Regulatory Express_Q2 2019

1.      The Use of Real World Evidence in Recent FDA and EMA Approvals

真实世界证据的使用在最近FDA和EMA审评中获批

(FDA May 2019)

Summary:

While debate continues over the acceptability of real-world evidence for regulatory decision making, especially for demonstrating efficacy, there have been several cases in the recent past where RWE has played a "pivotal" role in decisions by the EMA and FDA.

虽然关于监管决策中是否可接受真实世界证据（RWE）的争议仍在继续，尤其是证明有效性的情况，但最近有几个案例表明RWE在EMA和FDA的决策中发挥了“关键作用”。

The EMA has accepted real-world data "where available evidence of efficacy required contextualization" or where uncertainties existed around "long‐term safety and efficacy," three senior officials from the EMA wrote in an article in one of the journals of the American Society for Clinical Pharmacology and Therapeutics (see attached). It said that the EMA had accepted RWE where either there was a need to enable "safe and early access to promising medicines for patients with limited treatment options" or where "uncertainties around the medicines remained."

EMA已经在“可用的有效性证据需要情境化的情况下” 或围绕“长期安全性和有效性”存在不确定性的情况下接受了真实世界的数据，EMA的三名高级官员在一篇发表于“美国临床药理学和治疗学协会”的一本期刊上的文章（见附件）中写道：EMA在需要“为治疗方案有限的患者早日获得安全和有前途的药物”或“药物的不确定性仍然存在”时接受了RWE。

The FDA has recently published a draft guidance to help sponsors provide information to the agency on their use of RWD and RWE in a uniform format.  Relevant submissions may include RWE used to support study objectives, such as: “IND submissions for randomized clinical trials that use RWD to capture clinical outcomes or safety data, including pragmatic and large simple trials; New protocols for single arm trials that use RWE as an external control; Observational studies that generate RWE intended to help to support an efficacy supplement; Clinical trials or observational studies using RWE to fulfill a post marketing requirement to further evaluate safety or effectiveness and support a regulatory decision.”  In the cover letter accompanying a submission, FDA explains how the sponsor or applicant should identify the submission as containing RWE by including the following information: Purpose of using RWE as part of a regulatory submission; study design using RWE; RWD source(s) used to generate RWE.

FDA近日公布了一项 指南草案帮助申办者以统一格式向其提供有关使用真实世界的数据(RWD) 和RWE的资料。相关提交可包括使用RWE支持的研究目标，例如：“使用RWD获得临床结果或安全性数据的随机临床试验的IND提交，包括实用和大型简单试验；使用RWE作为外部对照的单臂试验的新方案；产生RWE的观察性研究旨在帮助支持补充疗效；临床试验或观察性研究使用RWE来满足上市后要求，以进一步评估安全性或有效性并支持监管决策“。在递交材料的附函中，FDA解释了申办者或申请人应如何通过包括以下信息来确认递交资料中包含RWE：使用RWE作为注册递交资料一部分的目的；采用RWE的研究设计；用于生成RWE的RWD源。

EMA Examples:

·        Kite Pharma Inc.'s CAR-T therapy Yescarta (axicabtagene ciloleucel)

RWE was used for a retrospective patient-level pooled analysis of two Phase III randomized control trials (RTCs), and 2 observational studies were developed as a companion study to contextualize the results of an open-label, single arm study.

·        Novartis AG's CAR-T therapy, Kymriah (tisagenlecleucel)

Efficacy results were compared against three external data sets to contextualize the results of a single arm trial.

·        MolMed SPA's somatic cell therapy product Zalmoxis.

A patient registry was used to compile an appropriate control group selected on the same criteria as the control arm of the on-going Phase III trial and a specific set of matching parameters.

EMA示例：

·        Kite Pharma Inc.的CAR-T疗法Yescarta(axicabtagene ciloleucel)

RWE用于2项III期随机对照试验（RTC）的回顾性患者水平汇总分析，以及2项作为伴随研究的观察性研究，作为开放性单臂研究结果的背景信息。

·        诺华公司的CAR-T疗法，Kymriah(tisagenlecleucel)

将有效性结果与三个外部数据集进行比较，作为单臂试验结果的背景。

·        MolMed SPA的体细胞治疗产品Zalmoxis。

使用患者登记，按照与正在进行的III期试验的对照组相同的标准选择适当的对照组和一组特定的匹配参数。

FDA Examples:

·        Pfizer Ibrance

The approval for breast cancer in males was based largely on real-world evidence.  Regulators studied data from electronic health records and post-marketing reports from the IQVIA Insurance database, the Flatiron Health Breast Cancer database and Pfizer's own global safety database.

·        BioMarin Pharmaceutical Inc.’s Brineura (cerliponase alfa)

Approved on the basis of a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort.

·        Amgen Inc.’s Blincyto

The accelerated approval rested on a single arm Phase II trial, the 185-patient Study, and a historical control arm of patients who received the standard of care. 

FDA示例：

·        辉瑞Ibrance

男性乳腺癌适应症的批准主要基于大量的真实世界证据。监管机构研究了来自IQVIA保险数据库，Flatiron health乳腺癌数据库和辉瑞自己的全球安全数据库的电子健康记录和上市后报告的数据。

·        BioMarin Pharmaceutical Inc.的Brineura（cerliponase alfa)

在22名有症状的CLN2疾病儿科患者的非随机单臂剂量递增临床研究的基础上批准，并与来自自然疾病史队列的42名未治疗的CLN2疾病患者进行比较。

·        安进公司的Blincyto

加速批准取决于单臂II期试验，185名患者研究以及接受标准治疗的患者的历史对照组。

Key Takeaways:

·        In 2016, the US 21st Century Cures Act laid the groundwork for greater use of real-world data in drug approvals, these recent approvals show the progress in that area, particularly in rare diseases or novel treatments.

·        A recent analysis by EMA revealed they expect that that the acceptance of RWE is likely to increase with advancements in personalized medicine.

·        EMA experts believe that "compliance with the best methodological standards, a detailed description of study design and data collected, and full transparency on the protocol and study report (with registration in a publicly available database) would do much to build confidence in results and avoid the confusion created by disparate results.”

关键信息：

·        2016年，美国21世纪治愈法案为更多地在药物批准中使用真实世界的数据奠定了基础，这些最近的批准显示了该领域的进展，特别是在罕见疾病或新型治疗方面。

·        EMA最近的一项分析显示，他们预计随着个性化医疗的发展，RWE的接受程度可能会增加。

·        EMA专家认为，“遵守最佳的方法学标准，详细描述研究设计和收集的数据，以及方案和研究报告的完全透明度（在公开可用的数据库中注册）将为建立对结果的信心和避免因不同的结果造成的混乱。“

2.      ICH Plans to Revise ICH E8 on General Considerations for Clinical Trials

ICH计划修订ICH E8“临床试验的一般考虑事项”

(ICH May2019)

Summary:

The International Council for Harmonization has proposed modernizing its July 1997 guideline on general considerations for clinical trials (E8). The proposal also kick-starts the GCP renovation project, which aims to remove inconsistencies in how randomized control trials are conducted.  The ICH's GCP framework - comprising E8 and E6 (Guideline for Good Clinical Practice) – has been criticized by some in industry, who claim it has made randomized control trials complex and costly.

国际协调委员会建议更新1997年7月版的“关于临床试验一般考虑的指南（E8）”。该提案还启动了GCP更新项目，旨在消除随机对照试验进行过程中的不一致性。ICH的GCP框架-包括E8和E6（良好临床实践指南）-受到了一些行业内的批评，他们声称它使随机对照试验变得复杂和昂贵。

E8(R1) is broken down by sections on designing quality into clinical trials, drug development planning, design elements for clinical studies, conduct and reporting and considerations in identifying critical-to-quality factors.  Several of the subsections of the guideline deal with methods to reduce or assess bias, protocol adherence, safety monitoring and the data monitoring committee.

E8（R1）按照临床试验质量设计、药物研发计划、临床研究设计要素、实施和报告以及确定关键质量因素时的考虑等章节进行细分。指南的几个分章节涉及减少或评估偏倚的方法、方案遵守、安全监察和数据监察委员会。

ICH lays out four objectives for the document:

1.      To describe principles and practices related to the design and conduct of clinical studies to ensure data and results are accepted by regulators;

2.      To provide guidance on considering quality in designing and conducting trials, including identifying factors that are critical to quality in the study planning phase and how to manage certain risks;

3.      To provide an overview of the types of studies conducted, as well as to describe how to determine which quality factors can ensure study subject protection, integrity of data, the reliability of results and the ability of studies to meet their objectives;

4.      To provide a guide to the ICH efficacy documents in two annexes.

ICH规定了本文件的四个目标：

1.      描述与临床研究设计和实施相关的原则和实践，以确保数据和结果得到监管机构的接受；

2.      对质量设计的考虑和如何进行试验提供指导，包括在研究计划阶段如何确定质量至关重要的因素以及如何管理该风险；

3.      提供所进行研究类型的概述，以及描述如何确定哪些质量因素能够确保研究受试者的保护、数据的完整性、结果的可靠性以及研究达到其目的的能力；

4.      在两个附件中提供ICH有效性文件的指南。

Key Takeaways:

·        The new E8(R1) guideline aims to review the issues that are most critical to the quality of a clinical trial and its ability to achieve meaningful and reliable results.

·        It incorporates the most current concepts for achieving fit-for-purpose data quality, which ICH says is “one of the essential considerations for all clinical trials.”

·        The guideline provides advice on designing quality into clinical studies and also offers a broad overview of clinical development program planning, the types of studies and study objectives that are important at different points in the program, and issues of study feasibility from the perspective of sponsors, investigators, regulatory authorities and patients.

关键信息：

·        新的E8（R1）指南旨在审查对临床试验质量最关键的问题及其获得有意义和可靠结果的能力。

·        它包含了实现适合目的数据质量的最新概念，ICH认为这是“所有临床试验的基本考虑因素之一”。

·        本指导原则提供了有关临床研究质量设计的建议，并从申办者、研究者、监管机构和患者的角度对临床研发计划、在项目不同节点上重要的研究类型和研究目的以及研究可行性问题进行了广泛的概述。

3.      ICH Releases Draft Guideline on E19 on Optimization of Safety Data Collection.

ICH发布了关于优化安全性数据收集的E19指南草案

(ICH Apr 2019)

Summary:

ICH has released a draft guideline on E19 on optimization of safety data collection.  It is intended to provide harmonized guidance on when it would be appropriate to use a targeted approach to safety data collection in some late-stage pre-marketing or post-marketing studies, and how such an approach would be implemented.  Although safety monitoring of patients during clinical studies remains critically important, unnecessary and burdensome data collection may serve as a disincentive to participation in clinical studies (e.g., frequent and time-consuming patient visits; laboratory tests; and/or physical examinations).  By tailoring safety data collection in some circumstances, the burden to patients would be reduced, a larger number of informative clinical studies could be carried out with greater efficiency, studies could be conducted with greater global participation, and the public health would be better served. The proposed Guideline would be consistent with risk-based approaches and quality-by-design principles.  ICH is targeting to finalize the guideline by June 2021 at which point it would then be up to participating Health Authorities to adopt locally.

ICH发布了E19优化安全数据收集的指南草案。它旨在提供统一的指导，说明何时在一些上市前后期或上市后研究中采用有针对性的方法收集安全性数据，以及如何实施这种方法。虽然在临床研究期间对患者进行安全性监测仍然至关重要，但不必要和繁重的数据收集可能会阻碍患者参与临床研究（例如，频繁且耗时的患者访问；实验室检查；和/或体格检查）。通过在某些情况下定制安全数据收集，将减少患者的负担，可以以更高的效率进行大量的信息性临床研究，可以在更大的全球参与下进行研究，并且更好地服务于公共卫生。建议的指导原则将符合基于风险的方法和质量源于设计的原则。ICH的目标是在2021年6月之前完成指导原则，此时将由作为ICH成员的各卫生当局决定是否在当地采纳实施。

Proposed Types of Safety Data Where It May be Appropriate to Limit or Stop Collection

·        Non-serious adverse events

·        Routine laboratory tests

·        Information on concomitant medications

·        Physical examinations (including vital signs)

·        Electrocardiograms

可能需要限制或停止收集的安全性数据的拟定类型

·        非严重不良事件

·        常规实验室检查

·        合并用药信息

·        体格检查（包括生命体征）

·        心电图

When sponsors choose to implement selective safety data collection for a clinical study, scientific justification should be provided.  Factors that contribute to a determination that selective safety data collection would be appropriate include:

1.      The medicinal product has received marketing authorization from a regulatory authority for the indication under investigation

2.      Availability of post-approval safety data and findings

3.      The dose, dosing regimen, dosage form, route of administration and treatment duration used in the previously conducted studies are comparable to the planned use of the drug in the proposed study

4.      The patient population from previously conducted studies is representative of subjects in the planned study regarding demographic characteristics, underlying medical conditions, concomitant drugs, and other important factors (e.g., Cytochrome P450 enzymes (CYP) metabolizer status)

5.      Exposure in previously conducted (or ongoing, if applicable) studies that contribute to the overall safety database, i.e., number exposure to drug, treatment duration

6.      Consistency of the safety profile across previous studies

7.      Characteristics of previous studies, e.g., study design; study conduct; adequacy of safety monitoring/safety data collection; availability of protocols; statistical analysis plan; and/or access to data

8.      Knowledge of the mechanism of action of the medicinal product under study

9.      Knowledge of the safety profile of approved drugs in the same pharmacologic class

当申办者选择为临床研究收集选择性安全性数据时，应提供科学依据。有助于确定选择性安全性数据收集是否合适的因素包括：

1.      该药品已获得监管机构关于正在研究的适应症的上市许可

2.      上市后安全性数据和发现的可用性

3.      既往研究中使用的剂量，给药方案，剂型，给药途径和治疗持续时间与拟定研究中药物的计划使用相当

4.      既往研究的患者人群可代表拟定研究的受试者人群，包括人口统计学特征，基础医学状况，伴随药物和其他重要因素（例如细胞色素P450酶(CYP)代谢状态）的受试者

5.      对整体安全性数据库有贡献的既往（或正在进行，如适用）研究中的暴露量，即药物暴露次数、治疗持续时间

6.      既往研究中安全性特征的一致性

7.      既往研究的特点，如研究设计；研究实施；安全性监测/安全性数据收集的充分性；方案的可用性；统计分析计划；和/或访问数据

8.      研究中药品的作用机制

9.      同一药理学类别中已批准药物的安全性特征

Key Takeaways:

·        Optimization of safety data collection using a selective approach may improve the efficiency of clinical studies while reducing the burden to study participants.

·        Adoption of an internationally harmonized approach to selective safety data collection may facilitate global participation in clinical studies.

·        Sponsors and investigators should ensure that routine patient care is not compromised by the selective safety data collection approach outlined in this Guideline.

关键信息：

·        使用选择性方法优化安全性数据收集可以提高临床研究的效率，同时减轻研究参与者的负担。

·        采用国际统一的方法收集选择性安全性数据可能有助于全球参与临床研究。

·        申办者和研究者应确保患者的日常医疗不会受到本指导原则中概述的选择性安全性数据收集方法的影响。