海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Fri, 13 Jan 2023 09:00:22 +0000

论文：

解决生物疗法中新型生物偶联物的日趋复杂化和给药途径问题

关键词：

生物分析；生物疗法；药物发现

本周介绍一篇由海洋之神优惠大厅主站首席技术官兼生物分析和生物标志物总裁梁美娜博士参与研究，发布在BioDrugs的论文。

梁美娜博士在GxP生物分析和药政事务方面积累了30余年的专业知识，并在建立海洋之神优惠大厅主站GxP实验室的过程中发挥了重要作用。她近期的一篇综述文章介绍了生物分析方法正在经历的深刻发展和突出挑战。

生物偶联物复杂性的不断增加，新型赋形剂的使用以及新的给药途径正在推动一系列新技术和新仪器的开发。

综合生物分析工具的快速发展将有助于更好理解和评价复杂生物偶联物的药代动力学、代谢和生物分布特性，从而有效支持新药的发现和开发。

梁美娜博士

海洋之神优惠大厅主站

CTO

生物分析和生物标志物总裁

转化医学专家
前阿斯利康生物分析全球负责人，管理全球5个基地的100多名科学家
30余年体外药理调查、药代动力学和药效学表征、生物标志物开发、免疫原性评估、GxP生物分析和提交监管文件方面的经验
十多项发明专利的拥有者，60多篇同行评议文章的作者，也是诸多国际行业会议的组织者和特邀发言人。曾多次受邀参加美国医药行业工作组制定行业指导性文件（白皮书）
在法规提交（IND、BLA、NDA）、体外药理调查、药代动力学、药效学特性、生物标志物开发、辅助诊断开发、免疫原性评估、GxP生物分析、DMPK和临床药理学等方面经验丰富

点击此处，即可查看完整论文。

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Fri, 06 Jan 2023 09:00:58 +0000

论文：

定量系统药理学建模平台用于评价接受evinacumab治疗的高甘油三酯患者的甘油三酯曲线特征单克隆抗体治疗

关键词：

血管生成素样蛋白3；Evinacumab；纯合子家族性高胆固醇血症；甘油三酯；高密度脂蛋白胆固醇

本周的刊物根据海洋之神优惠大厅主站临床药理总裁Nidal Al-Huniti博士参与的研究发表。

血管生成素样蛋白3（ANGPTL3）通过抑制脂蛋白脂肪酶和内皮脂肪酶的活性在脂质代谢中发挥作用，使上游富含甘油三酯（TG）脂蛋白（TRL）的清除率降低，并升高血浆中TG和高密度脂蛋白胆固醇的浓度。

Evinacumab是一种处于试验阶段的ANGPTL3抑制剂，可降低健康受试者和患有纯合子家族性高胆固醇血症（HoFH）患者，或TG和/或低密度脂蛋白胆固醇（LDL）轻度至中度升高受试者的血脂水平。

定量系统药理学（QSP）作为一种建模手段，将不同的机制数据整合进药物和生物系统之间的动态相互作用中，包括对各种降脂疗法的有效性进行建模。

为了进一步了解evinacumab的作用机制，研究人员开发了一种QSP建模方法来评价evinacumab给药后脂质转运的变化，并预测不同TRL颗粒对evinacumab下游脂蛋白脂肪酶活性调节的瞬时反应。

文章对QSP模型特点的说明有助于对evinacumab作用机制的进一步理解，为临床试验中观察到的血脂反应变异性提供了潜在解释，这一发现有助于医生最大化不同人群中的高甘油三酯血症患者的治疗效益。

Nidal Huniti 博士

海洋之神优惠大厅主站临床药理总裁

知名定量药理和临床药理专家
17+年药物研发经验，前再生元（Regeneron）执行总监和定量药理负责人；曾在阿斯利康工作了9年，担任执行总监和美国肿瘤及数据编程&运营负责人
70+篇同行评议文章和200+篇论文摘要的作者
曾支持多个治疗各种疾病领域的生物和化学药物的临床开发和申报
BS：约旦大学获得药学学士学位；MS：爱荷华大学临床医药学；PhD：爱荷华大学药代动力学和药效动力学

点击链接，即可查看完整论文：https://ascpt.onlinelibrary.wiley.com/doi/10.1002/psp4.12694

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Fri, 23 Dec 2022 09:00:58 +0000

论文：

NASH纤维化的慢性炎症和趋化因子生物标志物的方法学验证和临床表现

关键词：

生物标志物；细胞因子；趋化因子；肝病；NASH纤维化

本周介绍一篇由海洋之神优惠大厅主站马里兰生物分析和生物标志物副总裁Rafiq Islam参与研究，发布在公共科学图书馆（PLOS）的论文。

非酒精性脂肪性肝炎（NASH）是一种慢性的代谢性肝脏疾病，可进展为重度肝纤维化，并最终需要肝移植。目前，肝穿刺活检是NASH诊断的参考标准，尽管已得到广泛应用，但仍为创伤性操作，因此无创替代方法（如NASH可溶性生物标志物）的使用将会为肝病管理带来重大进步。

这项研究对一系列与肝炎相关的促炎细胞因子和趋化因子进行了分析和临床验证，即白细胞介素-6（IL-6）、C反应蛋白（CRP）、肿瘤坏死因子α（TNFα）、MCP-1、巨噬细胞炎症蛋白1β（MIP-1β）、嗜酸性粒细胞活化趋化因子（eotaxin）和血管细胞粘附分子1（VCAM-1）。

研究结果表明，虽然所分析的一些促炎生物标志物的浓度水平并不随纤维化的严重程度而变化，但通过观察细胞因子IL-6和VCAM-1的水平差异能够区分疾病的轻度和重度阶段。值得一提的是，VCAM-1的表现优于该研究中测试的所有其他促炎细胞因子和趋化因子。

文章提供的新信息支持将促炎细胞因子和趋化因子作为NASH的生物标志物用于支持诊断。这些发现同样可能具有临床意义，可在未来肝病管理的临床试验设计中予以考虑。

Rafiq Islam

海洋之神优惠大厅主站马里兰生物分析和生物标志物副总裁

在CRO领域的 GxP生物分析和转化科学方面有超过20年经验
曾任Smithers公司的副总裁，成功建立并领导新药研发服务团队，为免疫肿瘤和基因治疗产品提供生物分析服务
曾先后在Celerion、EMD Millipore、Covance、Huntingdon Life Sciences和CuraGen担任过多个领导职位

查看完整论文：https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217263

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Fri, 16 Dec 2022 09:00:43 +0000

论文：

单克隆抗体治疗、预防和疫苗相结合以减少SARS CoV-2的传播

要点:

文章通过应用代理人基模型（ABM）探讨了抗病毒单克隆抗体（mAb）与疫苗联用对于新冠疫情的控制作用。

本周的刊物根据海洋之神优惠大厅主站临床药理总裁Nidal Al-Huniti博士参与的研究发表。

在不便于对合并干预进行前瞻性评估的场景中，快速发展的数学建模工具可为帮助决策提供信息。

文章中，研究人员使用ABM表征SARS-CoV-2在美国人群中传播的个体的异质性。该模型能够模拟疫情的各类场景，包括单独使用疫苗，以及mAb与疫苗联用等情况。mAb在其中用作“治疗即预防策略”的主动疗法和暴露后预防（PEP）的被动免疫。

结果表明，使用抗病毒mAb为疗法，以及PEP联合疫苗接种计划，将大幅减少SARS-CoV-2的传播并减轻这场大流行病带来的负担。这种方法可以为公共卫生政策提供参考，并适用于未来对大流行病的应对准备。

Nidal Huniti 博士

海洋之神优惠大厅主站临床药理总裁

知名定量药理和临床药理专家
17+ 年药物研发经验，前再生元（Regeneron）执行总监和定量药理负责人；曾在阿斯利康工作了9年，担任执行总监和美国肿瘤及数据编程&运营负责人
70+篇同行评议文章和200+篇论文摘要的作者
曾支持多个治疗各种疾病领域的生物和化学药物的临床开发和申报
BS：约旦大学获得药学学士学位；MS：爱荷华大学临床医药学；PhD:爱荷华大学药代动力学和药效动力学

查看完整论文：https://www.medrxiv.org/content/10.1101/2021.05.21.21257624v1

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Fri, 09 Dec 2022 09:00:52 +0000

论文：

远程稽查:CRO的虚拟现实——意外隔离时期的收获

关键词：

audit · CRO · inspection · pandemic · quality assurance · remote · virtual

该研究围绕海洋之神优惠大厅主站马里兰生物分析和生物标志物副总裁Rafiq M Islam和经验丰富的实验室科学家团队针对后疫情时代开展的远程稽查工作。

文章以科普的方式清晰地带我们了解了稽查的步骤，说明了远程稽查模式的挑战和机遇。文章指出，新冠疫情造成的出行限制和居家办公政策促使企业开始审视其常规工作模式。面对这一挑战，医药行业应对迅速，短时间内远程稽查便发展为新的标准操作。

文章最终得出结论，远程稽查已经能够实现现场稽查所能完成的目标，通过使用合适的软硬件工具，远程稽查在全球范围内均可实现。

Rafiq Islam

海洋之神优惠大厅主站

马里兰生物分析和生物标志物副总裁

在CRO领域的 GxP生物分析和转化科学方面有超过20年经验
曾任Smithers公司的副总裁，成功建立并领导新药研发服务团队，为免疫肿瘤和基因治疗产品提供生物分析服务
曾先后在Celerion、EMD Millipore、Covance、Huntingdon Life Sciences和CuraGen担任过多个领导职位

查看完整论文：https://www.future-science.com/doi/10.4155/bio-2021-0126

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Fri, 02 Dec 2022 09:00:32 +0000

《复发或转移性宫颈癌患者中西米普利单抗（cemiplimab）的群体药代动力学建模和暴露-反应分析》（Population pharmacokinetics modeling and exposure-response analyses of cemiplimab in patients with recurrent or metastatic cervical cancer）发表于2022年10月，介绍了PD-1抑制剂西米普利单抗（cemiplimab）的稳定性、稳健性和最新PopPK模型的验证，海洋之神优惠大厅主站临床药理总裁Nidal Al-Huniti博士是该论文的通讯作者。

为将研究不同类型实体瘤的多项临床试验中的 PK 数据纳入PopPK模型，研究人员更新了初始模型中模拟的西米普利单抗的药时曲线，进行了适当修改以改善模型的稳定性和鲁棒性，并与之前的模型进行比较。此外，论文中还报告了西米普利单抗在多个肿瘤类别患者中的PK 外部验证，以及在复发或转移性宫颈癌（R/M CC）患者中有效性和安全性的暴露-反应关系。

西米普利单抗在美国和欧洲获批用于治疗晚期皮肤鳞状细胞癌，剂量为350mg Q3W静脉滴注（i.v.），在美国获批用于治疗晚期基底细胞癌和一线治疗PD-1表达≥50%的晚期非小细胞肺癌。

论文的研究结果表明，R/M CC患者的西米普利单抗暴露量与其他肿瘤类型相当，暴露-反应分析显示，西米普利单抗暴露量与评价的有效性或安全性终点之间没有关系。这一数据对使用剂量为350 mg Q3W i.v. 的西米普利单抗作为R/M CC的二线治疗方案可能具有支持作用。

这项研究验证了PopPK模型和暴露-反应分析在确定肿瘤患者治疗剂量方面的应用。

查看完整论文 https://ascpt.onlinelibrary.wiley.com/doi/10.1002/psp4.12855

Nidal Huniti 博士

海洋之神优惠大厅主站临床药理总裁

知名定量药理和临床药理专家
17+ 年药物研发经验，前再生元（Regeneron）执行总监和定量药理负责人；曾在阿斯利康工作了9年，担任执行总监和美国肿瘤及数据编程&运营负责人
70+篇同行评议文章和200+篇论文摘要的作者
曾支持多个治疗各种疾病领域的生物和化学药物的临床开发和申报
BS：约旦大学获得药学学士学位；MS：爱荷华大学临床医药学；PhD:爱荷华大学药代动力学和药效动力学

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Fri, 04 Nov 2022 10:40:35 +0000

定量药理学离不开数学建模与模拟（Modeling and Simulation）技术，这需要有专业的软件作为数据分析的支撑工具。

海洋之神优惠大厅主站有幸请到香港中文大学医学院副教授闫晓宇博士进行定量药理系列公益培训，本文介绍了多款闫教授推荐的业内广泛使用的软件，这些软件均获得了大型跨国制药企业及美国食品药品监督管理局（FDA）、欧洲药品管理局（EMA）、日本厚生省及中国国家药品监督管理局（NMPA）等药物监管部门的认可。

popPK /PD

NONMEM

定量药理学离不开数学建模与模拟（Modeling and Simulation）技术，这需要有专业的软件作为数据分析的支撑工具。定量药理学的研究以非线性混合效应模型法（Nonlinear Mixed Effects Modeling，NONMEM）为主，以该方法命名的NONMEM软件是当前该领域内的国际主流分析软件和重要工具。通过不断地改进与升级，ICON旗下的NONMEM已成为群体药动学-药效学数据分析的“金标准”软件，也是应用最广泛的定量药理建模和模拟软件。

可结合《海洋之神优惠大厅主站云课堂 | 定量药理学专业书籍推荐》中介绍的Introduction to Population Pharmacokinetic / Pharmacodynamic Analysis with Nonlinear Mixed Effects Models学习该软件的使用方法。

PBPK

Simcyp

Simcyp模拟器Certara开发的基于生理学的药代动力学（PBPK）平台，可用于确定首次人体剂量、优化临床研究设计、评价新药制剂、设定未测试人群剂量、进行虚拟生物等效性分析和预测药物相互作用（DDI）。Simcyp在小分子药物、生物制剂、ADC、仿制药和New Modality药物开发均已得到广泛使用。

PK-Sim®

PK-Sim®是拜尔科技（Bayer AG，Germany）自主开发的整体PBPK工具，可用于建立基于生理学的全身药代动力学模型。该工具能够快速获取集成数据库中包含的人类和最常见的实验动物（小鼠、大鼠、迷你猪、狗和猴子）的所有相关解剖和生理参数，还提供了不同的PBPK计算方法，高效创建模型并参数化。

GastroPlus®

GastroPlus® 是制药模拟软件开发商Simulations Plus开发的PBPK/PD及制剂模拟软件，可以进行人类和动物的静脉注射、口服、口腔、眼部、吸入、皮肤、皮下和肌内吸收、生物药理学、药代动力学和药效学模拟。软件分为多个功能模块，包括基础模块、生理药代动力学PBPK模块、药代动力学参数计算PK 模块、代谢酶与转运体模块、药物相互作用DDI模块、药效动力学PD模块、优化模块、体内外相关IVIVC模块、其他给药途径模块、理化与代谢性质预测模块、生物大分子模块，可根据需求获得授权。

NCA

Phoenix® WinNonlin®

Phoenix® WinNonlin®是Certara开发的非临床和临床PK/PD研究分析平台。作为一款集成式工具，拥有数据处理、非房室模型分析（NCA）、PK/PD建模、分析后统计、表格创建和图形绘制等多种功能，其NCA引擎、独立的PK/PD建模引擎和统计分析工具可用于从早期非临床研究到大型临床试验的各种研究和分析工作。直观的图形化用户界面可为用户节省大量学习软件和管理数据的时间，从而留出更多的时间来建模、解读和理解数据。

上述信息来源于软件版权所属公司，在官方网站均可找到软件获取方法及使用教程。

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Fri, 20 May 2022 08:00:03 +0000

《联邦食品、药品和化妆品法案》(FD&C Act)第505条规定了可以提交给FDA批准的所有三种类型的新药申请：505(b)(1)、505(b)(2)、505(j)。其中，由于505(b)(2)类途径所需的申请数据相对减少，且可使用先前已获得批准的资料，因此研发费用和开发时间较创新药更少，开发风险更低，广泛受到药品开发者的青睐。

海洋之神优惠大厅主站全球监管注册业务副总裁Kamali Chance博士曾撰文对505(b)(2)类申请途径进行深度解析。

文章主要内容包括：
505(b)(2)应用案例分析
不符合505(b)(2)的情况
专利和排他性保护
通过505(b)(2)类途径进行申请的方法

Kamali Chance
海洋之神优惠大厅主站全球监管注册副总裁

25年监管事务工业界经验，涵盖各类药物开发的临床前，临床和全球入市申报阶段
曾助力多个药物在美国、欧盟、加拿大、中国及其他亚洲国家的成功上市
曾撰写和合著了许多关于创新药和生物仿制药监管实践的文章和书籍章节
拥有监管事务专业协会颁发的监管事务证书
博士:北卡罗来纳大学格林斯博罗分校；硕士:北卡罗来纳大学教堂山分校

Is the 505 (b)(2) Drug Application Process Right for You?

By Kamali Chance, MPH, PhD, RAC

The 505(b)(2) section of the Federal Food, Drug, & Cosmetic Act (FD&C Act) describes the new drug application (NDA) process, which incorporates some characteristics of both NDAs and Abbreviated New Drug Applications (ANDAs)¹. This application process replaces FDA’s paper NDA policy, which had allowed reliance on safety and efficacy data published in scientific literature. This section was added to the FD&C Act by the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman), which permitted FDA to rely upon data not developed by the applicant for approval of an NDA. In October 1999, FDA issued a Draft Guidance for Industry entitled Application Covered by Section 505(b)(2) that clearly identified the application types that would be covered by this section.²

Section 505 of the FD&C Act describes all three types of new drug applications that can be submitted to FDA for approval:

New Drug Applications covered under FD&C Act section 505(b)(1)—This type of application contains full reports of safety and efficacy investigations as well as some of the information from studies not conducted by or for the applicant for which the applicant has obtained a right of reference.
505(b)(2) New Drug Applications—This type of application relies upon “at least some of the information from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference,” although some studies may have been conducted by the sponsor.
Abbreviated New Drug Applications covered under FD&C Act section 505(j)—This type of application includes information that shows that the proposed product is identical to a previously approved drug product in the following respects: active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics and intended use.

Protein products originally approved under the FD&C Act now also are subject to the 505(b)(2) rule as follow-on proteins. Sandoz’s Omnitrope (somatropin [rDNA origin]) NDA was submitted to FDA through this pathway and referenced Pfizer Inc.’s listed drug Genotropin (somatropin [rDNA origin]).³ Omnitrope is not a generic biologic since it is not rated by FDA as being therapeutically equivalent to Genotropin or any other human growth hormone product. In other words, this product (Omnitrope) cannot be substituted for another human growth hormone product in a pharmacy. The physician will have to write a specific prescription for Omnitrope, as for any other innovator drug. It should be noted that there is no abbreviated approval pathway for protein products licensed under section 351 of the Public Health Service Act.³

The type of information that an applicant can rely upon for which it does not have the right of reference include:

1. Published literature

If a drug application’s approval will rely upon published literature to any extent, a 505(b)(2) application [a literature-based 505(b)(2)] should be submitted. In this case, the applicant does not have right of reference to the raw data underlying the published study.

It should be noted that this only applies to referencing such information as clinical trials and animal studies that is necessary to obtain approval of the drug application, not any reference to published general information (e.g., about disease etiology, methods of analysis, etc.). However, if the applicant obtains a right of reference to the raw data, the application may be filed as a full NDA [505(b)(1)].^{2, 4}

2. The agency’s finding of safety and efficacy for an approved drug

If a drug application’s approval relies upon the agency’s previous finding of safety and/or efficacy for a reference listed drug, a 505(b)(2) application should be submitted. This approach encourages innovation in drug development (e.g., different dosage form, strength, route of administration, etc.) of the same drug product without requiring duplication of safety and efficacy studies. The patent(s) and exclusivity rights for the approved reference listed drug are protected. This scenario would require, at a minimum, a bioequivalence study with the reference listed drug, and possibly some bridging toxicology studies or perhaps mutagenicity or genotoxicity studies if the impurity profile is different from the reference listed drug.

Examples of 505(b)(2) Drug Applications²

new dosage form—If the approved drug is a tablet that is taken multiple times daily, a 505(b)(2) application can be submitted for an extended release version of that product [example: Naproxen sodium extended release tablets (Naprelan)] or orally disintegrating tablets, etc.
strength—A drug application could request a change to a lower or higher strength of the currently approved drug product.
route of administration—This could include a change from an intravenous to an oral route of administration, etc.
formulation—An application could propose a drug product containing a quality or quantity of an excipient(s) different from that of the reference listed drug (e.g., novel excipient). Studies required for this application type are beyond those required for generic drug applications (e.g., bioequivalence confirmatory studies⁵). The additional studies that may be required include safety studies on the novel excipient and its interaction with the remaining drug product ingredients.
dosing regimen—This application type would include a change from the currently approved dosing regimen (e.g., from every four hours to once per day).
active ingredient—This type of drug application would include a different salt, ester, complex, chelate, clathrate, racemate or enantiomer of the active ingredient of an already approved drug product containing the same active moiety. One example would be the approval of the drug product Pexeva (Paroxetine mesylate), which is a different salt form of Paxil (Paroxetime hydrochloride), via the 505(b)(2) route.
new molecular entity/new chemical entity— For new molecular entities such as different salt or ester forms of the approved active in a reference listed drug, the new drug sponsor can rely upon safety and efficacy data from both the reference listed drug and literature. Bridging safety studies may be required. For NCEs, even drugs with similar pharmacologic effects (pharmaceutically equivalent) may be eligible for consideration in the approval of a new drug.
combination product—A new combination product would include one or both of the active ingredients that previously had been approved individually. If only one of the actives was approved previously, the sponsor can rely partially on the efficacy and safety data for that active. However, additional clinical studies will need to be conducted to show the combination’s safety and efficacy.
indication—If applying for a new indication of a previously approved drug product, the innovator company should file a supplemental NDA. Other applicants who do not have the right of reference to the innovator/reference listed drug can file a 505(b)(2) application and ask the agency to rely upon a previous finding of safety and/or effectiveness for the innovator product.
Rx/OTC switch—A request is submitted to change the prescription (Rx) status of an already approved prescription drug to over-the-counter (OTC) status for marketing approval. The product’s safety profile is reviewed by the agency, which looks at US and worldwide adverse event data. Consideration is given to how long the product has been on the market and how extensively it has been used. Label comprehension studies may be required. Normally, the applicant requests the Rx to OTC switch; however, health insurers and even FDA have been known to initiate the switch (e.g., Claritin).
OTC monograph—A 505(b)(2) drug application is submitted for a nonmonograph indication or a new dosage form of a product described in an OTC monograph (21 CFR 330.11).
naturally derived or recombinant active ingredient—In this case, the active ingredient is the same as that in a reference listed drug, but it is derived from animal or botanical sources or recombinant technology. Clinical studies would be required to show that the active ingredient has the same drug impact (pharmacokinetic/ pharmacodynamic) as the one in the reference listed drug.
bioinequivalence— If the rate and/or extent of absorption are different from those of the reference listed drug (e.g., exceed standards for bioequivalence), a 505(b)(2) drug application can be submitted. Additional clinical studies may be required to document the new drug product’s safety and efficacy (e.g., a controlled- release drug product that is bioinequivalent to a reference listed drug may qualify). This change would be reflected in product labeling. It should be noted that if the proposed drug product is an exact duplicate of the reference drug product, a 505(j) application should be submitted.

The Following Do Not Qualify for 505(b)(2) Status²

A drug application that is a duplicate of a reference listed drug should be submitted for approval under section 505(j) (ANDA route) of the FD&C Act (also see 21 CFR 314.101(d)(9)). However, a 505(b)(2) application can be submitted for a change in a drug product that also may be eligible for consideration under suitability petition guidelines under Section 505(j)(2)(C) of the FD&C Act.
A drug application for a product where the only difference from the reference listed drug is that the extent and/or rate of absorption of the active ingredient(s) or delivery to the site of action are less than for the reference listed drug (21 CFR 314.54(b)(1)).

Patent and Exclusivity Protections

Patent/exclusivity certifications must be filed for 505(b)(2) applications for any references to a listed drug.^2,6 Existing patents and/or exclusivities can delay the approval of a 505(b)(2) application. A 505(b)(2) application also can be eligible for patents and exclusivities:

A 505(b)(2) application can be eligible for three years of exclusivity under the Hatch-Waxman Act, if one or more clinical studies were essential for product approval and these studies were conducted or sponsored by the applicant [21 CFR 314.50(j); 314.108(b)(4) and (5)].
Five years of exclusivity may be granted if the drug product contains a new chemical entity [21 CFR 314.50(j); 314.108(b)(2)].
Orphan drug exclusivity (21 CFR 314.20-316.36) and pediatric exclusivity (section 505A of the Act) also apply to 505(b)(2) drug applications.

How to Begin the 505(b)(2) Application Process

It is highly recommended that the 505(b)(2) applicants request a meeting with the appropriate FDA division before an official drug application is filed for review. This could be a pre-IND or pre-NDA meeting, depending upon clinical study status. Meeting with the agency early in the planning process can help:

establish a good working relationship with the particular FDA division
get input from potential reviewers to guide the robust protocol development to address all agency’s concerns.
avoid unnecessary studies that the applicant may have been considering
determine the issues of importance to the particular division that should be addressed, perhaps as a different arm of one clinical trial as opposed to conducting a different trial
gain early acceptance of the number of pivotal studies, if any, or perhaps of confirmatory bioequivalence study by the drug approval division
gain early acceptance of the appropriate reference listed drug by the division the applicant may have identified; this information would be crucial if the applicant is planning any comparative studies with the reference listed drug

In general, early agreements with the division can save the applicant time, from concept development through drug approval. Best of all, the agency does not charge for these meetings.

Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products outlines FDA requirements for making meeting requests and includes information on what should be included in the briefing (information) package. The following information generally is required:⁷

identification of any application components for which the applicant will rely upon FDA’s finding of safety and effectiveness of a previously approved drug product; identity of the reference listed drug.identification of any studies the applicant does not own or has the right to reference (includes any preclinical or clinical studies) from published literature
identification of proposed bridging studies for the approval of the 505(b)(2) application
for a 505(b)(2) application for a New Chemical Entity, identification of a pharmaceutically equivalent drug, if the application will rely upon any data from the pharmaceutically equivalent drug; provide certifications for patents listed for the pharmaceutically equivalent drug
identification of any patents and/or exclusivities (per FDA’s Orange Book) that claim the reference listed drug or the use of drug in the proposed 505(b)(2) drug application
if seeking marketing exclusivity for the 505(b)(2) drug product, include information required under 314.50(j), e.g., if approval is sought for a new patient population, identify clinical studies that will be the basis for the new exclusivity
if seeking approval for a new indication for a reference listed drug, certification to that effect is required per (21 CFR 314.54(a)(1)(iv)
information on any Bioavailability /Bioequivalence (BA/BE) study conducted or planned comparing the proposed drug product to the reference listed drug
information on any proposed studies that may be necessary to support changes to the reference listed drug (i.e., studies using the new dosage form, dosing regimen change, new patient population, etc.); often, appropriate bridging studies may meet FDA requirements for safety and efficacy in addition to what exists in literature

and/or previous finding of safety and efficacy by the agency for the reference listed drug

Conclusion

It should be noted that the standards required to gain approval of a drug via the 505(b)(2) route are the same as those that apply to 505(b)(1) applications. The difference is that the 505(b)(2) applicant can rely upon studies conducted by others (literature-based), for which the applicant has not obtained a right of reference, and also can request reliance upon FDA’s safety and efficacy findings for the reference listed drug.

REFERENCES

1. Federal Food, Drug, and Cosmetic Act as amended by the FDA Modernization Act of 1997.

2. FDA Guidance for Industry: Applications Covered by Section 505(b)(2). This guidance is available at www.fda.gov/cder/guidances.

3. www.fda.gov/cder/drug/infopage/somatropin/default.htm

4. 21 CFR Part 314.54. Procedure for submission of an application requiring investigations for approval of a new indication for, or other change from, a listed drug.

5. Limited confirmatory testing is explained in further detail in 54 Federal Register 288872, 28880 (10 July 1989) and 57 Federal Register 17950, 17957-58 (28 April 1992).

6. “Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions; Final Rule,” Federal Register. Vol. 59, No.190, Monday, 3 October 1994, page 50338. Also found under 21 CFR 314.107 Effective date of approval of a 505(b)(2) application.

7. FDA Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products. This guidance is available at 222.fda.gov/cder/guidances.

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

admin — Mon, 09 May 2022 15:55:55 +0000

抗体偶联药物(antibody-drug conjugate，ADC)是将单克隆抗体药物的高特异性和小分子药物的高活性相结合，利用抗体与靶抗原特异性结合的特点，将小分子药物靶向递送至肿瘤细胞进而发挥杀伤肿瘤的作用, 从而提高肿瘤药物的靶向性、减少毒副作用。与传统的完全或部分人源化抗体或抗体片段相比，ADC因能在肿瘤组织内释放高活性的细胞毒素从而理论上疗效更高。近年来，ADC药物已经成为国内外抗体药物研发的新热门方向，备受医药研发领域人员的关注。
ADC的研究可以追溯到1980年，但是直到2000年，首个ADC药物才被FDA批准用于治疗急性粒细胞白血病，但由于致死性的毒性的产生，于2010年撤市。随着原有技术的改进，研究人员开发了新型ADC药物，并于2011年被FDA批准用于治疗霍奇金淋巴瘤和系统性间变性大细胞淋巴瘤。2013年ADC药物再次取得突破，Genentech/ImmunoGen联合开发的Ado-trastuzumabemtansine被FDA批准用于HER2阳性乳腺癌，这是首个针对实体瘤的抗体偶联药物。随着这两个药物的研发成功，ADC药物再次以火热的状态进入人们的研究视野。截至2020年9月共有10款ADC药物获批上市，并且有80多个ADC药物处于积极的临床研究中。

2020年8月28日，中国国家药品监督管理局（NMPA）发布公告，荣昌生物制药自主研发的注射用纬迪西妥单抗（商品名：爱地希®，研究代号：RC48）用于治疗局部晚期或转移性胃癌（包括胃食管结合部腺癌）患者的新药上市申请被正式受理，并被纳入优先审评审批程序，成为中国第一个提交新药上市申请的自主开发的ADC药物。

海洋之神优惠大厅主站 - 海洋之神优惠大厅网页

amador — Thu, 21 Apr 2022 09:29:34 +0000

近期，海洋之神优惠大厅主站联合北京肿瘤医院在Frontiers in Pharmacology 发表论文“儿科实体瘤患者用药剂量确认的TQ-B3101群体药代动力学建模与模拟”。

论文讨论了根据从Ⅰ期和Ⅱ期研究中采集到的成人及少数青少年的PK数据，如何使用群体PK建模和模拟方法对TQ-B3101（一种新型激酶抑制剂）进行儿科用药剂量推荐。

论文具体内容请见下方：

TQ-B3101是一种开发中的新型激酶抑制剂，可以用于治疗晚期恶性肿瘤和复发性或顽固性的ALK阳性间变性大细胞淋巴瘤（ALCL）。此为首个在口服TQ-B3101后，对TQ-B3101及其活性代谢物（TQ-B3101M）在人体内的群体PK模型进行研究的报告。
人口统计学协变量包括体重、BMI、BSA、年龄、性别、肥胖程度、白蛋白、肝脏和肾脏功能的标志物，对TQ-B3101和TQ-B3101M的PK不会造成实际影响。
基于临床模拟，建议在TQ-B3101的进一步开发中，对ALCL的儿童患者（6-<18岁）采用以下BSA分级给药方案：0.74-0.89 m2：250 mg BID；0.90-1.22 m2：350 mg BID；1.23-1.38 m2，400 mg BID；1.39-1.59 m2：450 mg BID；>1.6 m2：550 mg BID。