeng 于 2017-11-10 15:24 编辑
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The FDA Process for Approving Generic Drugs 美国仿制药审批流程
Gary J. Buehler, R.Ph. Director 主任 Division of Bioequivalence生物等效性部门 Office of Generic Drugs仿制药办公室
Did you know that generic drugs... 你是否知道仿制药… Are safe and effective alternatives to brand name prescriptions 是安全有效可以替代品牌处方药 Can help both consumers and the government reduce the cost of prescription drugs 可以帮助消费者和政府降低处方药成本 Are currently used in 50% of all prescriptions dispensed 目前在处方药中的使用量占50% Save an average of $50 for every prescription sold 每一份处方的售出平均节约50美元
Hatch-Waxman Amendments to FFD&C Act - 1984 Hatch-Waxman修正案 FFD&C法案-1984 Considered one of the most successful pieces of legislation ever passed 被认为是有史以来最成功的立法之一 Created the generic drug industry 创造了仿制药工业 Increased availability of generics 提高了仿制药的可及性 1984 12% prescriptions were generic 1984年 12%的处方药是仿制药 2000 44% prescriptions were generic - yet only 8% of revenue for prescription drugs 2000年 44%的处方药是仿制药 – 但处方药的利润只有8% Compromise legislation to benefit both brand and generic firms 原研药和仿制药企业共同受益的妥协立法
Hatch-Waxman Amendments to FFD&C Act – 1984 Hatch-Waxman修正案 FFD&C法案-1984 Allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities (do not have to repeat expensive clinical and pre-clinical trials) 允许仿制药公司在创新药专利和独占期满后依靠创新药物的安全性和有效性数据（不需要重复进行昂贵的临床和临床前试验） Allowed patent extensions and exclusivities to innovator firms 允许创新企业的专利期延长和市场独占权
NDA vs. ANDA
fda
What are the requirements for a generic drug? 仿制药的要求是什么？
How do we assure the quality of generic drugs?
我们如何保证仿制药的质量 First 5 steps of review process are identical to NDA process 审评程序的前5步与NDA申请一致 Bioequivalence for complicated products is discussed with the same staff that reviewed the brand product 复杂产品生物等效性由审评过相应原研药的审评员来讨论 FDA has experience with the product FDA对产品有经验 Scientific literature published 科学文献发表 Product is known to be safe 产品认为是安全的
仿制药审评程序
What are the requirements for a generic drug? 仿制药的要求是什么？ Compared to reference listed drug (RLD) 对比参考目录药物
Labeling 标签 “Same” as brand name labeling 与原研药标签“相同” May delete portions of labeling protected by patent or exclusivity 可能删除专利或独占保护的部分 May differ in excipients, PK data and how supplied 可能存在不同：辅料，PK数据及其如何提供数据
Chemistry 化学 Components and composition 成分与组成 Manufacturing and controls 生产和控制 Batch formulation and records 批处方与记录 Description of facilities 设备与描述 Specs and tests 规格和测试 Packaging 包装 Stability 稳定性
Manufacturing Compliance Programs 生产合规性程序 – Surveillance 监视 – Manufacturing/Testing plant inspections 生产/检测车间检查 – Assess firm’s compliance with good manufacturing processes 评估企业GMP的符合性 “Orange Book”橙皮书 All FDA approved drug products listed (NDA’s, OTC’s & ANDA’s) 所有FDA批准的药品均被列入（NDA’s, OTC’s & ANDA’s）
– Therapeutic equivalence codes 治疗等效代码  “A” = Substitutable 可替代  “B” = Inequivalent, NOT Substitutable 不等效，不是可替代的 – Expiration dates:失效期 patent and exclusivity 专利和独占权 – Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products 参考目录药物/品牌药由FDA鉴定，为仿制药企业与他们提交的产品比较
Definition of Bioequivalence 生物等效性的定义 Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions
药物等效是指在相同的实验条件下，患者或受试者在相同摩尔剂量下的吸收率和吸收程度没有统计学上的差异
Purpose of BE BE的目的 Therapeutic equivalence (TE) 治疗等效（TE） Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring 生物等效产品可以相互替代，而不需要任何剂量的调整或额外的治疗监测 The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner 确保 TE 最有效的方法是确保配方以等效的方式运行
Model of Oral Dosage Form Performance 口服制剂运行模型
Clinical/PD Dose-Response 临床/PD 剂量-响应
Plasma Concentration-Dose 血药浓度-剂量
Approaches to Determining Bioequivalence (21 CFR 320.24) 确定生物等效性的方法 — FeV1 Albuterol FeV1沙丁胺 — Blanching Study 褪色试验 — Topical Corticosteroid 局部用皮质激素 — Topicals 局部制剂 — Nasal Suspensions 鼻悬浮液 — Questran - Binding Studies 考来烯胺吸附研究 — Nasal Solutions-Sprayer Evaluation 鼻喷雾制剂评估 — Propofol - Droplet Size 丙泊酚 - 液滴尺寸
Study Designs 研究设计 Single-dose, two-way crossover, fasted 单剂量，双向交叉，空腹 Single-dose, two-way crossover, fed 单剂量，双向交叉，进食 Alternatives 替代选择
– Single-dose, parallel, fasted 单剂量，平行，空腹 Long Half-Life (wash-out) 长半衰期（清除） Amiodarone, Etidronate 胺碘酮，依替膦酸钠
– Single-dose, replicate design 单剂量，重复设计 Highly Variable Drugs 高变异药物
– Multiple-dose, two-way crossover, fasted 多剂量，双向交叉，空腹
Less Sensitive 较不敏感 Clozapine (Patient Trials) Chemotherapy Trials氯氮平(病人试验)化疗试验
– Clinical endpoint study 临床终点研究 Topicals 局部 Nasal Suspensions 鼻悬浮液
Waivers of In Vivo Study Requirements 体内研究要求的豁免 – In vivo bioequivalence is self-evident 体内生物等效性是不证自明的 – Parenteral solutions 注射液 – Inhalational anesthetics 吸入性麻醉药 – Topical (skin) solution 外用（皮肤）溶液 – Oral solution 口服液 – Different proportional strength of product with demonstrated BE 已生物等效的产品，其他含量比例相同规格不同产品
Statistical Analysis 统计分析 (Two One-sided Tests Procedure) – 90% Confidence Intervals (CI) must fit between 80%-125% 90%置信区间必须符合）80~125%范围
Statistical Analysis 80 – 125 % 统计分析 80~125% What does this mean? 这是什么意思？ Can there be a 46% difference? 可以有46%的不同吗？ What is a point estimate? 什么是点估计？ What is a confidence interval? 什么是置信区间？
Statistical Analysis 统计学分析 – Two one-sided tests procedure 两个单面测试过程
Test (T) is not significantly less than reference 测试不显著低于参比 Reference (R) is not significantly less than test 参比不显著低于测试 Significant difference is 20% ( = 0.05 significance level) 显著差异是2%（0.05 显著水平）
– T/R = 80/100 = 80% – R/T = 80% (all data expressed as T/R so this becomes 100/80 = 125%)
Possible BE Results (90% CI) 可能的BE结果（90%置信区间）
Narrow Therapeutic Range (NTI) Drugs 治疗窗窄的药物 Drug Products that are subject to therapeutic drug concentration or pharmacodynamic monitoring 服从治疗药物浓度或药效学监测的药物 – Examples are: Digoxin 地高辛, Lithium 锂制剂, Phenytoin 苯妥英, Warfarin 华法林
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发表于 2017-11-10 15:23:02
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