FDA刚刚发布《基于药代动力学标准支持PD-1 或PD-L1阻断抗体用于治疗癌症患者治疗替代剂量范围...

I. INTRODUCTION AND BACKGROUND

This document provides recommendations for sponsors of investigational new drug applications (INDs) and biologics license applications (BLAs) under 42 U.S.C. § 262 and 21 CFR Parts 312 and 601 on the use of pharmacokinetic (PK)-based criteria to support the approval of alternative dosing regimens for programmed cell death receptor-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) blocking antibodies. This guidance is based on accumulated scientific and regulatory experience for PD-1 and PD-L1 drugs, and as such, does not address development of alternative dosing regimens for other  drugs or biologics, changes in route of administration, or novel formulations of previously-approved PD-1/PD-L1 products.

一、引言和背景

本文件为根据 42 U.S.C. § 262 和 21 CFR Parts 312 和 601 关于使用基于药代动力学 (PK) 的标准来支持批准程序性细胞死亡受体 1 (PD-1) 或程序性细胞死亡配体 1 (PD- L1) 阻断抗体。 本指南基于 PD-1 和 PD-L1 药物积累的科学和监管经验，因此，不涉及其他药物或生物制剂的替代给药方案的开发、给药途径的改变或先前- 批准的 PD-1/PD-L1 产品。

PD-1 and PD-L1 blocking antibody products have been developed for various cancer indications. These antibodies are usually administered intravenously. Sponsors may seek approval of alternative intravenous (IV) dosing regimens that are different from those tested in clinical efficacy and safety trials. These alternative IV dosing regimens are typically designed to change doses (e.g., body weight adjusted doses to flat doses) and/or dosing intervals (e.g., once every 3 weeks to once every 6 weeks). Longer dosing interval periods can minimize patient burden and reduce risks associated with more frequent administration (e.g., infusion reactions), as well as exposure to communicable diseases (e.g., SARS-CoV-2) associated with visits to hospitals or infusion centers. This guidance provides a PK-based approach to support approval of alternative  dosing regimens for intravenously administered PD-1/PD-L1 blocking antibody products.

PD-1 和 PD-L1 阻断抗体产品已开发用于各种癌症适应症。 这些抗体通常静脉内给药。 申办者可能会寻求批准与临床疗效和安全性试验中研究的方案不同的替代静脉 (IV) 给药方案。 这些替代的 IV 给药方案通常设计为改变剂量（例如，体重调整剂量为固定剂量）和/或给药间隔（例如，每 3 周一次到每 6 周一次）。 更长的给药间隔期可以最大限度地减少患者负担并降低与更频繁给药（例如，输液反应）相关的风险，以及与医院访视或输液中心相关的传染病（例如，SARS-CoV-2）的风险。 该指南提供了一种基于 PK 的方法，以支持批准静脉内给药的 PD-1/PD-L1 阻断抗体产品的替代给药方案。

The contents of this guidance do not have the force and effect of law and are not meant to bind  the public in any way, unless specifically incorporated into a contract. This document is intended only to provide clarity to the public regarding existing requirements under the law. FDA  guidance documents, including this guidance, should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

本指南的内容不具有法律效力，不以任何方式对公众具有约束力，除非明确纳入合同。 本文件仅旨在向公众澄清法律规定的现有要求。 FDA 指南文件，包括本指南，应仅被视为建议，除非引用了特定的监管或法定要求。 机构指南中使用“应该”一词意味着建议或推荐某事，但不是必需的。

II. PK-BASED APPROACH

A PK-based approach relying on population-PK (Pop-PK) modeling and simulation can be applied to support the approval of alternative dosing regimens for a PD-1 or PD-L1 blocking antibody that is already approved based on clinical efficacy and safety trials. The Pop-PK model  should be established with sufficient PK data from all indicated patient populations over a wide range of dosing regimens (i.e., different from the alternative dosing regimens). The model itself should be well validated and determined to be fit for the purpose. Refer to the FDA Pop-PK draft guidance for recommendations about Pop-PK models.2 Simulation can be performed to derive the PK profiles and parameters following the alternative dosing regimens.

An application for an alternative dosing regimen of a PD-1 or PD-L1 blocking antibody based on modeling and simulation should have the following features:

· The reference dosing regimen used for the comparison is the one used to establish efficacy in clinical trials.

· Both average AUC and Ctrough following the alternative dosing regimen at steady state and/or in the first dosing cycle are no more than 20% lower compared to those of the reference dosing regimen.

· Average steady state Cmax following the alternative dosing regimen does not increase more than 20% compared to that of the reference dosing regimen unless there is adequate clinical evidence that the average steady state Cmax for the new regimen is unlikely to be associated with an unacceptable safety profile (e.g., safety already demonstrated at higher doses; flat or shallow exposure (dose)-safety relationship).

If the features described above are not present, additional clinical data to support the efficacy and safety with the new regimen may be needed. The nature of such clinical data may depend on the  specific product under development, patient population and pre-existing clinical and clinical pharmacology data. The sponsor should discuss alternative pathways of development with the appropriate review division.

二、基于PK的方法

可以应用依赖于群体 PK (Pop-PK) 建模和模拟的基于 PK 的方法来支持批准已根据临床疗效和安全性批准的 PD-1 或 PD-L1 阻断抗体的替代给药方案试验。Pop-PK 模型应使用来自所有指定患者人群的足够 PK 数据在广泛的给药方案（即不同于替代给药方案）的情况下建立。模型本身应该经过充分验证并确定适合该目的。有关 Pop-PK 模型的建议，请参阅 FDA Pop-PK 指南草案。可以执行模拟以得出替代给药方案后的 PK 曲线和参数。

基于建模和模拟的 PD-1 或 PD-L1 阻断抗体的替代给药方案的应用程序应具有以下特征：

· 用于比较的参考给药方案是用于确定临床试验疗效的方案。

· 在稳态和/或第一个给药周期中，替代给药方案后的平均 AUC 和 Ctrough 与参考给药方案相比均低不超过 20%。

· 与参考给药方案相比，替代给药方案后的平均稳态 Cmax 增加不超过 20%，除非有足够的临床证据表明新方案的平均稳态 Cmax 不太可能与不可接受的安全性相关概况（例如，在较高剂量下已经证明安全性；平坦或浅暴露（剂量）-安全关系）。

如果上述特征不存在，则可能需要额外的临床数据来支持新方案的有效性和安全性。此类临床数据的性质可能取决于正在开发的特定产品、患者群体以及预先存在的临床和临床药理学数据。申办者应与适当的审查部门讨论替代的发展途径。

III. REGULATORY INTERACTION AND SUBMISSION

A sponsor who plans to apply the PK-based criteria to support an alternative dosing regimen is encouraged to interact with Agency early in the development program. The sponsor can seek regulatory input through regular IND meetings. If a more detailed discussion on modeling and simulation strategies is necessary, the sponsor may request specific meetings through the model-informed drug development (MIDD) paired meeting pilot program. To facilitate the discussion, the sponsor should include the following information in the meeting package:

· Background information for the product including all supporting data (such as receptor occupancy status, response biomarkers, etc.) to support the intended change in the dosing regimens, and summary of the planned strategies and approaches.

· Summary information for the exposure-response relationships for safety and efficacy, and the population PK model building, validation, and performance.

· Simulation strategy and plan.

· Specific questions related to the modeling and simulation strategy.

The following documents are expected in BLA or supplemental BLA submissions seeking approval for alternative dosing regimens:

· A summary document illustrating the objectives of the submission, proposed changes in the label, relevant information on exposure-response relationship for target engagement (if available), efficacy and safety, summary of findings, and links to the relevant reports and supporting documents.

· A population PK report that includes the up-to-date model which is built upon all available PK data in all indicated patient populations over all available dosing regimens. The report should provide adequate information on model validation and performance check in different indicated patient populations and dosing levels.

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· A PK study report, if applicable, summarizing the observed PK findings of the reference  dosing regimen.

· A simulation report that provides the simulation strategy and outcomes related to the alternative dosing regimens. A direct comparison of PK profiles and parameters from alternative and reference dosing regimens should also be provided.

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· Supporting documents in the appropriate format, including original data, relevant codes, and modeling and simulation outcomes.

Please refer to the Draft Guidance for Industry Population Pharmacokinetics (July 2019) regarding the format, content, and location of each document.

三、监管互动和提交

鼓励计划应用基于 PK 的标准来支持替代给药方案的申办者在开发计划的早期与机构进行互动。申办者可以通过定期的 IND 会议寻求监管意见。如果需要对建模和模拟策略进行更详细的讨论，申办者可以通过模型知情药物开发 (MIDD) 配对会议试点计划请求特定会议。为方便讨论，申办方应在会议资料中包含以下信息：

· 产品的背景信息，包括所有支持数据（如受体占用状态、反应生物标志物等），以支持给药方案的预期变化，以及计划策略和方法的总结。

· 有关安全性和有效性的暴露-反应关系以及群体 PK 模型构建、验证和性能的汇总信息。

· 模拟策略和计划。

· 与建模和仿真策略相关的具体问题。寻求批准替代给药方案的 BLA 或补充 BLA 提交中需要以下文件：

· 说明提交目标的摘要文件、标签中的拟议更改、目标参与的暴露-反应关系的相关信息（如果有）、有效性和安全性、发现摘要以及相关报告和支持文件的链接。

· 包含最新模型的群体 PK 报告，该模型基于所有可用给药方案的所有指定患者群体的所有可用 PK 数据。该报告应提供有关不同指定患者人群和剂量水平的模型验证和性能检查的足够信息。

· PK 研究报告，如果适用，总结参考给药方案的观察到的 PK 结果。

· 提供与替代给药方案相关的模拟策略和结果的模拟报告。还应提供替代和参考给药方案的 PK 曲线和参数的直接比较。

· 适当格式的支持文件，包括原始数据、相关代码以及建模和模拟结果。

有关每个文件的格式、内容和位置，请参阅行业人群药代动力学指南草案（2019 年 7 月）。

2021年8月24日，科临达康医药生物科技（北京）有限公司（以下简称'科临达康’）的合作伙伴恩康药业科技（广州）有限公司（以下简称'恩康药业’）传来好消息：恩康药业交由科临达康中美双报团队通力合作完成的EN002项目获得临床试验默示许可。EN002为全球新分子实体1类创新药，用于治疗非黑色素瘤皮肤癌及癌前病变。

科临达康中美双报团队始终贯彻早期介入、客户第一的价值观，秉承将客户变成全球创新药研发的领跑者的服务宗旨，在临床前实验阶段介入到IND的准备、设计和策略的制定过程中。本项目48个工作日获得批准。

在IND资料撰写的整个过程中，科临达康与恩康药业团队保持高频高效沟通，提高抗肿瘤创新药上市的成功率，缩短上市的时间，科临达康采用独家创新药决策系统，在符合国家局及ICH的要求的前提下，设计撰写出时间短、质量高、成功率大的最适合的临床试验方案。

临床试验默示许可，仅仅是新药开发在临床上的开始，科临达康将与合作伙伴恩康药业一路前行，全力以赴支持恩康药业，通力合作，最终实现EN002早日上市，造福肿瘤患者。科临达康不忘以患者为中心，科学临床达到人类健康的初心，牢记研发出治愈肿瘤等重大疾病新药的使命，砥砺前行！