關于IMDRF醫療器械臨床評價工作組延續項目“上市后臨床隨訪研究”成果文件草案公開征求意見的通知

 

各有關單位：
　　由中國藥監部門牽頭的IMDRF醫療器械臨床評價工作組（以下簡稱“IMDRF工作組”）延續項目“上市后臨床隨訪研究”成果文件草案,于2020年9月在線上召開的國際醫療器械監管機構論壇第18次IMDRF管委會會議上經各成員國一致同意，現已進入全球征求意見階段。
　　2019年9月IMDRF工作組延續項目“上市后臨床隨訪研究”在第16次IMDRF管委會會議被批準立項，對原GHTF指南文件進行更新。器審中心高度重視，組織成立中國研究組，納入來自器審中心、行業協會、企業等的代表，收集和整理IMDRF成員國相關法規和技術文件，形成“上市后臨床隨訪研究”和“真實世界臨床經驗數據”等綜述文件并起草形成《上市后臨床隨訪研究（討論稿）》。在此基礎上，器審中心組織IMDRF工作組召開了11次電話會議，進行了3輪討論，共解決了工作組成員提出的360余條意見和建議。2020年8月，《上市后臨床隨訪研究（征求意見稿）》正式遞交至IMDRF管委會。
　　《上市后臨床隨訪研究（征求意見稿）》已于2020年10月11日在IMDRF官方網站發布，面向全球醫療器械監管機構與產業利益相關方公開征求意見，為期2個月。
　　為推動中國醫療器械監管機構與產業利益相關方參與國際協調文件的制定過程，提出客觀準確的意見，器審中心對成果文件草案進行翻譯，形成中英文對照版本（見附件）。如有相關意見和建議，請按照IMDRF官方網站（http://www.imdrf.org/consultations/cons-mdce-pmcfus.asp）發布的征求意見要求，于2020年12月11日前將反饋意見（以英文書寫）發送至liuyh@cmde.org.cn.

　　附件：1.Post-Market Clinical Follow-Up Studies（Proposed Document）（下載）
　　　　　2.醫療器械上市后臨床隨訪研究（征求意見稿）中英文對照版（下載）
　　　　　3.醫療器械上市后臨床隨訪研究（征求意見稿）反饋意見表（下載）

 

國家藥品監督管理局
醫療器械技術審評中心
2020年10月21日

 

醫療器械上市后臨床隨訪研究（征求意見稿）中英文對照版

 

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.

本文件由國際醫療器械監管機構論壇（IMDRF）制定，此論壇是一個由世界各地的醫療器械監管者參與的非官方性組織。

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.

對本文件的復制、分發和使用沒有限制，但是，在任何其它文件中部分或全部采用本文件或翻譯成除英語以外的語言時，并不表明或代表已得到國際醫療器械監管機構論壇的任何性質的批準。

 

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.

臨床證據是上市前符合性評價過程的一個基本要素，以證明與安全有效基本原則的符合性。然而需認識到上市前階段可獲得的臨床數據可能存在局限性。這些局限性可能包括但不限于：上市前臨床試驗的時間，臨床試驗涉及的受試者數量和試驗機構，受試者和研究者的相對同質性，以及臨床試驗場景中各變量的控制與在常規使用中遇到的各種情形。此外，對于那些技術已經得到公認的器械，應認識到將對比器械臨床數據用于待評價器械，其適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.

當產品符合相關的安全有效基本原則時，包括可接受的風險/受益比，產品即可上市。在上市前階段完整表征產品所有的風險和潛在受益也許不可行或不現實。因此，開展一個或多個系統的上市后臨床隨訪(PMCF)研究可以解決一些需要在上市后階段解決的不確定性(如罕見的不良事件、潛在受益、長期安全性、臨床性能和/或有效性)。PMCF研究不能取代產品上市審批時所需的臨床數據。

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

PMCF研究是上市后監測項目的可用選項之一，其結果有助于風險管理過程。

 

2.0 Scope

2.0 范圍

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

本文件旨在為PMCF研究的設計、實施和適當使用提供指導。

This document provides guidance in relation to:

本文件提供以下方面的指導:

i)          the circumstances where a PMCF study is indicated;

i）    可能需要開展PMCF研究的情形;

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

ii）    醫療器械PMCF研究的一般原則;

iii)        the design and implementation of PMCF studies; and

iii）  PMCF研究的設計和實施;和

iv)        the use of information from PMCF studies

iv）  PMCF研究結果的使用

 

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.

以監管決策為目的的臨床評價，請參閱IMDRF MDCE WG/ N55:2019臨床證據-關鍵定義和概念、IMDRF MDCE WG/N56:2019臨床評價、IMDRF MDCE WG/N57:2019臨床試驗。

This document does not apply to in vitro diagnostic devices.

本文件不適用于體外診斷器械。

 

3.0 References

3.0 參考文獻

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  醫療器械和IVD的安全和性能基本原則

 

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

IMDRF MDCE WG/ N55:2019  臨床證據-關鍵定義和概念

 

IMDRF MDCE WG/N56FINAL:2019 Clinical Evaluation

IMDRF MDCE WG/N56:2019 臨床評價

 

IMDRF MDCE WG/N57FINAL:2019 Clinical Investigation

IMDRF MDCE WG/N57:2019 臨床試驗

 

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

IMDRF登記工作組/N33:2016  與其他數據源和工具鏈接的國際登記數據系統的基本原則

 

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

IMDRF登記工作組/N42:2017  國際醫療器械登記數據使用的方法學原則

 

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

IMDRF登記工作組/N46 : 2018  用于監管決策中評價登記數據可用性的工具

 

GHTF Documents:

GHTF文件：

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

SG1/ N065:2010     醫療器械制造商和其他相關方的登記和醫療器械列表

 

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

SG1/ N44:2008       標準在醫療器械評價中的作用

 

International Standards:      

國際標準：

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

ISO 14155: 2020     醫療器械臨床試驗質量管理規范

 

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

ISO 14971: 2019     醫療器械-醫療器械風險管理的應用

 

 

Others:

其它                         

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

衛生健康研究與質量管理機構：評價患者結局的注冊登記庫使用者指南

4.0 Definitions

4.0 定義

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

臨床數據:由醫療器械的臨床使用而產生的安全性、臨床性能和/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.

臨床評價：一組持續進行的活動，使用科學可靠的方法對臨床數據進行評價和分析，以驗證醫療器械在按照生產商的預期使用時的安全性、臨床性能和/或有效性。

 

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

臨床證據：與醫療器械有關的臨床數據及其評價。

 

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.

臨床試驗：，在一個或多個受試者中進行醫療器械的安全性、臨床性能和/或有效性的評價的、系統的試驗或研究。

 

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.

上市后臨床隨訪研究：產品上市批準后進行的研究，旨在回答按照批準范圍使用的器械在安全性、臨床性能和/或有效性方面的具體問題(不確定性)。

 

5.0 Circumstances Where a PMCF Study May Be Indicated

5.0可能需要開展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.

器械上市批準時進行整體受益-風險時，該器械的潛在受益和剩余風險的程度可能存在不確定性。PMCF研究可用于收集更多的臨床數據，以解決器械的存在的不確定性。

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.

在某些監管區域，PMCF研究也用于解決上市后不良事件趨勢、文獻信息、來自不良事件報告提示信息、主動監測項目或其他來源提出的新問題。

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

在以下情形時，器械的受益-風險更可能存在不確定性:

·           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.

·           上市前評價未解決的長期安全、臨床性能和/或有效性問題。器械特定方面的長期安全、臨床性能和/或有效性可能難以在上市前研究時進行評價，為了充分建立器械長期安全、臨床性能和/或有效性,可能需要收集若干年的數據。

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

此外，器械長期安全性、臨床性能和/或有效性的未解答的問題可能來自其他信息，例如:

-        results of existing clinical investigations;

-   現有臨床試驗結果；

-        adverse events identified from post-market surveillance activities;

-   上市后監測活動的不良事件；

-        interaction with other medical products or treatments;

-   與其他醫療產品或治療方法的相互作用；

·           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;

·           新技術及新適用范圍。新技術特點，如新設計、材料、作用原理；或擴展/擴大現有技術的預期用途，如新適應癥或新患者群體；

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

·           高風險器械和使用場景。高風險解剖部位；或嚴重程度更高的疾病/治療挑戰;

·           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.

·           將臨床試驗結果進行外推時存在的不確定性；將試驗結果從試驗人群推廣到其他人群，例如從成人推廣到兒童，從一個種族推廣到其他種族。將其它監管區域的試驗結果推廣到擬申報的監管區域。

·           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.

·           基于對比器械臨床數據批準的產品。對于技術已經得到公認的器械，若基于對比器械的臨床數據和/或臨床前數據，獲得上市批準，其中一些臨床數據可能需要在上市后收集臨床數據。

·           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. ?

·           新出現的安全性、臨床性能和/或有效性信息。當器械上市后發生非預期的或難以解釋的嚴重不良事件，或者預期嚴重不良事件的性質（例如，嚴重程度）或發生頻率升高，PMCF研究可以評價器械和安全性信號的潛在關聯。

·           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. ?

·           公共衛生相關事件中的緊急獲得。發生公共衛生緊急事件（例如，大流行）時，對某些器械的受益-風險的考慮可能不同。授予產品加快上市，某些數據可在上市后獲得。

·           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;

·           罕見預期不良事件。罕見預期不良事件(例如冠狀動脈支架血栓形成)可能難以在上市前進行評價，但可通過大數據進行識別；因此，可能需要在PMCF計劃中評價罕見不良事件；

·           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.?

·           風險控制措施的效果評價。對于與使用該器械相關的已知安全風險，可能需要采取控制措施?？缮鲜泻笤u價控制措施是否充分。

 

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.

如果已知該器械的中長期安全性、臨床性能和/或有效性，或可通過其他合適的上市后監測活動提供足夠的數據來解決這些不確定性，則可能沒有必要進行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研究需基于產品的預期用途和使用說明開展臨床試驗。需要注意的是，PMCF研究必須符合適用的法律和法規、倫理要求，并應遵循適用的指導和標準。

The elements of a PMCF study should include:

PMCF研究的要素應包括:

?

?  Clearly stated objective(s);

?  明確的目標;

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

?  科學合理的設計依據和統計分析方法應在研究設計中概述；

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

?  根據計劃開展研究，解釋結果并得出恰當的結論。

 

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研究應明確其研究目的，并應解決與該器械的安全性、臨床性能和/或有效性相關的一個或多個已知的或新出現的不確定因素。研究假設應清晰描述在某些情況下，例如描述性研究，正式的統計假設可能是不必要的。

 

6.2 The Design of PMCF Studies

6.2 PMCF研究設計

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

研究設計應解決研究目的相關的問題，PMCF研究可采取幾種形式，如：

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

·         上市前臨床試驗納入患者的繼續隨訪；

·         a new post-market clinical investigation;

·         開展新的上市后臨床試驗；

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

·         器械登記數據庫中的數據回顧；或

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

·         過去使用過該器械患者的回顧性數據

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).

有關臨床試驗設計更多信息，請參閱IMDRF MDCE WG / N57：2019：臨床試驗。產品上市后，通過恰當的研究設計使用在常規臨床實踐中收集或產生的臨床經驗數據可能會有更多機會來回答器械安全性、臨床性能和/或有效性問題。附錄A（資料性）提供了PMCF研究臨床經驗數據來源舉例。

 

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:

適當的研究設計應科學合理，以便得出有效的結論。研究設計應考慮幾個因素，例如：

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

·           明確描述研究場景，包括地點、研究者和臨床研究機構的選擇；

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

·           通過明確納入和排除標準、受試者來源和選擇方法，明確界定研究人群；

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

·           對照/比較組（如有）應明確定義并說明其合理性；

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

·           明確樣本量并說明其合理性（如果適用）；

·           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);

·           明確定義所有變量/指標/測量方法，包括臨床結局/終點指標、不良事件、風險因素、混雜因素和效應修飾因子。對于某些PMCF研究，數據是在常規臨床實踐中獲得的。應明確數據來源和評價方法。附錄B（資料性）將臨床經驗數據用于PMCF研究的考慮要素；

·           The duration of patient follow-up

·           受試者隨訪時間

·           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)).

·           識別和評價潛在的偏倚源，并討論相關的控制方法（PMCF研究中的偏倚及其控制方法描述見附錄C（資料性））。

·           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.

·           明確統計分析方法。應考慮采用適當的統計方法以檢測潛在對分析結果的影響因素（例如混雜因素、效應修飾因子或數據缺失）對分析結果的影響。

 

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.

對于治療分配（包括隨機分配）的PMCF研究，應明確描述用于分配治療的方法和程序。如果使用病例對照或隊列設計，應描述暴露分類、病例和對照的選擇，包括匹配比率（如適用）。

 

6.3 The Implementation of PMCF Studies

6.3 PMCF研究的實施

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

應根據研究計劃開展研究，收集的數據應進行分析和解釋以得出結論。

 

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

在開展研究過程中應考慮一些因素，例如：

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

·           數據收集：應使用經過驗證的測量方法/工具，并考慮和控制數據的異質性；

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

·           質量控制：應進行研究者選擇、培訓、研究的監查和核查應確保質量；

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

·           結果報告和解釋：應論證撰寫研究報告以證明假設是否達到研究目的。

 

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：

來自PMCF研究的數據和結論是上市后監測的一部分，并用于臨床評價和風險管理過程的輸入。其可能導致器械是否仍然符合安全有效基本原則的重新評估，可能會導致糾正或預防措施，例如：

·           changes to the labelling/instructions for use,

·           更改標簽/使用說明書

·           changes to manufacturing processes,

·           變更生產過程

·           changes to the device design,

·           變更器械設計

·           public health notifications, or

·           公共衛生通告，或

·           product removal.

·           產品退市

 

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

此外，由PMCF研究產生的臨床數據/證據可用于：

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

·           在其他監管區域申請上市時，成為上市前臨床證據的一部分。

·           derive objective performance criteria and performance goals;

·           形成客觀性能標準和性能目標；

·           form control/comparison groups;

·           作為對照/比較組

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

作為補充數據，支持新一代或類似技術的上市。 

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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.

在某些監管區域，與患者健康狀況和/或常規使用情況下的醫療服務相關的臨床經驗數據也可描述為“真實世界數據”（RWD）描述，該類數據可從多種來源收集。