MEDDEV2-122rev2
EUROPEAN COMMISSION
DIRECTORATE GENERAL for HEALTH and CONSUMERS
Consumer Affairs
Health technology and Cosmetics
MEDDEV 2.12/2 rev2
January 2012 GUIDELINES ON MEDICAL DEVICES
POST MARKET CLINICAL FOLLOW-UP STUDIES
A GUIDE FOR MANUFACTURERS AND NOTIFIED BODIES
Note
The present Guidelines are part of a set of Guidelines relating to questions of
application of EC-Directives on medical Devices. They are legally not binding. The
Guidelines have been carefully drafted through a process of intensive consultation of
the various interest parties (competent authorities, Commission services, industries,
other interested parties) during which intermediate drafts where circulated and
comments were taken up in the document. Therefore, this document reflects positions
taken by representatives of interest parties in the medical devices sector.
1 2 3 4 5 6 7 8 9 10 11 12 13 14CONTENTS
1. Introduction (3)
2. Scope (4)
3. References (4)
4. Definitions (6)
5. Circumstances where a post market clinical follow up study in indicated (8)
6. Elements of a post-market clinical follow up study (10)
7. The use of study data (12)
8 The role of the notified body in post-market clinical follow up (12)
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25 26 27 28 29 30 31 32Preface
This document is intended to be a guide for manufacturers and Notified Bodies on how to carry out Post-Market Clinical Follow-up (PMCF) studies in order to fulfil Post-Market Surveillance (PMS) obligations according to Section 3.1 of Annex II, Section 3 of Annex IV, Section 3 of Annex V, Section 3.1 of Annex VI or Section 4 of Annex VII of the Medical Devices Directive (93/42/EEC) and Section 3.1 of Annex 2, Section 3 of Annex 4, Section 3.1 of Annex 5 of the Active Implantable Medical Devices Directive (90/385/EEC). These Sections refer to requirements of Annex X of Directive 93/42/EEC and Annex 7 of Directive 90/385/EEC, respectively. Attention is drawn to paragraph 8 of Article 15 of Directive 93/42/EEC which spells out the provisions of Article 15 that are not applicable to clinical investigations conducted using CE-marked devices within their intended use.
Similarly when PMCF studies are conducted using CE marked devices within their intended use, the provisions of section 2.3.5 of Annex X of Directive 93/42/EEC do not apply. However, the provisions of Directive 93/42/EEC concerning information and notification of incidents occurring following placing devices on the market are fully applicable.
.
33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 651. Introduction
While clinical evidence is an essential element of the premarket conformity assessment process to demonstrate conformity to Essential Requirements, it is important to recognise that there may be limitations to the clinical data available in the pre-market phase. Such limitations may be due to the duration of pre-market clinical investigations, the number of subjects and investigators involved in an investigation, the relative heterogeneity of subjects and investigators and/or the controlled setting of a clinical investigation versus the full range of clinical conditions encountered in general medical practice.
A precondition for placing a product on the market is that conformity to the relevant Essential Requirements, including a favourable benefit/risk ratio, has been demonstrated. The extent of the data that can be gathered in the pre-market phase does not necessarily enable the manufacturer to detect rare complications or problems that only become apparent after wide-spread or long term use of the device. As part of the manufacturer’s quality system, an appropriate post-market surveillance plan is key to identifying and investigating residual risks associated with the use of medical devices placed on the market. These residual risks should be investigated and assessed in the post-market phase through systematic Post-Market Clinical Follow-up (PMCF) study(ies).
Clinical data obtained from post-market surveillance and during PMCF studies by the manufacturer are not intended to replace the pre-market data necessary to demonstrate conformity with the provisions of the legislation. However, they are critical to update the clinical evaluation throughout the life-cycle of the medical device and to ensure the long term safety and performance of devices after their placing on the market.
PMCF studies are one of several options available in post-market surveillance and contribute to the risk management process.
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67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 872. Scope
The objective of this document is to provide guidance on the appropriate use and
conduct of PMCF studies to address issues linked to residual risks. The intention is
not to impose new regulatory requirements.本文档的目的是提供指导,对合理使用
PMCF进行研究,用以解决问题与残留的风险。其目的是不实施新的法规要求
PMCF studies are an important element to be considered in PMCF or PMS plans. The
principles for PMCF studies set out in this guidance are not intended to replace PMCF
or PMS plans. They are or may be applicable to PMCF studies conducted for other
purposes. PMCF研究是一项重要的因素来考虑PMCF或pms计划。这个PMCF原则研究中提出指导不是为了取代或
PMS计划。他们是或可能也适用于PMCF研究其他目的。
This document provides guidance in relation to:本文档提供了指导有关:
i)
ii)
iii)
the circumstances where a PMCF study is indicated;这个情况下的一个PMCF研究;
the general principles of PMCF studies involving medical devices; PMCF的一般原理研究涉及医疗设备;
the use of study data (for example to update instructions for use and labelling);研究数据的使用(例如更新使用说明和标签);
and
iv)the role of a notified body for medical devices in the assessment of PMCF plans
and of the results obtained from the plans as part of conformity assessment.为医疗设备评估
PMCF计划和该计划获取结果作为符合性评估一部份的公告机构的角色
This document does not apply to in vitro diagnostic devices.本文档并不适用于体外诊断设备。
88 89 90 91 92 93 94 95 96 97 98 99 1003. References
Council Directive 93/42/EEC of 14 June 1993 concerning medical devices as last
amended by Directive 2007/47/EC of the European Parliament and of the Council of
5 September 2007.欧洲议会和理事会1993年6月14日关于医疗设备委员会指令93/42 / EEC的修
改指令2007/47 / EC,2007年9月5日
Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of
the Member States relating to active implantable medical devices last amended by
Directive 2007/47/EC of the European Parliament and of the Council of 5 September
1990年6月20日委员会指令90/385 / EEC的及最后修正指令2007/47 / EC,欧洲议会和理事会2007年9月5日
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136Interpretative Documents
MEDDEV 2.7.1Clinical Evaluation: A Guide for Manufacturers and Notified
Bodies
MEDDEV 2.7.1, Appendix 1
Evaluation of Clinical Data – A Guide for Manufacturers and
Notified Bodies – Appendix 1: Clinical Evaluation of Coronary
Stents
GHTF Final Documents:
SG1/N41:2005
SG1/N44:2008
SG1/N065:2010
Essential Principles of Safety & Performance of Medical Devices医疗设备安全和性
能的基本原则
The Role of Standards in the Assessment of Medical Devices标准在医疗设备评
价中的作用
Registration of Manufacturers and Other Parties and Listing of
Medical Devices
SG2/N47:2005
SG5/N1:2007
SG5/N2:2007
SG5/N3:2010
Review of Current Requirements on Post-Market Surveillance
Clinical Evidence – Key Definitions and Concepts
Clinical Evaluation
Clinical Investigations
International Standards:
EN ISO 14155:2011 Clinical investigation of Medical Devices for human subjects
Good clinical practice; Second edition 2011-02-01
EN ISO 14971:2009
Others:
Application of risk management to medical devices
US Department of Health and Human Service, Agency for Healthcare Research
and Quality:
Registries for Evaluating Patient Outcomes: a User’s Guide (Executive
Summary, April 2007).
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4. Definitions Clinical Data 1: The safety and/or performance information that is generated from the use of a device. 由使用设备所产生的安全性和/或性能信息 Clinical data are sourced from: - - clinical investigation(s) of the device concerned; or 设备的临床调查(s);或 clinical investigation(s) or other studies reported in the scientific literature of a similar device for which equivalence to the device in question can be demonstrated; or 在科学文献中报道一个类似的设备的临床调查(s)或其他的研究,相关的安全性问题都可以被证实 证明; - published and/or unpublished reports on other clinical experience of either the device in question or a similar device for which equivalence to the device in question can be demonstrated. 出版和/或未出版的报告在其他的临床经验或者 设备的关键设备,或类似的等价性可以证明其装置的难题。 Clinical Evaluation 2: The assessment and analysis of clinical data pertaining to a medical device to verify the clinical safety and performance of the device when used as intended by the manufacturer. 由制造商评估和分析临床数据以验证医疗设备临床的性能和安全性 Clinical Evidence 2: The clinical data and the clinical evaluation report pertaining to a medical device. 医疗设备的临床资料和临床评估报告 Clinical Investigation 2: Any systematic investigation or study in or on one or more human subjects, undertaken to assess the safety or performance of a medical device. 对一个医疗设备进行任何系统的调查或研究或在一个或更多的人类受试者,开展评估安全或性能的。 Device Registry 3: An organised system that uses observational study methods to collect defined clinical data under normal conditions of use relating to one or more devices to Council Directives 90/385/EEC and 93/42/EEC GHTF document SG5/N1R8: 2007: Clinical Evidence – Key Definitions and Concepts 3GHTF document SG5/N4:2010: Post Market Clinical Follow-Up Studies, based on the definition in Agency for Healthcare Research and Quality, “Registries for Evaluating Patient Outcomes: A User’s Guide”, as modified. 2
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evaluate specified outcomes for a population defined by a particular disease,
condition, or exposure and that serves predetermined scientific, clinical or
policy purpose(s).
Note: The term “device registry” as defined in this guidance should not be
confused with the concept of device registration and listing. (See GHTF
SG1N065)
Post-market clinical follow-up (PMCF) study:
A study carried out following the CE marking of a device and intended to
answer specific questions relating to clinical safety or performance (i.e. residual
risks) of a device when used in accordance with its approved labelling. CE标志后的设备依
照其批准的标签开展的一项研究和打算回答有关临床安全或性能(例如残留风险)的使用时的特
定问题。
PMCF plan:
The documented, proactive, organised methods and procedures set up by the
manufacturer to collect clinical data based on the use of a CE-marked device
corresponding to a particular design dossier or on the use of a group of medical
devices belonging to the same subcategory or generic device group as defined
in Directive 93/42/EEC. The objective is to confirm clinical performance and
safety throughout the expected lifetime of the medical device, the acceptability
of identified risks and to detect emerging risks on the basis of factual evidence.由制造商基于所使用的一个设备，采用文件化的,主动的,有组织的方法和程序而设立的，收集对应于特定设计档案或使用的一群医学设备属于同一类别的临床数据。目标是确定医疗设备的临床表现和在整个使用寿命期间的安全,可接受性识别出的风险,并检测新的风险。
Residual Risk:
Risk remaining after risk control measures has been taken4 .
4EN ISO 14971
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?
5. Circumstances where a PMCF study is indicated
Following a proper premarket clinical evaluation, the decision to conduct PMCF
studies must be based on the identification of possible residual risks and/or unclarity
on long term clinical performance that may impact the benefit/risk ratio.一个适当的盘后临
床评估,决定进行PMCF研究必须建立在确定可能残留的风险和/或这些不确定中在长期的临床表现,
可能会影响好处/风险率
PMCF studies may review issues such as long-term performance and/or safety, the
occurrence of clinical events (e.g. delayed hypersensitivity reactions, thrombosis),
events specific to defined patient populations, or the performance and/or safety of the
device in a more representative population of users and patients. PMCF研究可能审查问题,比如长期性能和/或安全发生的临床事件(如延迟过敏反应,血栓形成),事件定义特定于患者群体,或性能和/或安全的设备在一个更有代表性的用户群和病人。
Circumstances that may justify PMCF studies include, for example:可以证明的情况下,PMCF研究包括,例如:?innovation, e.g., where the design of the device, the materials, substances,
the principles of operation, the technology or the medical indications are
novel;创新,例如,在设备的设计、材料、物质,工作原理、技术或适应症是新颖的;
significant changes to the products or to its intended use for which pre-
market clinical evaluation and re-certification has been completed;产品或其预期用途
在其完成再认证或临床评估后的重要改变。
·
?
?
?
?
?
?
?
high product related risk e.g. based on design, materials, components,
invasiveness, clinical procedures;与产品相关的高风险，例如基于设计、材料、组件侵入性、临床手
续;
high risk anatomical locations;解剖位置的高风险
high risk target populations e.g. paediatrics, elderly;高风险的目标人群如老人、儿童
severity of disease/treatment challenges;严重的疾病/治疗挑战;
questions of ability to generalise clinical investigation results;概括临床调查结果问题的能力;
unanswered questions of long-term safety and performance;悬而未决的长期安全性和性能问题;
results from any previous clinical investigation, including adverse events
or from post-market surveillance activities;结果来源于以往任何临床调查,包括不良事件或上市后
的监测活动;
?identification of previously unstudied subpopulations which may show
different benefit/risk-ratio e.g. hip implants in different ethnic
populations;很多不确定先前亚种也许这揭示不同的好处/ risk-ratio如髋关节植入物在不同的种族
人口;
?
?
continued validation in cases of discrepancy between reasonable
premarket follow-up time scales and the expected life of the product;持续验证的情况下
合理之间的差异盘随访时间尺度和预期寿命产品;
risks identified from the literature or other data sources for similar
marketed devices;
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?
?
?
?
interaction with other medical products or treatments;
verification of safety and performance of device when exposed to a larger
and more varied population of clinical users;
emergence of new information on safety or performance;
where CE marking was based on equivalence.
PMCF studies may not be required when the medium/long-term safety and clinical performance are already known from previous use of the device or where other appropriate post-market surveillance activities would provide sufficient data to address the risks.
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243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 2756. Elements of a PMCF study
Post-market clinical follow-up 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 and should involve an appropriate methodology and follow appropriate guidance and standards.
PMCF studies must be outlined as a well designed clinical investigation plan or study plan, and, as appropriate, include:
? clearly stated research question(s), objective(s) and related endpoints;
? scientifically sound design with an appropriate rationale and statistical analysis plan;
? a plan for conduct according to the appropriate standard(s);
? a plan for an analysis of the data and for drawing appropriate conclusion(s).
Objectives of PMCF studies
The objective(s) of the study should be stated clearly and should address the residual risk(s) identified and be formulated to address one or more specific questions relating to the clinical safety or clinical performance of the device. A formal hypothesis should be clearly expressed.
Design of PMCF studies
PMCF studies should be designed to address the objective(s) of the study. The design may vary based on the objective(s), study hypothesis research question and endpoints and should be scientifically sound to allow for valid conclusions to be drawn.
PMCF studies can follow several methodologies, for example:
?
?
?
?
the extended follow-up of patients enrolled in premarket investigations;
a new clinical investigation;
a review of data derived from a device registry; or
a review of relevant retrospective data from patients previously exposed to
the device.
276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307PMCF studies should have a plan describing the design and methodologies appropriate for addressing the stated objectives. The clinical investigation plan/study plan should identify and where needed justify at a minimum:
?
?
?
?
?
?
?
?
?
?
?
?
the study population (corresponding to the CE-mark scope);
inclusion/exclusion criteria;
rational and justification of the chosen study design including use of
controls/control groups (where relevant; randomised or not);
the selection of sites and investigators;
study objectives and related study endpoints and statistical considerations;
the number of subjects involved;
the duration of patient follow-up;
the data to be collected;
the analysis plan including any interim reporting where appropriate to
ensure continuous risk management based on clinical data; and
procedures/criteria for early study termination;
ethical considerations;
methods of quality control of data where appropriate.
The points above may not all apply to a retrospective data review.
Implementation of the PMCF study, analysis of data and conclusion(s)
The study should:
? be executed with adequate control measures to assure compliance with the clinical investigation or study plan;
? include data analysis with conclusions drawn according to the analysis plan by someone with appropriate expertise; and
? have a final report with conclusions relating back to original objective(s) and hypothesis/hypotheses.
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316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 3397. The use of study data
The data and conclusions derived from the PMCF study are used to provide clinical evidence for the clinical evaluation process. This may result in the need to reassess whether the device continues to comply with the Essential Requirements. Such assessment may result in corrective or preventive actions, for example changes to the labelling/instructions for use, changes to manufacturing processes, changes to the device design, or public health notifications.
8The role of the notified body in PMCF
When auditing the quality system of the manufacturer in the framework of one of the conformity assessment annexes of Directive 90/385/EEC or of Directive 93/42/EEC, the Notified Body (NB) shall review the appropriateness of the manufacturer’s general post-market surveillance procedures and plans, including plans for PMCF, as relevant.
The Notified Body shall verify that PMCF as part of the overall clinical evaluation is conducted by or on behalf of the manufacturer by appropriately competent assessors (as per section 10.3 of MEDDEV 2.7/1).
The NB shall verify that clinical investigations conducted as part of PMCF plans are conducted in accordance with the relevant provisions of Annex X (as per Article 15.8 of 93/42/EEC), related guidance and relevant standards.
The NB shall as part of its assessment of a specific medical device5:
?verify that the manufacturer has appropriately considered the need for PMCF as part of post market surveillance based on the residual risks
including those identified from the results of the clinical evaluation and
from the characteristics of the medical device in accordance with section 5
of the guidance;
?verify that PMCF is conducted when clinical evaluation was based exclusively on clinical data from equivalent devices for initial conformity
5in accordance with Annex II.4, Annex II.7, Annex III, Annex V.6 and Annex VI.6 of Directive
93/42/EEC and Annex II.4, Annex II.7, Annex III and Annex V.6 of Directive 90/385/EEC
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assessment and that PMCF addresses the residual risks identified for the
equivalent devices;
?assess the appropriateness of any justification presented by a manufacturer for not conducting a specific PMCF plan as part of post market surveillance and seek appropriate remedy where the justification is not valid;
?assess the appropriateness of the proposed PMCF plan in demonstrating the manufacturer’s stated objectives and addressing the residual risks and issues of long term clinical performance and safety identified for the specific
device;
?verify that data gathered by the manufacturer from PMCF, whether favourable or unfavourable, is being used to actively update the clinical
evaluation (as well as the risk management system);
?consider whether, based on the specific device assessment, data obtained from PMCF should be transmitted to the NB between scheduled assessment activities (e.g. surveillance audit, recertification assessment);
?consider an appropriate period for certification of the product in order to set
a particular time point at which PMCF data will be assessed by the NB or
specific conditions relating to certification for subsequent follow up. (This decision may be based on the residual risks, the characteristics presented in section 5 and the clinical evaluation presented at the time of initial
assessment. Conditions the NB may consider could include the need for the manufacturer to submit interim reports between certification reviews, of the clinical data generated from the PMCF and post-market surveillance
system).