关于IMDRF医疗器械临床评价工作组延续项目“上市后临床随访研究”成果文件草案公开征求意见的通知

 

各有关单位：
　　由中国药监部门牵头的IMDRF医疗器械临床评价工作组（以下简称“IMDRF工作组”）延续项目“上市后临床随访研究”成果文件草案,于2020年9月在线上召开的国际医疗器械监管机构论坛第18次IMDRF管委会会议上经各成员国一致同意，现已进入全球征求意见阶段。
　　2019年9月IMDRF工作组延续项目“上市后临床随访研究”在第16次IMDRF管委会会议被批准立项，对原GHTF指南文件进行更新。器审中心高度重视，组织成立中国研究组，纳入来自器审中心、行业协会、企业等的代表，收集和整理IMDRF成员国相关法规和技术文件，形成“上市后临床随访研究”和“真实世界临床经验数据”等综述文件并起草形成《上市后临床随访研究（讨论稿）》。在此基础上，器审中心组织IMDRF工作组召开了11次电话会议，进行了3轮讨论，共解决了工作组成员提出的360余条意见和建议。2020年8月，《上市后临床随访研究（征求意见稿）》正式递交至IMDRF管委会。
　　《上市后临床随访研究（征求意见稿）》已于2020年10月11日在IMDRF官方网站发布，面向全球医疗器械监管机构与产业利益相关方公开征求意见，为期2个月。
　　为推动中国医疗器械监管机构与产业利益相关方参与国际协调文件的制定过程，提出客观准确的意见，器审中心对成果文件草案进行翻译，形成中英文对照版本（见附件）。如有相关意见和建议，请按照IMDRF官方网站（http://www.imdrf.org/consultations/cons-mdce-pmcfus.asp）发布的征求意见要求，于2020年12月11日前将反馈意见（以英文书写）发送至liuyh@cmde.org.cn.

　　附件：1.Post-Market Clinical Follow-Up Studies（Proposed Document）（下载）
　　　　　2.医疗器械上市后临床随访研究（征求意见稿）中英文对照版（下载）
　　　　　3.医疗器械上市后临床随访研究（征求意见稿）反馈意见表（下载）

 

国家药品监督管理局
医疗器械技术审评中心
2020年10月21日

 

医疗器械上市后临床随访研究（征求意见稿）中英文对照版

 

Preface

前言

The document herein was produced by the International Medical Device Regulators Forum (IMDRF), a voluntary group of medical device regulators from around the world. The document has been subject to consultation throughout its development.

本文件由国际医疗器械监管机构论坛（IMDRF）制定，此论坛是一个由世界各地的医疗器械监管者参与的非官方性组织。

There are no restrictions on the reproduction, distribution or use of this document; however, incorporation of this document, in part or in whole, into any other document, or its translation into languages other than English, does not convey or represent an endorsement of any kind by the International Medical Device Regulators Forum.

对本文件的复制、分发和使用没有限制，但是，在任何其它文件中部分或全部采用本文件或翻译成除英语以外的语言时，并不表明或代表已得到国际医疗器械监管机构论坛的任何性质的批准。

 

1.0 Introduction

1.0引言

While clinical evidence is an essential element of the premarket conformity assessment process to demonstrate conformity to Essential Principles, it is important to recognise that there may be limitations in the clinical data available in the premarket phase. Such limitations may be due to, for example, the duration of premarket clinical investigations, the number of subjects and the study sites involved in an investigation, the relative homogeneity of subjects and investigators and the control of variables in the setting of a clinical investigation versus use in the full range of conditions encountered in routine use. Also, for some devices based on scientifically well-established technologies, it may be important to recognise that there may be limitations in the applicability of clinical data from comparable devices to the device in question.

临床证据是上市前符合性评价过程的一个基本要素，以证明与安全有效基本原则的符合性。然而需认识到上市前阶段可获得的临床数据可能存在局限性。这些局限性可能包括但不限于：上市前临床试验的时间，临床试验涉及的受试者数量和试验机构，受试者和研究者的相对同质性，以及临床试验场景中各变量的控制与在常规使用中遇到的各种情形。此外，对于那些技术已经得到公认的器械，应认识到将对比器械临床数据用于待评价器械，其适用性可能存在局限性。

It is appropriate to place a product on the market once conformity to the relevant Essential Principles, including a favorable risk/benefit ratio, has been demonstrated. Complete characterization of all risks and potential benefits may not always be possible or practicable in the premarket phase. Therefore, there may be uncertainties (such as rare adverse events, potential benefits, long-term safety, clinical performance and/or effectiveness,) that should be addressed in the post-market phase using one or more systematic post-market clinical follow-up (PMCF) studies. PMCF studies are not intended to replace the premarket data necessary for market authorization.

当产品符合相关的安全有效基本原则时，包括可接受的风险/受益比，产品即可上市。在上市前阶段完整表征产品所有的风险和潜在受益也许不可行或不现实。因此，开展一个或多个系统的上市后临床随访(PMCF)研究可以解决一些需要在上市后阶段解决的不确定性(如罕见的不良事件、潜在受益、长期安全性、临床性能和/或有效性)。PMCF研究不能取代产品上市审批时所需的临床数据。

PMCF studies are one of several options available in a post-market surveillance program and contribute to the risk management process.

PMCF研究是上市后监测项目的可用选项之一，其结果有助于风险管理过程。

 

2.0 Scope

2.0 范围

This document is intended to provide guidance on the design, implementation and appropriate use of PMCF studies.

本文件旨在为PMCF研究的设计、实施和适当使用提供指导。

This document provides guidance in relation to:

本文件提供以下方面的指导:

i)          the circumstances where a PMCF study is indicated;

i）    可能需要开展PMCF研究的情形;

ii)         the general principles of PMCF studies involving medical devices;

ii）    医疗器械PMCF研究的一般原则;

iii)        the design and implementation of PMCF studies; and

iii）  PMCF研究的设计和实施;和

iv)        the use of information from PMCF studies

iv）  PMCF研究结果的使用

 

For clinical evaluation for the purposes of regulatory decision, refer to IMDRF MDCE WG/ N55FINAL:2019 Clinical Evidence – Key definitions and Concepts, IMDRF MDCE WG/N56FINAL:2019 Clinical Evaluation, IMDRF MDCE WG/N57FINAL:2019Clinical Investigation.

以监管决策为目的的临床评价，请参阅IMDRF MDCE WG/ N55:2019临床证据-关键定义和概念、IMDRF MDCE WG/N56:2019临床评价、IMDRF MDCE WG/N57:2019临床试验。

This document does not apply to in vitro diagnostic devices.

本文件不适用于体外诊断器械。

 

3.0 References

3.0 参考文献

IMDRF Documents:       

IMDRF文件：

IMDRF GRRP WG/N47 FINAL: 2018     Essential Principles of Safety & Performance of Medical Devices and IVD Medical Devices

IMDRF GRRP WG/N47:2018  医疗器械和IVD的安全和性能基本原则

 

IMDRF MDCE WG/ N55FINAL:2019 Clinical Evidence – Key definitions and Concepts

IMDRF MDCE WG/ N55:2019  临床证据-关键定义和概念

 

IMDRF MDCE WG/N56FINAL:2019 Clinical Evaluation

IMDRF MDCE WG/N56:2019 临床评价

 

IMDRF MDCE WG/N57FINAL:2019 Clinical Investigation

IMDRF MDCE WG/N57:2019 临床试验

 

IMDRF Registry WG/N33FINAL:2016 Principles of International System of Registries Linked to Other Data Sources and Tools

IMDRF登记工作组/N33:2016  与其他数据源和工具链接的国际登记数据系统的基本原则

 

IMDRF Registry WG/N42FINAL:2017 Methodological Principles in the Use of International Medical Device Registry Data

IMDRF登记工作组/N42:2017  国际医疗器械登记数据使用的方法学原则

 

IMDRF Registry WG/N46 FINAL: 2018 Tools for Assessing the Usability of Registries in Support of Regulatory Decision-Making

IMDRF登记工作组/N46 : 2018  用于监管决策中评价登记数据可用性的工具

 

GHTF Documents:

GHTF文件：

SG1/N065:2010        Registration of Manufacturers and Other Parties and Listing of Medical Devices

SG1/ N065:2010     医疗器械制造商和其他相关方的登记和医疗器械列表

 

SG1/N44:2008          The Role of Standards in the Assessment of Medical Devices

SG1/ N44:2008       标准在医疗器械评价中的作用

 

International Standards:      

国际标准：

ISO 14155: 2020     Clinical investigation of medical devices for human subjects, Good clinical practice

ISO 14155: 2020     医疗器械临床试验质量管理规范

 

ISO 14971: 2019     Medical devices -Application of risk management to medical devices

ISO 14971: 2019     医疗器械-医疗器械风险管理的应用

 

 

Others:

其它                         

Agency for Healthcare Research and Quality Registries for Evaluating Patient Outcomes: A User’s Guide

卫生健康研究与质量管理机构：评价患者结局的注册登记库使用者指南

4.0 Definitions

4.0 定义

Clinical data: Safety, clinical performance and/or effectiveness information that is generated from the clinical use of a medical device.

临床数据:由医疗器械的临床使用而产生的安全性、临床性能和/或有效性信息。

 

Clinical evaluation: A set of ongoing activities that use scientifically sound methods for the assessment and analysis of clinical data to verify the safety, clinical performance and/or effectiveness of the medical device when used as intended by the manufacturer.

临床评价：一组持续进行的活动，使用科学可靠的方法对临床数据进行评价和分析，以验证医疗器械在按照生产商的预期使用时的安全性、临床性能和/或有效性。

 

Clinical evidence: The clinical data and its evaluation pertaining to a medical device.

临床证据：与医疗器械有关的临床数据及其评价。

 

Clinical investigation: Any systematic investigation or study in or on one or more human subjects, undertaken to assess the safety, clinical performance and/or effectiveness of a medical device.

临床试验：，在一个或多个受试者中进行医疗器械的安全性、临床性能和/或有效性的评价的、系统的试验或研究。

 

Post-market clinical follow-up study: A study carried out following marketing authorization intended to answer specific questions (uncertainties) relating to safety, clinical performance and/or effectiveness of a device when used in accordance with its approved labelling.

上市后临床随访研究：产品上市批准后进行的研究，旨在回答按照批准范围使用的器械在安全性、临床性能和/或有效性方面的具体问题(不确定性)。

 

5.0 Circumstances Where a PMCF Study May Be Indicated

5.0可能需要开展PMCF研究的情行

When considering the overall benefit-risk profile of a device for market authorization, uncertainties may remain regarding the extent of potential benefits and residual risks of the device. PMCF studies can be used to collect additional clinical data to address the remaining uncertainties about a device.

器械上市批准时进行整体受益-风险时，该器械的潜在受益和剩余风险的程度可能存在不确定性。PMCF研究可用于收集更多的临床数据，以解决器械的存在的不确定性。

In some jurisdictions, PMCF studies may also be appropriate to address new concerns arising from post-market adverse event trends, information from the literature, signals from adverse event reports, active surveillance program or other sources.

在某些监管区域，PMCF研究也用于解决上市后不良事件趋势、文献信息、来自不良事件报告提示信息、主动监测项目或其他来源提出的新问题。

Uncertainties in the benefit-risk profile of a device are more likely to exist when dealing with the following:

在以下情形时，器械的受益-风险更可能存在不确定性:

·           Unanswered questions of long-term safety, and clinical performanceand/or effectiveness. Long-term safety, clinical performance and/or effectiveness of a specific aspect of a device may be difficult to assess in a premarket study as it may be necessary to collect data over several years in order to fully establish the long-term safety, clinical performance and/or effectiveness of the device.

·           上市前评价未解决的长期安全、临床性能和/或有效性问题。器械特定方面的长期安全、临床性能和/或有效性可能难以在上市前研究时进行评价，为了充分建立器械长期安全、临床性能和/或有效性,可能需要收集若干年的数据。

Additionally, unanswered questions about long-term safety, clinical performance and/or effectiveness of the device may arise from other information, such as:

此外，器械长期安全性、临床性能和/或有效性的未解答的问题可能来自其他信息，例如:

-        results of existing clinical investigations;

-   现有临床试验结果；

-        adverse events identified from post-market surveillance activities;

-   上市后监测活动的不良事件；

-        interaction with other medical products or treatments;

-   与其他医疗产品或治疗方法的相互作用；

·           Novel technologies or new intended use. New technological characteristics, e.g., the design, the materials, the principles of operation are novel; or extending/expanding intended use of existing technologies, e.g., new indication or new patient population;

·           新技术及新适用范围。新技术特点，如新设计、材料、作用原理；或扩展/扩大现有技术的预期用途，如新适应症或新患者群体；

·           Higher-risk device and use scenarios. Higher risk anatomical locations; or higher severity of disease/treatment challenges;

·           高风险器械和使用场景。高风险解剖部位；或严重程度更高的疾病/治疗挑战;

·           Uncertainties in generalizing clinical investigation results; Generalizing results from study populations to other populations, e.g. from adults to children, from an ethnicity to others. Generalizing results from other jurisdictions to intended jurisdictions.

·           将临床试验结果进行外推时存在的不确定性；将试验结果从试验人群推广到其他人群，例如从成人推广到儿童，从一个种族推广到其他种族。将其它监管区域的试验结果推广到拟申报的监管区域。

·           Devices approved with clinical data from comparable devices. For devices based on scientifically well-established technologies that have been approved with clinical data from comparable devices and/or preclinical data, it may be appropriate for some of the clinical data collection to occur post-market.

·           基于对比器械临床数据批准的产品。对于技术已经得到公认的器械，若基于对比器械的临床数据和/或临床前数据，获得上市批准，其中一些临床数据可能需要在上市后收集临床数据。

·           Emergence of new information relating to safety, clinical performanceand/or effectiveness. When unexpected or unexplained serious adverse events occur after a device is marketed, or if there is a change in the nature (e.g., severity) or an increase in the frequency of expected serious adverse events, PMCF studies may be conducted to evaluate the potential association of the safety signal and the device. 

·           新出现的安全性、临床性能和/或有效性信息。当器械上市后发生非预期的或难以解释的严重不良事件，或者预期严重不良事件的性质（例如，严重程度）或发生频率升高，PMCF研究可以评价器械和安全性信号的潜在关联。

·           Urgent market access in public health emergencies. In event of public health emergencies (e.g., a pandemic), considerations of benefit-risk profiles of some devices may be different. Expedited market access may be granted with some data generation to occur post-market. 

·           公共卫生相关事件中的紧急获得。发生公共卫生紧急事件（例如，大流行）时，对某些器械的受益-风险的考虑可能不同。授予产品加快上市，某些数据可在上市后获得。

·           Rare anticipated adverse events. Rare anticipated adverse events (e.g. stent thrombosis of the coronary stent) may be difficult to assess in a premarket study but could potentially be identified using large datasets; therefore, it may be necessary to assess the rare adverse events as part of a PMCF plan;

·           罕见预期不良事件。罕见预期不良事件(例如冠状动脉支架血栓形成)可能难以在上市前进行评价，但可通过大数据进行识别；因此，可能需要在PMCF计划中评价罕见不良事件；

·           Effectiveness for a known risk. Mitigations may be necessary for known safety risks associated with the use of the device. Confirmation of the adequacy of the mitigation may be evaluated post-market.

·           风险控制措施的效果评价。对于与使用该器械相关的已知安全风险，可能需要采取控制措施。可上市后评价控制措施是否充分。

 

PMCF studies may not be necessary in cases where the medium/long-term safety, clinical performance and/or effectiveness are already known from previous use of the device or where other appropriate post-market surveillance activities would provide sufficient data to address the uncertainties.

如果已知该器械的中长期安全性、临床性能和/或有效性，或可通过其他合适的上市后监测活动提供足够的数据来解决这些不确定性，则可能没有必要进行PMCF研究。

 

6.0 Elements of a PMCF Study

6.0  PMCF研究要素

PMCF studies are performed on a device within its intended use/purpose(s) according to the instructions for use. It is important to note that PMCF studies must be conducted according to applicable laws and regulations, ethical requirements and should follow appropriate guidance and standards.

PMCF研究需基于产品的预期用途和使用说明开展临床试验。需要注意的是，PMCF研究必须符合适用的法律和法规、伦理要求，并应遵循适用的指导和标准。

The elements of a PMCF study should include:

PMCF研究的要素应包括:



Ÿ  Clearly stated objective(s);

Ÿ  明确的目标;

Ÿ  Scientifically sound study design with an appropriate rationale and statistical analysis methods summarized in a study plan;

Ÿ  科学合理的设计依据和统计分析方法应在研究设计中概述；

Ÿ Implementation of the study according to the plan, an interpretation of the results and appropriate conclusion(s).

Ÿ  根据计划开展研究，解释结果并得出恰当的结论。

 

6.1 The Objective(s) of PMCF Studies

6.1 PMCF研究的目的

The objective(s) of the study should be stated clearly and should address one or more remaining or newly developed uncertainties related to the safety, and clinical performance and/or effectiveness of the device. A formal hypothesis should be clearly expressed, with the acknowledgement that formal statistical hypothesis testing may not be necessary in some circumstances, e.g. descriptive studies.

PMCF研究应明确其研究目的，并应解决与该器械的安全性、临床性能和/或有效性相关的一个或多个已知的或新出现的不确定因素。研究假设应清晰描述在某些情况下，例如描述性研究，正式的统计假设可能是不必要的。

 

6.2 The Design of PMCF Studies

6.2 PMCF研究设计

The study should be designed to address the objective(s) of the study. The PMCF study can take several forms, for example:

研究设计应解决研究目的相关的问题，PMCF研究可采取几种形式，如：

·         the extended follow-up of patients enrolled in premarket investigations;

·         上市前临床试验纳入患者的继续随访；

·         a new post-market clinical investigation;

·         开展新的上市后临床试验；

·         a review of data derived from a device registry; or

·         器械登记数据库中的数据回顾；或

·         a review of relevant retrospective data from patients previously exposed to the device.

·         过去使用过该器械患者的回顾性数据

For additional information on the design of clinical investigations, refer to IMDRF MDCE WG/N57FINAL:2019: Clinical Investigation. After a device has obtained market authorization, there may be more opportunities to address device safety, clinical performance and/or effectiveness questions using clinical experience data^[1] collected or generated from routine use under ordinary care, with appropriate study designs. Examples of clinical experience data sources for PMCF studies are described inAppendix A (informative).

有关临床试验设计更多信息，请参阅IMDRF MDCE WG / N57：2019：临床试验。产品上市后，通过恰当的研究设计使用在常规临床实践中收集或产生的临床经验数据可能会有更多机会来回答器械安全性、临床性能和/或有效性问题。附录A（资料性）提供了PMCF研究临床经验数据来源举例。

 

An appropriate study design should be scientifically sound to allow for valid conclusions to be drawn. Several factors should be considered during the design of the study, for example:

适当的研究设计应科学合理，以便得出有效的结论。研究设计应考虑几个因素，例如：

·           Study setting should be clearly described, including the locations and selection of sites and investigators;

·           明确描述研究场景，包括地点、研究者和临床研究机构的选择；

·           Study population should be clearly targeted by providing inclusion and exclusion criteria, and the sources and methods for the selection of subjects;

·           通过明确纳入和排除标准、受试者来源和选择方法，明确界定研究人群；

·           The control/comparison groups (if any) should be clearly defined and justified;

·           对照/比较组（如有）应明确定义并说明其合理性；

·           Sample size should be clearly stated and justified, if applicable;

·           明确样本量并说明其合理性（如果适用）；

·           All variables/indicators/measures should be clearly defined, including outcomes/endpoints, adverse events, risk factors, confounding factors, and effect modifiers. For some PMCF studies, data are obtained from routine use in clinical practice. The sources of data and methods of assessment should be provided. Considerations for using clinical experience data for a PMCF study are described in Appendix B (informative);

·           明确定义所有变量/指标/测量方法，包括临床结局/终点指标、不良事件、风险因素、混杂因素和效应修饰因子。对于某些PMCF研究，数据是在常规临床实践中获得的。应明确数据来源和评价方法。附录B（资料性）将临床经验数据用于PMCF研究的考虑要素；

·           The duration of patient follow-up

·           受试者随访时间

·           Potential sources of bias should be identified and evaluated; and related control methods should be discussed (potential biases in PMCF studies and controlling methods are described in Appendix C (informative)).

·           识别和评价潜在的偏倚源，并讨论相关的控制方法（PMCF研究中的偏倚及其控制方法描述见附录C（资料性））。

·           Statistical analysis methods should be clearly described. Appropriate statistical methods should be considered to examine impact of potential factors, such as confounding factors, effect modification, or missing data, on the analysis results.

·           明确统计分析方法。应考虑采用适当的统计方法以检测潜在对分析结果的影响因素（例如混杂因素、效应修饰因子或数据缺失）对分析结果的影响。

 

For PMCF studies that involve a treatment assignment, including randomization, the approach and procedures used for assigning treatment should be clearly described. If a case-control or cohort design is used, the exposure classification, choice of cases and controls including matching ratio, as applicable, should be described.

对于治疗分配（包括随机分配）的PMCF研究，应明确描述用于分配治疗的方法和程序。如果使用病例对照或队列设计，应描述暴露分类、病例和对照的选择，包括匹配比率（如适用）。

 

6.3 The Implementation of PMCF Studies

6.3 PMCF研究的实施

The study should be executed according to the study plan, and the collected data should be analysed and interpreted to draw the conclusion.

应根据研究计划开展研究，收集的数据应进行分析和解释以得出结论。

 

Some factors should be considered during the implementation of the study, for example:

在开展研究过程中应考虑一些因素，例如：

·           Data collection: validated measurement methods/instruments should be utilized, and heterogeneity of data should be considered and controlled;

·           数据收集：应使用经过验证的测量方法/工具，并考虑和控制数据的异质性；

·           Quality control: investigator selection, training, inspection and supervision of the study should be performed to ensure quality;

·           质量控制：应进行研究者选择、培训、研究的监查和核查应确保质量；

·           Results reporting and interpretation: a study report should be developed to demonstrate if conclusions relate back to original objective(s) and hypothesis/hypotheses.

·           结果报告和解释：应论证撰写研究报告以证明假设是否达到研究目的。

 

7.0 The Use of Information from PMCF Studies

7.0 PMCF研究信息的使用

 

The data and conclusions derived from the PMCF studies are part of the post-market surveillance program and used as input to the clinical evaluation and risk management process. This may result in the need to reassess whether the device continues to comply with the Essential Principles. Such assessment may result in corrective or preventive actions, for example：

来自PMCF研究的数据和结论是上市后监测的一部分，并用于临床评价和风险管理过程的输入。其可能导致器械是否仍然符合安全有效基本原则的重新评估，可能会导致纠正或预防措施，例如：

·           changes to the labelling/instructions for use,

·           更改标签/使用说明书

·           changes to manufacturing processes,

·           变更生产过程

·           changes to the device design,

·           变更器械设计

·           public health notifications, or

·           公共卫生通告，或

·           product removal.

·           产品退市

 

In addition, clinical data/evidence generated from PMCF studies can be used to:

此外，由PMCF研究产生的临床数据/证据可用于：

·           become the part of premarket clinical evidence when applying for marketing authorization in other jurisdictions.

·           在其他监管区域申请上市时，成为上市前临床证据的一部分。

·           derive objective performance criteria and performance goals;

·           形成客观性能标准和性能目标；

·           form control/comparison groups;

·           作为对照/比较组

·           serve as supplementary data supporting marketing authorization of next-generation or similar technologies.

作为补充数据，支持新一代或类似技术的上市。 

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[1] In some jurisdictions, clinical experience data relating to patient health status and/or the delivery of health care under routine use is described in the term of “real-world data” (RWD),which can be collected from a variety of sources.

在某些监管区域，与患者健康状况和/或常规使用情况下的医疗服务相关的临床经验数据也可描述为“真实世界数据”（RWD）描述，该类数据可从多种来源收集。