Clinical Evaluations for Medical Devices 177469414X, 9781774694145

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Clinical Evaluations for Medical Devices

CLINICAL EVALUATIONS FOR MEDICAL DEVICES

Shalinee Naidoo

ARCLER

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www.arclerpress.com

Clinical Evaluations for Medical Devices Shalinee Naidoo

Arcler Press 224 Shoreacres Road Burlington, ON L7L 2H2 Canada www.arclerpress.com Email: [email protected]

e-book Edition 2023 ISBN: 978-1-77469-575-3 (e-book)

This book contains information obtained from highly regarded resources. Reprinted material sources are indicated and copyright remains with the original owners. Copyright for images and other graphics remains with the original owners as indicated. A Wide variety of references are listed. Reasonable efforts have been made to publish reliable data. Authors or Editors or Publishers are not responsible for the accuracy of the information in the published chapters or consequences of their use. The publisher assumes no responsibility for any damage or grievance to the persons or property arising out of the use of any materials, instructions, methods or thoughts in the book. The authors or editors and the publisher have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission has not been obtained. If any copyright holder has not been acknowledged, please write to us so we may rectify.

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ABOUT THE AUTHOR

Shalinee Naidoo is currently the Regulatory and Product Development Manager of a medical device manufacturer based in South Africa. She is directly involved in global regulatory compliance and the design and development of new medical devices from idea conception to market. She is also the founder of Life of Shal (www. lifeofshal.com) an online travel journal created to inspire others to explore the world and Scientist’s Sanctuary (www.scientistssanctuary.com) – a science communication company that specializes in bridging the gap between scientific knowledge and creative communication for both the academic and corporate world.

TABLE OF CONTENTS

List of Abbreviations .............................................................................................ix Introduction .........................................................................................................xi Preface........................................................................ .......................................xiii Chapter 1

What Is a Clinical Evaluation Report (CER)? ............................................. 1

Chapter 2

Understanding MEDDEV 2.7/1 (Revision 04) in Greater Detail: MEDDEV 2.7/1 (Rev 04) – Clinical Evaluation: A Guide for Manufacturers and Notified Bodies Under Directives 93/42/EEC and 90/385/EEC ........................................................................................ 3

Chapter 3

Essential Requirements (ERs) of Medical Devices (Under the MDD 93/42 EEC) .................................................................................... 71

Chapter 4

General Safety and Performance Requirements (GSPRs) of Medical Devices (Under the MDR 2017/745) ......................................... 83

Chapter 5

Claiming Equivalence Between Medical Devices .................................... 89

Chapter 6

MDCG 2020-5: Clinical Evaluation – Equivalence: A Guide for Manufacturers and Notified Bodies ................................................... 91

Chapter 7

Differences in Technical, Biological, and Chemical Characteristics ........ 93

Chapter 8

Demonstration of Equivalence ................................................................ 99

Chapter 9

Use of Data From Similar Devices ........................................................ 105

Chapter 10 How to Conduct a Literature Review? .................................................. 107 Chapter 11 When to Update Your CER? .................................................................. 111 Chapter 12 What Is a Clinical Evaluation Plan? ....................................................... 113

Chapter 13 Post-market Clinical Follow-Up (PMCF)................................................ 115 Appendices............................................................................................ 117 Bibliography .......................................................................................... 181 Index ..................................................................................................... 185

viii

LIST OF ABBREVIATIONS AIMDD

active implantable medical device directive

AR

authorized representatives

CA

competent authorities

CEAR

clinical evaluation assessment report

CER

clinical evaluation report

CS

common specifications

EMA

European Medicines Agency

ER

essential requirements

FDA

Food and Drug Administration

GCP

good clinical practice

GSPR

general safety and performance requirements

HTA

health technology assessment

ICTRP

International Clinical Trials Registry Platform

IFU

instructions for use

ISO

International Organization for Standardization

IVD

in-vitro diagnostic

MDCG

Medical Device Coordination Group

MDD

medical device directive

MDR

medical device regulation

NB

notified body

NBOG

notified bodies operations group

PMCF

post-market clinical follow up

PMS

post-market surveillance

PRISMA

preferred reporting items for systematic reviews and meta-analyzes

QMS

quality management system

INTRODUCTION In 2000, it was estimated that one and a half million different medical devices were available on the market worldwide. As innovation and rapid advancement in technologies take over, medical devices have now become one of the fastest-growing industries globally. Medical devices cannot be placed on the European market without a manufacturer proving conformance to the strict safety requirements of the European Union. These safety requirements are laid out in relevant regulations, previously known as the medical device directive (MDD) and now the medical device regulation (MDR). The MDR requires manufacturers to perform a clinical evaluation of their device and prepare a compliant clinical evaluation report (CER) as part of the CE marking process and commercialization in Europe. This compliant clinical evaluation report (CER) must be produced and continuously maintained. Many manufacturers struggle to comply with the European CER requirements as strong clinical evidence and data appraisals around the device are required. Often this clinical data can come from various sources such as existing literature, clinical trials, and of course, the manufacturer’s quality management system (QMS) such as post-market surveillance (PMS) monitoring and risk management. The clinical evaluation report forms a critical component of the technical file and requires a systematic and planned process that contributes to the generation, collection, analysis, and evaluation of a particular device. Ideally, this is done with the intention of verifying the safety and performance of the device as well as highlighting the clinical benefits for use as intended by the manufacturer. This volume provides an insight into what a clinical evaluation report is, how it is prepared and how it relates to other chapters of the technical file.

PREFACE A compliant clinical evaluation report (CER) is required for all medical devices that are commercialized in Europe. These reports are essential to sell or distribute medical devices in Europe and often form a critical part of the conformity assessment done by the notified body (NB) and are submitted with the technical file. Clinical evaluation is a continuous process completed throughout the entire lifecycle of a medical device, and all manufacturers are obliged to perform them. The clinical evaluation report is used to prove a device performs as intended without compromising the safety of its end users. Often strong clinical evidence is required, and this should come from existing literature, clinical experience, clinical trials, and the manufacturer’s quality management system (QMS). This volume aims to provide an introduction to the basic concepts of preparing and documenting a clinical evaluation report. Important concepts such as claiming equivalence and how to conduct a literature review and covered. In addition, useful templates that manufacturers can use are also provided.

CHAPTER

1

WHAT IS A CLINICAL EVALUATION REPORT (CER)?

A Clinical Evaluation Report (CER) describes the clinical evaluation process for a medical device and contains an analysis of all inputs from risk management, verification testing, literature reviews, and any forms of clinical investigation. The main aim of preparing a CER is to determine if there is enough clinical evidence to show safety and performance of the medical device based on the intended use and claims made by the manufacturer. Clinical evaluation should be a structured ongoing procedure to collect, appraise, and analyze clinical data in relation to the medical device in question. This evaluation aims to assess whether there is sufficient clinical evidence available to confirm compliance with the relevant essential requirements (ERs) or general safety and performance requirements (GSPRs) to show safety and performance when using the device according to the manufacturer’s instructions for use (IFU). There are four stages of clinical evaluation: • • • • •

Stage 0: Scope and plan. Stage 1: Identification of pertinent data. Stage 2: Appraisal of pertinent data. Stage 3: Analysis of the clinical data. Stage 4: CER (including post-market surveillance (PMS) and post-market clinical follow-up plan). It should be noted that the clinical evaluation is an ongoing process conducted throughout the life cycle of a medical device. The data should be updated whenever:

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•

new PMS information is received that effects some form of change in the current clinical evaluation; • annually when the device carries significant risks or is not yet well established; • every 2–5 years if the device dos not carry any significant risks or is well established. The CER is the document that holds all the information intended for review by the notified body (NB) who will in essence, review and assess the medical device for initial approval or renewal of market approval for the CE mark. This CER will form part of the Technical File or Design Dossier that is submitted for review to the NB. The guideline determining the structure and content of the CER is MEDDEV 2.7/1 (Rev. 4). Let’s look at the MEDDEV 2.7/1 (Rev 04) in greater detail.

CHAPTER

2

UNDERSTANDING MEDDEV 2.7/1 (REVISION 04) IN GREATER DETAIL: MEDDEV 2.7/1 (REV 04) – CLINICAL EVALUATION: A GUIDE FOR MANUFACTURERS AND NOTIFIED BODIES UNDER DIRECTIVES 93/42/EEC AND 90/385/EEC The MEDDEV document starts with an introduction as below indicating which medical device directives (MDD) it is applicable to. Specifically, the MEDDEV Guidance Document is applicable to Directive 93/42/EEC and Directive 90/385/EEC. The introduction goes on to explain, that, as per the Directives mentioned, demonstration of conformity with the ERs must include a clinical evaluation. It also guides manufacturers to the correct Annex in each respective Directive.

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Clinical Evaluations for Medical Devices

1. Introduction Pursuant to: · Section 6a of Annex I to Directive 93/42/EEC (amended by Directive 2007/47/EC); and · Section 5a of Annex 1 to Directive 90/385/EEC (amended by Directive 2007/47/ EC). The demonstration of conformity with ERs for a medical device must include a clinical evaluation, which is conducted in accordance with Annex X to Directive 93/42/ EEC or with Annex 7 to Directive 90/385/EEC. This document promotes a common approach to clinical evaluation for medical devices regulated by directives 90/385/EEC and 93/42/EEC. It does not concern in vitro diagnostic (IVD) devices. The depth and extent of clinical evaluations should be flexible and appropriate to the nature, intended purpose, and risks of the device in question. Therefore, this guidance is not intended to impose device-specific requirements. This document uses the terms “must,” “shall,” “have to” where these terms are used in the directives. “Should” is used in other instances.

The MEDDEV then goes on to detail the scope. 2. Scope This guide is not legally binding; only the text of the Directives is authentic in law. It is recognized that under given circumstances, for example as a result of scientific developments, an alternative approach may be possible or appropriate to comply with the legal requirements. Nevertheless, due to the participation of interested parties and of experts from national Competent Authorities (CA), it is anticipated that this guide will be followed within the Member States, thereby supporting uniform application of relevant provisions of EU Directives and common practices. On certain issues not addressed in the Directives, national legislation may be different from this guide. This guide is regularly updated according to regulatory developments. The latest version of the guide should always be used. This version is a complete revision of the previous texts. The medical device legislation in Europe is currently being significantly revised. A new Regulation of the European Parliament and of the Council on medical devices will be published, which may result in changes to important concepts or definitions relating to clinical evaluation. Parts or all of this document are likely to be revised. Some contents (such as contents about notified bodies) are likely to be removed and integrated in other series of documents.

Relevant references are cited. These include references from European Legislation, Harmonized, and International Standards, European Guidance Documents and other Guidance Documents.

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3. References European legislation: • Council Directive 90/385/EEC of 20 June 1990 relating to active implantable medical devices. • Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. • Commission Regulation 722/2012 of 8 August 2012 concerning active implantable medical devices and medical devices manufactured utilizing tissues of animal origin. • Commission Implementing Regulation 920/2013 of 24 September 2013 on the designation and the supervision of notified bodies under Council Directive 90/385/EEC on active implantable medical devices and Council Directive 93/42/EEC on medical devices. Harmonized and International standards: • EN ISO 14155:2011 Clinical investigation of medical devices for human subjects – good clinical practice (GCP). • EN ISO 14971:2012 medical devices – application of risk management to medical devices. European guidance documents: • MEDDEV 2.12/1 Guidelines on a medical devices vigilance system. • MEDDEV 2.12/2 Guidelines on post-market clinical follow-up studies: a guide for manufacturer and NB. • MEDDEV 2.4/1 Classification of medical devices. • MEDDEV 2.7/2 Guidelines for CA for making a validation/assessment of a clinical investigation application under directives 90/385/EEC and 93/42/EC. • Manual on borderline and classification in the Community regulatory framework for medical devices. • NBOG BPG 2006-1 Change of NB. • NBOG BPG 2009-1 Guidance on design-dossier examination and report content. • NBOG BPG 2009-4 Guidance on NB’s tasks of technical documentation assessment on a representative basis. • NBOG BPG 2010-2 Guidance on audit report content. • NBOG BPG 2014-1 Renewal of EC design-examination and type-examination certificates: Conformity assessment procedures and general rules. • NBOG BPG 2014-2 Guidance on the information required for NB medical device personnel involved in conformity assessment activities. • NBOG BPG 2014-3 Guidance for manufacturers and notified bodies on reporting of design changes and changes of the quality system. • Other guidance documents: • GHTF SG5 N1R7:2007: Clinical evidence – key definitions and concepts. • GHTF SG5 N2R8:2007: Clinical evaluation. • GHTF SG5 N41R9:2005: Essential principles of safety and performance. This list contains documents available at the time this MEDDEV document was published. In general, the most recent versions of standards and legal texts should be used.

Definition used in the guidance document are also provided to ensure ease of use. These definitions are provided below:

Clinical Evaluations for Medical Devices

6 4.

Definitions Adverse Event: Any untoward medical occurrence, unintended disease or injury, or any untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other persons whether or not related to the investigational medical device. o Note 1: This includes events related to the investigational device or the comparator. o Note 2: This includes events related to the procedures involved. o Note 3: For users or other persons this is restricted to events related to the investigational medical device [EN ISO 14155:2011]. • Bias: It is a systematic deviation of an outcome measure from its true value, leading to either an overestimation or underestimation of a treatment’s effect. It can originate from, for example, the way patients are allocated to treatment, the way treatment outcomes are measured and interpreted, and the way data are recorded and reported. [Adapted from GHTF SG5/ N2R8:2007] • Clinical Data: The safety and/or performance information that is generated from the clinical use of a device. Clinical data are sourced from: o Clinical investigation(s) of the device concerned; or o 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 o 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 [derived from Article 1.2.k MDD and Art. 1.2.k AIMDD]. • Clinical Evaluation: A methodologically sound ongoing procedure to collect, appraise, and analyze clinical data pertaining to a medical device and to evaluate whether there is sufficient clinical evidence to confirm compliance with relevant ERs for safety and performance when using the device according to the manufacturer’s IFU. Note: In exceptional cases where an instruction for use is not required, the collection, analysis, and assessment are conducted taking into account generally recognized modalities of use. • Clinical Evidence: The clinical data and the CER pertaining to a medical device. [GHTF SG5/N2R8:2007] • Clinical Investigation: Systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a medical device. Note: ‘Clinical trial’ or ‘clinical study’ are synonymous with ‘clinical investigation’ [EN ISO 14155:2011]. • Clinical Investigation Plan: Document that states the rationale, objectives, design, and proposed analysis, methodology, monitoring, conduct, and record-keeping of the clinical investigation. [EN ISO 14155:2011] •

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Clinical Investigation Plan: Document that states the rationale, objectives, design, and proposed analysis, methodology, monitoring, conduct, and record-keeping of the clinical investigation. [EN ISO 14155:2011] • Clinical Performance: Behavior of a medical device or response of the subject(s) to that medical device in relation to its intended use, when correctly applied to appropriate subject(s). [EN ISO 14155:2011] • Device Registry: An organized system that uses observational study methods to collect defined clinical data under normal conditions of use relating to one or more devices to 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” should not be confused with the concept of device registration and listing. [MEDDEV 2.12/2 rev2] • Clinical Safety: Freedom from unacceptable clinical risks, when using the device according to the manufacturer’s IFU. [MEDDEV 2.7/2 revision 2] Note: In exceptional cases where an instruction for use is not required, the collection, analysis, and assessment are conducted taking into account generally recognized modalities of use. • Clinical Use: Use of a medical device in or on living human subjects. • Note: Includes use of a medical device that does not have direct patient contact. • Equivalent Device: A device for which equivalence to the device in question can be demonstrated. [Derived from Art. 1.2.k MDD] • Feasibility Study: A clinical investigation that is commonly used to capture preliminary information on a medical device (at an early stage of product design) to adequately plan further steps of device development, including needs for design modifications or parameters for a pivotal study. [MEDDEV 2.7/2 revision 2] • Harmonized Standards: Standards whose references have been published in the Official Journal of the European Communities. [Derived from Article 5 of Directive 90/385/EEC and Article 5 of Directive 93/42/EEC] • Hazard: Potential source of harm. [EN ISO 14971:2012] • Hazard Due to Substances and Technologies: For the purpose of this MEDDEV document, a hazard that is seen with products that share specific characteristics. Note: This includes products that contain the same materials and substances, material combinations, use the same technologies, produce similar abrasion, are used with the same type of surgical approach, share the same manufacturing procedures or impurities, or share other characteristics. •

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Incident: Any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labeling or the IFU which, directly or indirectly, might lead to or might have led to the death of a patient, or user or of other persons or to a serious deterioration in their state of health. [MEDDEV 2.12/rev 8] • Information Materials Supplied by the Manufacturer: For the purpose of this document, this refers to the labeling, IFU and the manufacturer’s promotional materials for the device under evaluation. [Derived from MDD Art. 1.2.g, MDD Annex I, Section 13, AIMDD Art. 1.2.f, AIMDD Annex I, Sections 14 and 15] • Intended Purpose: The use for which the device is intended according to the data supplied by the manufacturer on the labeling, in the instructions and/or in promotional materials. [MDD Art. 1.2.g, AIMDD Art. 1.2.f] • Investigator: Individual member of the investigation site team designated and supervised by the principal investigator at an investigation site to perform critical clinical-investigation-related procedures or to make important clinical investigation-related decisions. [EN ISO 14155:2011] • PMCF Plan: The documented, proactive, organized 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. [MEDDEV 2.12/2 Rev. 2] • 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 labeling. [MEDDEV 2.12/2 Rev. 2] • Risk: Combination of the probability of occurrence of harm and the severity of that harm. [EN ISO 14971:2012] • Risk Management: Systematic application of management policies, procedures, and practices to the tasks of analyzing, evaluating, controlling, and monitoring risk. [EN ISO 14971:2012] • Serious Adverse Event: Adverse event that: i. led to death; ii. led to serious deterioration in the health of the subject, that either resulted in: a. a life-threatening illness or injury; or b. a permanent impairment of a body structure or a body function; or c. in-patient or prolonged hospitalization; or d. medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function. •

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iii. led to fetal distress, fetal death or a congenital abnormality or birth defect. Note: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP [clinical investigation plan], without serious deterioration in health, is not considered a serious adverse event. [EN ISO 14155:2011] • Sufficient Clinical Evidence: An amount and quality of clinical evidence to guarantee the scientific validity of the conclusions.

Any abbreviations used are then provided. 5.

• • • • • •

• •

Abbreviations AIMDD: Active implantable medical device directive (Council Directive 90/385/EEC amended by Directive 2007/47/EC) CEAR: Clinical evaluation assessment report CER: Clinical evaluation report ER: Essential requirement IFU: Instructions for use MDD: Medical device directive (Council Directive 93/42/EEC amended by Directive 2007/47/EC) PMS: Post-market surveillance PMCF: Post-market clinical follow-up

The general principles of a clinical evaluation are discussed. The MEDDEV defines a clinical evaluation as an ongoing procedure to collect, appraise, and analyze clinical data relevant to a medical device as well as to analyze whether there is sufficient clinical evidence to confirm compliance with relevant ERs for safety and performance when using the device according to the manufacturer’s IFU. The requirements for a clinical evaluation apply to all classes of devices however the depth of evaluation done should be appropriate to the risk related to the device under evaluation, as well as its specific properties and intended purpose. It should also be noted that carrying out a clinical evaluation is the responsibility of the manufacturer. The final CER should then form a component of the technical file related to the device.

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Clinical Evaluations for Medical Devices

6. General Principles of Clinical Evaluation 6.1. What Is Clinical Evaluation? Clinical evaluation is a methodologically sound ongoing procedure to collect, appraise, and analyze clinical data pertaining to a medical device and to analyze whether there is sufficient clinical evidence to confirm compliance with relevant ERs for safety and performance when using the device according to the manufacturer’s IFU. In exceptional cases where an instruction for use is not required, the collection, appraisal, and analysis are conducted taking into account generally recognized modalities of use. The requirements for clinical evaluation apply to all classes of medical devices. The evaluation should be appropriate to the device under evaluation, its specific properties, and its intended purpose. Benefits and risks should be specified, e.g., as to their nature, probability, extent, duration, and frequency. Core issues are the proper determination of the benefit/risk profile in the intended target groups and medical indications, and demonstration of acceptability of that profile based on current knowledge/the state of the art in the medical fields concerned. Clinical evaluation is a responsibility of the manufacturer and the CER is an element of the technical documentation of a medical device. For compliance with European MDDs: • The clinical evaluation addresses the following ERs: o Annex 1, Sections 1, 2, 5 of AIMDD (for active implantable medical devices); or o Annex I, Sections 1, 3, 6 of MDD (for medical devices); see Appendix A7 (analysis of the clinical data-compliance to specific ERs). • The evaluation must follow defined and methodologically sound procedures as described in: o Annex 7 of AIMDD (for active implantable medical devices); or o Annex X of MDD (for medical devices). • Where demonstration of conformity with ERs based on clinical data is not deemed appropriate, an adequate justification has to be given. The justification is included in the CER with contents according to: o Annex 7, Section 1.5 of AIMDD (for active implantable medical devices); or o Annex X, Section 1.1d of MDD (for medical devices). Conformity to the ERs can only be assumed when the following items are aligned with each other:

• •

The information materials supplied by the manufacturer (the labeling, IFU, available promotional materials, including accompanying documents foreseen by the manufacturer); The clinical evaluation (the device description used for the clinical evaluation, other contents of the CER);

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•

The available clinical data (such as results of Clinical Investigations, publications, PMS studies, etc.). Particularly, evaluators should address if the following points are adequately supported by sufficient clinical evidence: • The intended purpose described in the information materials supplied by the manufacturer (including for all medical indications); • The clinical performance and benefits described in the information materials supplied by the manufacturer (including, for example, any claims on product performance and safety); • Measures for risk avoidance and risk mitigation described in the information materials supplied by the manufacturer (including, for example the declaration of the residual risks, contraindications, precautions, warnings, instructions for managing foreseeable unwanted situations); • The usability of the device for the intended users and the suitability of the information materials supplied by the manufacturer for the intended users (including, if applicable, for lay or disabled persons); • Instructions for target population groups (including, for example, pregnant women, pediatric populations).

An overview of when a clinical evaluation should be performed and why it is important is also provided in Section 6.2. Generally, a clinical evaluation should be performed throughout the life cycle of a medical device. This should form an ongoing process. The clinical evaluation should start during the development process of a medical device to identify data needed for market access. Thereafter, it should be actively updated throughout the lifecycle of the device. The main purpose of performing a clinical evaluation is to ensure that the evaluation of safety and performance of the device is based on sufficient clinical evidence. This is done to allow manufacturers to provide notified bodies and CA with sufficient evidence to show conformity of the device with the ERs throughout its lifetime. 6.2. When Is Clinical Evaluation Undertaken and Why Is It Important? Clinical evaluation is conducted throughout the life cycle of a medical device, as an ongoing process. Usually, it is first performed during the development of a medical device in order to identify data that need to be generated for market access. Clinical evaluation is mandatory for initial CE-marking and it must be actively updated thereafter.

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Clinical Evaluations for Medical Devices

Clinical evaluation is necessary and important because it ensures that the evaluation of safety and performance of the device is based on sufficient clinical evidence throughout the lifetime that the medical device is on the market. This ongoing process enables manufacturers to provide notified bodies and CA with sufficient clinical evidence for demonstration of conformity of the device with the ERs throughout its lifetime (for example for CE marking, fulfillment of post-market surveillance and reporting requirements, or during surveillance procedures). 6.2.1. Clinical Evaluation Undertaken for the Development of a Medical Device Premarket research and development are guided by clinical evaluation and risk management. Typically, manufacturers carry out clinical evaluations to: • Define needs regarding clinical safety and clinical performance of the device. • In case of possible equivalence to an existing device, evaluate if there are clinical data available and determine equivalence; for additional information, see Appendix A1 (Demonstration of equivalence). • Carry out a gap analysis and define which data still need to be generated with the device under evaluation, whether clinical investigations are necessary and if so, to define the study design; for additional information, see Section 10 (Analysis of the clinical data) and Appendix A2 (When should additional clinical investigations be carried out?). As the initial clinical evaluation identifies the questions to be answered by a clinical investigation, the clinical evaluation process should generally commence in advance of any clinical investigation. 6.2.2. Clinical Evaluation for Initial CE-Marking Clinical evaluation is required to be carried out for the conformity assessment process leading to the CE-marking and placing on the market of a medical device. The purpose is to: • Document that there is sufficient clinical evidence to demonstrate conformity with the ERs covering clinical performance and clinical safety. • Identify aspects that need to be addressed systematically during post-market surveillance (PMS), e.g., in post-market clinical follow-up studies (PMCF Studies) required under the MDDs. Typically, these aspects include estimation of residual risks and uncertainties or unanswered questions (such as rare complications, uncertainties regarding long-term performance, safety under wide-spread use). 6.2.3. Updating the Clinical Evaluation a. Frequency of Updates: The manufacturer should define and justify the frequency at which the clinical evaluation needs to be actively updated. When doing so, the manufacturer should typically consider: • whether the device carries significant risks (e.g., based on design, materials, components, invasiveness, clinical procedures, high-risk anatomical locations, high-risk target populations (e.g., pediatrics, elderly), severity of disease/treatment challenges). • whether the device is well established, taking into consideration:

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innovation; relevant changes in clinical sciences, materials sciences or other sciences related to the device under evaluation; o the current level of confidence in the evaluation of clinical performance and clinical safety of the device; the manufacturer should consider; o the data available from clinical investigations, PMCF studies, registries or other systematic studies (including the number of devices used, if that usage was representative of the usage in the market, the results to date); o the total number of devices used so far in the market, and expected reporting rates under the vigilance system. • whether there are risks and uncertainties or unanswered questions, in the medium or long-term, that would influence the frequency of updates. • design changes or changes to manufacturing procedures (if any). The clinical evaluation is actively updated: • when the manufacturer receives new information from PMS that has the potential to change the current evaluation; • if no such information is received, then: o at least annually if the device carries significant risks or is not yet well established; or o every 2 to 5 years if the device is not expected to carry significant risks and is well established, a justification should be provided. When involvement of notified bodies is required, updates are usually coordinated with the NB. Typically, they are aligned with the timetable for surveillance audits and the renewal of the certificates. b. General Considerations on Updating the Clinical Evaluation: Manufacturers are required to implement and maintain a PMS system that routinely monitors the clinical performance and clinical safety of the device as part of their quality management system (QMS) [2]. The scope and nature of such PMS should be appropriate to the device and its intended purpose. PMS regularly generates new data (e.g., safety reports, results from published literature, registries, PMCF studies, and other data about device usage). Those data need to be evaluated for information that has a potential to change the evaluation of the risk/benefit profile, and the clinical performance and clinical safety of the device. Those data are required to be fed into the clinical evaluation process in a timely manner. In accordance with the directives, the clinical evaluation and the CER must be actively updated with data obtained from post-market surveillance. When updating the clinical evaluation, the evaluators should verify: • if the benefit/risk profile, undesirable side-effects (whether previously known or newly emerged) and risk mitigation measures are still: o compatible with a high level of protection of health and safety and acceptable according to current knowledge/the state of the art; o correctly addressed in the information materials supplied by the manufacturer of the device;

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o

correctly addressed by the manufacturer’s current PMS plan. • if existing claims are still justified; • if new claims the manufacturer intends to use are justified. While clinical evaluation requires data from PMS activities, it also generates new information that have to be fed into the PMS and risk management process. Clinical evaluation can therefore result in changes to the manufacturer’s risk management documents, IFU and PMS activities. If the manufacturer concludes there is not sufficient clinical evidence to be able to declare conformity with the ERs, the manufacturer will need to: • stop placing the devices on the market until conformity is restored; and • take necessary corrective and preventive action.

The next section covers how a clinical evaluation should be performed. The clinical evaluation is based on the analysis of pre-market and postmarket data that relates to the intended purpose of the device in question. A clinical evaluation covers four main stages as identified in the table below. 6.3. How Is a Clinical Evaluation Performed? The clinical evaluation is based on a comprehensive analysis of available pre- and post-market clinical data relevant to the intended purpose of the device in question, including clinical performance data and clinical safety data. There are discrete stages in performing a clinical evaluation: • Stage 0: Define the scope, plan the clinical evaluation (also referred to as scoping and the clinical evaluation plan). • Stage 1: Identify pertinent data. • Stage 2: Appraise each individual data set, in terms of its scientific validity, relevance, and weighting. • Stage 3: Analyze the data, whereby conclusions are reached about: o compliance with ERs (including ER1, ER3, ER6) on performance and safety of the device, including its benefit/risk profile. o the contents of information materials supplied by the manufacturer (including the label, IFU of the device, available promotional materials, including accompanying documents possibly foreseen by the manufacturer). o residual risks and uncertainties or unanswered questions (including on rare complications, long term performance, safety under wide-spread use), whether these are acceptable for CE-marking, and whether they are required to be addressed during PMS. • Stage 4: Finalize the CER. The CER summarizes and draws together the evaluation of all the relevant clinical data documented or referenced in other parts of the technical documentation. The CER and the relevant clinical data constitute the clinical evidence for conformity assessment.

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An overview of the stages is presented in the diagram below and a detailed explanation is provided later on in this volume.

Section 6.4 of the MEDDEV covers who should perform the clinical evaluation. This section covers the requirements of a suitably qualified individual. Manufacturers should take these requirements into consideration when choosing a suitable clinical evaluator for their device.

Clinical Evaluations for Medical Devices

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6.4. Who Should Perform the Clinical Evaluation? The clinical evaluation should be conducted by a suitably qualified individual or a team. The manufacturer should take the following aspects into consideration: • The manufacturer defines requirements for the evaluators that are in line with the nature of the device under evaluation and its clinical performance and risks. • The manufacturer should be able to justify the choice of the evaluators through reference to their qualifications and documented experience, and to present a declaration of interest for each evaluator. • As a general principle, the evaluators should possess knowledge of the following: o research methodology (including clinical investigation design and biostatistics); o information management (e.g., scientific background or librarianship qualification; experience with relevant databases such as Embase and Medline); o regulatory requirements; and o medical writing (e.g., post-graduate experience in a relevant science or in medicine; training and experience in medical writing, systematic review and clinical data appraisal). • With respect to the particular device under evaluation, the evaluators should in addition have knowledge of: o the device technology and its application; o diagnosis and management of the conditions intended to be diagnosed or managed by the device, knowledge of medical alternatives, treatment standards and technology (e.g., specialist clinical expertise in the relevant medical specialty). • The evaluators should have at least the following training and experience in the relevant field: o a degree from higher education in the respective field and 5 years of documented professional experience; or o 10 years of documented professional experience if a degree is not a prerequisite for a given task. There may be circumstances where the level of evaluator expertise may be less or different; this should be documented and duly justified.

The four stages of performing a clinical evaluation are explained in detail below. These four stages include: • • • • •

Stage 0: Definition of the scope of the clinical evaluation. Stage 1: Identification of pertinent data. Stage 2: Appraisal of pertinent data. Stage 3: Analysis of the clinical data. Stage 4: The CER.

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• Stage 0: Definition of the Scope of the Clinical Evaluation The manufacturer should ideally define the scope of the clinical evaluation before it is started. The scope should be based on the ERs (from a clinical perspective) as well as the nature and history of the device. Scoping of the clinical evaluation will aid in many downstream steps such as identifying pertinent data. The clinical evaluation should identify, appraise, and analyze both favorable and unfavorable data. 7. Definition of the Scope of the Clinical Evaluation (Stage 0) Before a clinical evaluation is undertaken the manufacturer should define its scope, based on the ERs that need to be addressed from a clinical perspective and the nature and history of the device. This is also referred to as scoping. The scope serves as a basis for further steps, including the identification of pertinent data. The manufacturer sets up a description of the device under evaluation, and a clinical evaluation plan. A clinical evaluation is required to be critical. Therefore, it needs to identify, appraise, and analyze both favorable and unfavorable data. Depending on the stage in the lifecycle of the product, considerations for setting up a clinical evaluation plan should include different aspects. Typical examples are listed below. Aspects (Non an Exhaustive List)

Before CE Marking

For CE Marked Devices

The device description. For additional information, see Appendix A3 (device description – typical contents)

X

X

Whether there are any design features of the device, or any indications or target populations, that require specific attention. The clinical evaluation should cover any design features that pose special performance or safety concerns (e.g., presence of medicinal, human or animal components), the intended purpose and application of the device (e.g., target treatment group and disease, proposed warnings, contraindications, precautions, and method of application) and the specific claims made by the manufacturer about the clinical performance and clinical safety of the device.

X

X

Information needed for evaluation of equivalence, if equivalence may possibly be claimed.

X

–

The risk management documents of the device, e.g., the hazard identification list, clinical risks identified from the risk analysis. The scope of the clinical evaluation will need data from and cross references to the manufacturer’s risk management documents. The risk management documents are expected to identify the risks associated with the device and how such risks have been addressed. The clinical evaluation is expected to address the significance of any clinical risks that remain after design risk mitigation strategies have been employed by the manufacturer.

X

X

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The current knowledge/state of the art in the corresponding medical field, such as applicable standards and guidance documents, information relating to the medical condition managed with the device and its natural course, benchmark devices, other devices and medical alternatives available to the target population.

X

X

Data source(s) and type(s) of data to be used in the clinical evaluation. Data relevant to the clinical evaluation may be generated and held by the manufacturer or available from scientific literature. For additional information, see Section 8.1 (Data generated and held by the manufacturer), and Appendix A4 (Sources of literature).

X

X

Whether the manufacturer has introduced/intends to introduce any relevant [5] – changes, including: • design changes; • changes to materials and manufacturing procedures; • changes to the information materials supplied by the manufacturer (label, IFU, available promotional materials including accompanying documents possibly foreseen by the manufacturer) or other claims; • and whether the claim of equivalence to an existing device is still appropriate.

X

Whether there are any specific clinical concerns that have newly emerged and need to be addressed.

–

X

PMS aspects that need regularly updating in the CER: – • new clinical data [7] available for the device under evaluation; • new clinical data available for the equivalent device (if equivalence is claimed); • new knowledge about known and potential hazards, risks, performance, benefits [9] and claims [10], including • data on clinical hazards seen in other products (hazard due to substances and technologies); • changes concerning current knowledge/the state of the art, such as changes to applicable standards and guidance documents, new information relating to the medical condition managed with the device and its natural course, medical alternatives available to the target population; • other aspects identified during PMS.

X

Needs for planning PMS activities.

X

–

It is important to recognize that there is considerable diversity in the types and history of technologies used in medical devices and the risks posed by them. Many devices are developed or modified by increments, so they are not completely novel. It may be possible to draw on the clinical experience and literature reports of the safety and performance of an equivalent device to establish the clinical evidence, thereby reducing the need for clinical data generated through clinical investigation of the device under evaluation. Similarly, it may be possible to use compliance with harmonized standards to satisfy the clinical evidence requirements for devices based on technologies with well-established safety and performance characteristics.

It should be noted that it may be possible to utilize the clinical experience and literature reports of the safety and performance of an equivalent device to establish clinical evidence. Similarly, it may be possible to use compliance with harmonized standards to satisfy the clinical evidence requirements for

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devices based on technologies with well-established safety and performance characteristics. • Stage 1: Identification of Pertinent Data This section deals with data generated and held by the manufacturer and data retrieved from literature. Data generated and held by the manufacturer come in various forms as listed in the table below. Literature searching on the other hand, is used to identify data not held by the manufacturer that are needed for the clinical evaluation. Various sources are also identified. 8.1. Data Generated and Held by the Manufacturer Data generated and held by the manufacturer typically include the following items (not a complete list): • All pre market clinical investigations. • All clinical data generated from risk management activities and the PMS programs which the manufacturer has implemented in Europe and in other countries, including the following items (not a complete list): o PMCF studies, such as post-market clinical investigations and any device registries sponsored by the manufacturer; o PMS reports, including vigilance reports and trend reports; o the literature search and evaluation reports for PMS; o incident reports sent to the manufacturer (including the manufacturer’s own evaluation and report); o complaints regarding performance and safety sent to the manufacturer, including the manufacturer’s own evaluation and report; o analysis of explanted devices (as far as available); o details of all field safety corrective actions; o use as a custom-made device; o use under compassionate use/humanitarian exemption programs; o other user reports. • Relevant pre-clinical studies (e.g., bench test reports including verification and validation data). With regard to those data: • All data generated and held by the manufacturer need to be identified. • Complete data need to be entirely disclosed and made available to the evaluators; this includes data from Europe and other countries; it includes clinical studies as well as use data. • All data sets should be documented (adequately summarized [11], appraised, analyzed, and referenced) in the CER.

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8.2. Data Retrieved from Literature Literature searching is used to identify data not held by the manufacturer that are needed for the clinical evaluation. Literature searching identifies potential sources of clinical data for establishing: • Clinical data relevant to the device under evaluation, which are data that relate either to the device under evaluation or to the equivalent device (if equivalence is claimed). • Current knowledge/the state of the art. Includes applicable standards and guidance documents, data that relate to benchmark devices, other devices, critical components and medical alternatives or to the specific medical conditions and patient populations intended to be managed with the device. The data are typically needed in order to describe the clinical background and identify the current knowledge/state of the art in the corresponding medical field: o Identify potential clinical hazards (including hazards due to substances and technologies, manufacturing procedures and impurity profiles); o Justify the validity of criteria used for the demonstration of equivalence (if equivalence is claimed); o Justify the validity of surrogate endpoints (if surrogate endpoints are used). The following aspects should be considered for literature searching: • The searching strategy should be thorough and objective, i.e., it should identify all relevant favorable and unfavorable data. For some devices, clinical data generated through literature searching will represent the greater part (if not all) of the clinical evidence. Thus, when conducting a literature review a comprehensive search should be conducted. If a comprehensive search is not deemed necessary, reasons should be documented. • Several searches with different search criteria or focus are usually necessary to obtain the necessary data. For additional information, see Appendix A4 (Sources of literature). • A literature search and other retrieval of data are carried out based on a search protocol. The search protocol documents the planning of the search before execution. For additional information, see Appendix A5 (Literature search and literature review protocol, key elements) and Appendix A6 (appraisal of clinical data – examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety). • Once the searches have been executed, the adequacy of the searches should be verified and a literature search report should be compiled to present details of the execution, any deviations from the literature search protocol, and the results of the search. • It is important that the literature search is documented to such degree that the methods can be appraised critically, the results can be verified, and the search reproduced if necessary.

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Abstracts lack sufficient detail to allow issues to be evaluated thoroughly and independently, but may be sufficient to allow a first evaluation of the relevance of a paper. Copies of the full text papers and documents should be obtained for the appraisal stage. The literature search protocol(s), the literature search report(s), and full text copies of relevant documents, become part of the clinical evidence and in turn, the technical documentation for the medical device.

•

Stage 2: Appraisal of Pertinent Data

9.1. General Considerations In order to determine the value of the data identified in stage 1, the evaluators should appraise each individual document in terms of its contribution to the evaluation of the clinical performance and clinical safety of the device. Uncertainty arises from two sources: the methodological quality of the data, and the relevance of the data to the evaluation of the device in relation to the different aspects of its intended purpose. Both sources of uncertainty should be analyzed to determine a weighting for each data set. The evaluators should therefore: • Identify information contained in each document; • Evaluate the methodological quality of work done by the authors and from that, the scientific validity of the information; • Determine the relevance of the information to the clinical evaluation; and • Systematically weight the contribution of each data set to the clinical evaluation. 9.2. The Appraisal Plan To ensure systematic and unbiased appraisal of the data, the evaluators should set up an appraisal plan that describes the procedure and the criteria to be used for the appraisal. • The appraisal plan typically includes: o criteria for determining the methodological quality and the scientific validity of each data set. o criteria for determining the relevance to the clinical evaluation (relevance to the device and to the different aspects of its intended purpose). o criteria for weighting the contribution of each data set to the overall clinical evaluation. • The appraisal should be thorough and objective, i.e., it should identify and attribute adequate weighting both to favorable and unfavorable contents of each document. • The criteria adopted for the appraisal should reflect the nature, history, and intended clinical use of the device. They should be documented and justified on the basis of current knowledge/the state of the art, applying accepted scientific standards. • There are many acceptable ways, both qualitative and quantitative, by which the appraisal can be carried out. For many well-established devices and lower-risk devices, qualitative data may be adequate to fulfill the requirements of the MDD and AIMDD. The evaluation criteria should be adjusted accordingly. • The appraisal plan should be documented in the CER.

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9.3. Conduct of the Appraisal The evaluators should: • Follow the pre-defined appraisal plan strictly and apply its criteria consistently throughout the appraisal; • Base their appraisal on the full text of publications and of other documents (not abstracts or summaries), so as to review all of the contents, the methodology employed, the reporting of results, the validity of conclusions drawn from the investigation or report, and evaluate any limitations and potential sources of error in the data; • Document the appraisal in the CER to the extent that it can be critically reviewed by others. 9.3.1. How to Evaluate Methodological Quality and Scientific Validity The evaluators should examine the methods used to generate/collect the data and evaluate the extent to which the observed effect (performance or safety outcomes) can be considered to be due to intervention with the device or due to: • Confounding influences (e.g., the natural course of the underlying medical condition/regression to the mean, concomitant treatments) bias; • Random error; • Inadequate disclosure of information; • Misinterpretation. Some papers considered unsuitable for demonstration of adequate performance because of poor elements of the study design or inadequate analysis may still contain data suitable for safety analysis or vice versa. Examples of aspects that can be taken into consideration for evaluating the methodological quality and the scientific validity of the evidence are detailed below. a. Study Design of Pre-Market and Post-Market Clinical Investigations: Considerations may need to include: • Adequacy of the sample size and power calculation; • Adequacy and relevance of endpoints (including validity of surrogate endpoints, if used); • Adequacy of applied controls (including choice of the study type and of comparators, if applicable); • Prospective randomization of patients (in case of multiple treatment arms); • Adequacy of inclusion and exclusion criteria, and of stratification of patients (e.g., in respect to age, medical indication, severity of the condition, gender, other prognostic factors);

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Distribution of prognostic factors (in case of multiple groups, were the groups comparable for these factors?); • Blinding of patients (may include use of sham devices or sham surgery), professional users, outcome assessors (blinded endpoints); • Adequacy of the follow-up period, including if follow-up was long enough for outcomes to occur, and if follow-up was frequent enough to detect temporary side effects and complications (such as prolonged wound healing); • Reliability of the methods used for quantifying symptoms and outcomes (including validation of the methods); • Adequate recording and reporting of serious adverse events and device deficiencies; • Adequate handling of medications and concomitant interventions; • Adequacy of procedures for retrieving complete information (e.g., procedures to be applied when contacts with patients are lost, disclosure of reasons for patients leaving the study, conduct of sensitivity analysis for determining if missing data affect conclusions). The evaluators should verify whether clinical investigations have been defined in such a way as to confirm or refute the manufacturer’s claims for the device; and whether these investigations include an adequate number of observations to guarantee the scientific validity of the conclusions. b. Additional Aspects for Appraisal of the Quality of Clinical Investigations Generated and Held by the Manufacturer: Where a clinical investigation has been carried out by or on behalf of a manufacturer, it is expected that documentation relating to the design, ethical, and regulatory approvals, conduct, results, and conclusions of the investigation needed for the clinical evaluation will be available for consideration, as appropriate. These may include: • Clinical investigation plan amendments and the rationale for these changes; • Case report form templates, monitoring, and audit records; • The relevant ethics committee documentation; • Regulatory authority approvals as required by applicable regulations; • The signed and dated clinical investigation report (for investigations that are terminated); • The latest intermediate report available and the latest collation on serious adverse events (for investigations that are ongoing); • When a clinical investigation is conducted outside of the EU, an analysis whether the results are transferable to the European population; • A gap analysis, when a clinical investigation is conducted to standards different from EN ISO 14155; the gap analysis should contain sufficient information to be read and understood by an independent party.

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The clinical investigation plan sets out how the study was intended to be conducted. It contains important information about the study design such as the selection and assignment of participants to treatment, masking (blinding of participants and investigators) and measurement of responses to treatment, which may be important sources of bias that can be assessed and possibly discounted when trying to determine the actual performance of the device. In addition, the clinical investigation plan sets out the intended participant follow-up, approaches to statistical analyzes and methods for recording outcomes, which may impact on the quality, completeness, and validity of results obtained for performance and safety outcomes. Also, by having the clinical investigation plan, its amendments and the clinical investigation report available, the evaluators will be able to assess the extent to which the investigation was conducted as planned and where deviations from the original plan have occurred, the impact those deviations had on the veracity of the data generated and the conclusions that can be drawn from the investigation about the performance and safety of the device. The clinical investigation report should be signed by the sponsor and the coordinating or principal investigator to provide assurance that the report is an accurate reflection of the conduct and results of the clinical investigation. Another important consideration of the evaluation will be to assess whether the conduct of the investigation was in accordance with applicable regulations, and in accordance with the current applicable ethical standards that have their origin in the Declaration of Helsinki. Clinical investigations not in compliance with applicable ethical standards, medical device standards (for example EN ISO 14155 or comparable standards) or regulations should not be used for demonstration of performance and/or safety of the device. The reasons should be noted in the report. c. Information Derived from Vigilance Data, Device Registry Data, Case Series, Patient Dossiers, and Other Use Data: Evaluators need to consider significant differences between sources of information in respect to: • Procedures used for retrieving information about outcomes; • Quality aspects of registers and patient dossiers. In case of information based on vigilance reporting, evaluators should consider that expected undesirable side-effects and complications of devices are not reportable under the vigilance reporting system. Under-reporting or lack of reporting of expected side effects or complications by users is common. Therefore, the vigilance system does not typically deliver adequate information about the true frequency of expected undesirable side-effects and complications. Systematic scientific data are needed for such purposes. Vigilance data, including trend analysis, should be used for identification of unexpected risks. In case of information based on device registries, case series, retrospective analyzes of patient dossiers, and other use data, the retrieval of information about outcomes may be incomplete and unreliable (have all the patients been considered? are the patients representative of the use of the device? did the register/professional lose contact with patients if they moved on to different professionals? was there a passive or active follow-up of patients by the professionals involved? for how long?).

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Significant differences may exist between device registries. For instance, they may offer an important or limited coverage of a country. The evaluators should take into account the possibility of patients leaving the coverage of a registry or the follow-up of a professional when experiencing serious adverse outcomes. In routine practice, there are also significant differences in the duration of the follow-up of patients by surgeons and other professionals, and in the quality of patient dossiers and data retrieval. For clinical experience data it is important that any reports or collations of data (e.g., the manufacturer’s PMS reports) contain sufficient information for the evaluators to be able to undertake a rational and objective evaluation of the information and make a conclusion about its significance with respect to the performance and safety of the device in question. Reports of clinical experience that are not adequately supported by data, such as anecdotal reports or opinions, may contribute to the evaluation, e.g., for the identification of unexpected risks, but should not be used as proof of adequate clinical performance and clinical safety of the device. d. Data Processing and Statistics: Aspects to consider may include: • Suitability of methods for data processing (transforming data that are suitable for analysis), converting data to a consistent format, reconstructing missing statistics from other statistics, dealing with missing data. • Exclusions from the analysis and their implications (including disclosure and adequacy of the intention-to-treat and per-protocol populations, disclosure of results from both the intention-to-treat and the per-protocol populations). • Adequacy of statistical methods. e. Quality Assurance: • Compliance with GCP, such as EN ISO 14155 or equivalent standards; • Compliance with the clinical investigation plan, independent monitoring and auditing; • Compliance with legal requirements. While a publication in a renowned peer reviewed scientific journal is generally accepted as an indicator of scientific quality, such publication is not considered an acceptable reason for bypassing or reducing appraisal activities. f. Report Quality: Evaluators should consider: • Adequacy of disclosure of methods used. • Adequacy of disclosure of data, including: o completeness of the reporting of adverse events and outcomes; o sufficient description about the distribution of prognostic factors in the study population and in different study arms; o disclosure of all the results the study was originally designed to generate. • Validity of conclusions drawn by the authors (example: conclusions not in line with the results section of the document). Possible conflicts of interest of the authors of the publications should also be taken into consideration.

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It is recognized that, where manufacturers source clinical investigation data reported in the scientific literature, the documentation readily available to the manufacturer for inclusion in the clinical evaluation is likely to be no more than the published paper itself. In case of missing information, the rating of the methodological quality of a publication may need to be downscaled. For additional information see Appendix A6 (appraisal of clinical data – examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety). 9.3.2. How to Determine the Relevance of a Data Set for the Clinical Evaluation When evaluating the relevance of collected data it is important to consider whether the data are intended to directly demonstrate adequate clinical performance and clinical safety of the device (often referred to as pivotal data), or whether the data serves an indirect supportive role. a. Pivotal Data: • Pivotal data must have the data quality necessary for demonstration of adequate clinical performance and clinical safety of the device under evaluation (see Appendix A6, Appraisal of clinical data – examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety). • Be generated either with the device under evaluation or with an equivalent device used in its intended purpose (for an equivalent device, equivalence must be demonstrated; see Appendix A1, Demonstration of equivalence). b. Other Data: Data that are not pivotal are generally appraised and weighted for their contribution for purposes such as: • Identifying and defining the current knowledge/state of the art in the corresponding medical field, so as to define acceptability criteria for the evaluation of the benefit/risk profile and of specific side-effects of the device under evaluation. • Identifying hazards (including hazards due to substances and technologies), individual case reports may be used for identification of new and previously unknown hazards that are associated with the device. • Justifying the validity of criteria used for the demonstration of equivalence (if equivalence is claimed). • Justifying the validity of surrogate endpoints (if surrogate endpoints are used). • Providing input for the planning of pivotal studies. The corresponding information is, in general, summarized in a literature review section of the CER. c. Aspects to Consider when Determining Relevance: The table below shows examples of aspects that could be used for determining if and in what respect data are relevant to the clinical evaluation.

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Description

Examples

To what extent are the data generated representative of the device under evaluation?

• • • • •

device under evaluation; equivalent device; benchmark device; other devices and medical alternatives; data concerning the medical conditions that are managed with the device.

What aspects are covered?

• • • • • •

pivotal performance data; pivotal safety data; claims; identification of hazards; estimation and management of risks; establishment of current knowledge/the state of the art; determination and justification of criteria for the evaluation of the risk/benefit relationship; determination and justification of criteria for the evaluation of acceptability of undesirable side-effects; determination of equivalence; justification of the validity of surrogate endpoints.

• • • • Are the data relevant to the intended purpose of the device or to claims about the device?

• representative of the entire intended purpose with all patient populations and all claims foreseen for the device under evaluation; • concerns specific models/sizes/settings, or concerns specific aspects of the intended purpose or of claims; • does not concern the intended purpose or claims.

If the data are relevant to specific aspects of the intended purpose or claims, are they relevant to a specificmodel, size, or setting of the device?

• smallest/intermediate/largest size; • lowest/intermediate/highest dose, etc.

User group

• specialists; • general practitioners; • nurses [MEDDEV 2.7/1 revision 4 page 26 of 65]; • adult healthy lay persons; • disabled persons; • children, etc.

Medical indication (if applicable)

• migraine prophylaxis; • treatment of acute migraine; • rehabilitation after stroke, etc.

Age group

• pre-term infants/neonates/children/adolescents/ adults/old age.

Gender

• female/male.

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Type and severity of the medical condition

• early/late stage; • mild/intermediate/serious form; • acute/chronic phase, etc.

Range of time

• duration of application or use; • number of repeat exposures; • duration of follow-up.

9.3.3. How to Weight the Contribution of Each Data Set Based on their scientific validity and relevance, the data should be weighted according to their relative contributions. Due to the diversity of medical devices, there is no single, well-established method for weighting clinical data: • the evaluators should identify appropriate criteria to be applied for a specific evaluation; • these pre-defined criteria should be followed strictly by the evaluators. Typically, clinical data should receive the highest weighting, when generated through a well-designed and monitored randomized controlled clinical investigation (also called randomized controlled trial), conducted with the device under evaluation in its intended purpose, with patients and users that are representative of the target population. Note: It is acknowledged that randomized clinical investigations may not always be feasible and/or appropriate and the use of alternative study designs may provide relevant clinical information of adequate weighting. When rejecting evidence, the evaluators should document the reasons (both for studies and reports that have been generated and are held by the manufacturer, and for other documents identified during Stage 1). 10. Analysis of the Clinical Data (Stage 3) 10.1. General Considerations The goal of the analysis stage is to determine if the appraised data sets available for a medical device collectively demonstrate compliance with each of the ERs pertaining to the clinical performance and clinical safety of the device, when the device is used according to its intended purpose. In order to demonstrate compliance, the evaluators should: • use sound methods; • make a comprehensive analysis; • determine if additional clinical investigations or other measures are necessary; • determine PMCF needs.

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10.2. Specific Considerations a. Use Sound Methods: A literature review that describes current knowledge/the state of the art should be prepared with relevant literature identified during Stage 1 and appraised during Stage 2. Weighting criteria developed and assigned during the appraisal stage can be used to identify those sets of data, which may be considered to be pivotal. The methods available for analyzing clinical data generally are either qualitative or quantitative. Depending on the nature of the medical device and the circumstances, it is likely that qualitative (i.e., descriptive) methods will need to be used for some devices. Reliance on qualitative methods should be justified. Generally, available clinical data such as numbers of incidents in the post-market phase should be assessed quantitatively in relation to current knowledge/the state of the art. The results of the pivotal datasets should be explored, looking for consistency of results across particular device performance characteristics and identified risks. If the different datasets report similar outcomes, confidence in the robustness increases. If different results are observed across the datasets, it will be helpful to determine the reason for such differences. Regardless, all data sets should be considered and included. The reviewers should take into account the weighting attributed to data sets during Stage 2 when addressing conflicting information. Where relevant, a rationale should be given for the lack of value of a data set to the evaluation. In general, data that are not methodologically sound (such as single patient reports) should not be used for demonstration of adequate clinical performance and clinical safety of a device. For additional information, see Appendix A6 (Appraisal of clinical data – examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety). In exceptional situations, when an evaluation is based on limited data, this shall be described and justified in the CER. See additional information and specific considerations in Appendix A8 (Devices for unmet medical needs – aspects to consider). b. Make a Comprehensive Analysis: The evaluators should: • Determine compliance with each of the ERs pertaining to the clinical performance and clinical safety of the device. For detailed information concerning specific ERs, see Appendix A7 (Analysis of the clinical data-compliance to specific ERs). • The evaluation includes: o The adequacy of pre-clinical testing (e.g., bench testing, animal testing) to verify safety; o Risks to patients, users or other persons associated with the intended purpose of the device; o Benefits to patients; o Confirmation that the device achieves the performance(s) intended by the manufacturer, including all claims made by the manufacturer; o Confirmation of usability, that the design adequately reduces the risk of use error as far as possible, and that the design is adequate for the intended users (lay, professional, disabled or other users, if applicable);

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Adequacy of the information materials supplied by the manufacturer, including if risk mitigation measures are correctly addressed in the IFU (handling instructions, description of risks, warnings, precautions, contraindications, instructions for managing foreseeable unwanted situations). • Take into consideration all products covered by the clinical evaluation and all aspects of their intended purpose. Any gaps in evidence need to be identified, including in respect to information relevant to: o understanding the interaction between the device and the body; o the comprehensiveness of the available data, taking into account; o the entire range of products/models/sizes/settings covered by the evaluation; o the entire range of conditions of use and of the intended purpose; o the estimated number of patients exposed to the device; o the type and adequacy of patient monitoring; o the number and severity of adverse events; o the adequacy of the estimation of associated risk for each identified hazard; o the severity and natural history of the condition being diagnosed or treated; o current standards of care, including the availability and the benefit/risk profiles of other devices and medical alternatives. • Assess if there is consistency and alignment between the clinical evaluation, the information materials supplied by the manufacturer, and the risk management documentation for the device under evaluation; any discrepancies should be identified in order to ensure that all the hazards and other clinically relevant information have been identified and analyzed appropriately. • Assess if there is consistency between the documents mentioned above and current knowledge/the state of the art. c. Determine if Additional Clinical Investigations or Other Measures are Necessary: The evaluators should identify additional clinical investigations or other measures that are necessary in order to generate any missing data and eliminate compliance issues. Data needed to address the identified gaps should be determined so that conclusions can be drawn with confidence in relation to conformity with the ERs, including: • Evaluation of the safety, performance, and the benefit/risk profile; • Compatibility with a high level of protection of health and safety (that can be determined by considering current knowledge/the state of the art, with reference to standards and available alternatives, risk minimization, patient needs and preferences); • The acceptability of any undesirable side-effects; • The risk of use error and the adequacy of the IFU to the intended users; • Consistency between available information. See Appendix A2 for detailed information on when additional clinical investigations should be carried out.

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d. Determine PMCF Needs: In order to determine needs, the evaluators should describe residual risks and any uncertainties or unanswered questions. The evaluators should also include aspects such as rare complications, uncertainties regarding medium- and long-term performance, or safety under wide-spread use. 10.3. Where Demonstration of Conformity Based on Clinical Data Is Not Deemed Appropriate Where demonstration of conformity with ERs based on clinical data is not deemed appropriate, adequate justification for any such exclusion has to be given: • The justification must be based on the output of the risk management process. This should include an evaluation of background clinical data identified from the literature, and an appraisal of their relevance to the device under evaluation. • The device/body interaction, the clinical performances intended and the claims of the manufacturer have to be specifically considered. • Adequacy of demonstration of conformity with the ERs based on performance evaluation, bench testing and pre-clinical evaluation in the absence of clinical data has to be duly substantiated. • A clinical evaluation is still required and the above information and evidencebased justification should be presented in the CER. 11. The Clinical Evaluation Report (CER, Stage 4) A CER shall be compiled to document the clinical evaluation and its output. The CER should contain sufficient information to be read and understood by an independent party (e.g., regulatory authority or NB). Therefore, it should provide sufficient detail for understanding the search criteria adopted by the evaluators, data that are available, all assumptions made and all conclusions reached. The contents of the CER shall be cross-referenced to the relevant documents that support them. It should be clear which statements are substantiated by which data, and which reflect the conclusions or opinions of the evaluators. The report should include references to literature-based data and the titles and investigational codes (if relevant and available) of any clinical investigation reports, with cross-references to the location in the manufacturer’s technical documentation. The amount of information may differ according to the history of the device or technology. Where a new device or technology has been developed, the report would need to include an overview of the developmental process and the points in the development cycle at which all clinical data have been generated. It is important that the report outlines the different stages of the clinical evaluation:

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• Stage 0: Scope of the Clinical Evaluation: o o

•

o o

•

o o o o

•

o

o o o

o o o o

Explains the scope and context of the evaluation, including which products/models/sizes/settings are covered by the CER, the technology on which the medical device is based, the conditions of use and the intended purpose of the device. Documents any claims made about the device’s clinical performance or clinical safety. Stage 1: Identification of Pertinent Data: Explains the literature search strategy; Presents the nature and extent of the clinical data and relevant pre-clinical data that have been identified. Stage 2: Appraisal of Pertinent Data: Explains the criteria used by the evaluators for appraising data sets; Summarizes the pertinent data sets (methods, results, conclusions of the authors); Evaluates their methodological quality, scientific validity, the relevance for the evaluation, the weighting attributed to the evidence, and any limitations; Presents justifications for rejecting certain data or documents. Stage 3: Analysis of the Clinical Data: Explains if and how the referenced information, such as confirmation of compliance with clinical data requirement from applicable harmonized standards and the clinical data, constitute sufficient clinical evidence for demonstration of the clinical performance and clinical safety of the device under evaluation; Explains whether there are adequate data for all aspects of the intended purpose and for all products/models/sizes/settings covered by the clinical evaluation; Describes the benefits and risks of the device (their nature, probability, extent, duration, and frequency); Explains the acceptability of the benefit/risk profile according to current knowledge/the state of the art in the medical fields concerned, with reference to applicable standards and guidance documents, available medical alternatives, and the analysis and conclusions of the evaluators on fulfillment of all ERs pertaining to clinical properties of the device (MDD ER1, ER3, ER6; AIMDD ER1, ER2, ER5); Analyzes if there is consistency between the clinical data, the information materials supplied by the manufacturer, the risk management documentation for the device under evaluation; Whether there is consistency between these documents and the current knowledge/the state of the art; Identifies any gaps and discrepancies; Identifies residual risks and uncertainties or unanswered questions (such as rare complications, uncertainties regarding medium- and long-term performance, safety under wide-spread use) that should be further evaluated during PMS, including in PMCF studies.

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The evaluators should check the CER, provide verification that it includes an accurate statement of their analysis and opinions, and sign the report. They should provide their CV and their declaration of interests to the manufacturer. The CER should be dated and version controlled. A suggested format for the CER is located at Appendix A9 (CER – proposed table of contents, examples of contents). Suggestions for aspects that should be checked for the release of a CER are summarized in Appendix A10 (Proposed checklist for the release of the CER). Information on declaration of interests can be found in Appendix A11 (Information on declarations of interests). 12. The Role of the Notified Body (NB) in the Assessment of Clinical Evaluation Reports (CERs) The NB plays a key role in the assessment and verification of CERs and supporting documentation provided by medical device manufacturers to support demonstration of conformity of a device with the ERs of the relevant directive. Detailed recommendations for notified bodies are given in Appendix A12 (Activities of notified bodies). These include: • Guidance for notified bodies on the assessment of CERs provided by medical device manufacturers as part of technical documentation (including design dossiers); and • Guidance for NB in development of their internal procedures for assessment of clinical aspects relating to medical devices. In addition, documents of the notified bodies operations group (NBOG) should also be consulted. NBOG documents include best practice guides, checklists, and forms. Pursuant to Section 6a of Annex I MDD and to Section 5a of Annex 1 AIMDD, the demonstration of conformity with the ERs must include a clinical evaluation conducted in accordance with Annex X of Directive 93/42/EEC or with Annex 7 AIMDD. This is applicable for all classes of medical device. Where demonstration of conformity with ERs based on clinical data is not deemed appropriate this must be adequately justified by the manufacturer and based on the output of the risk management process. The device-body interaction, the intended purpose and the claims of the manufacturer have to be specifically considered. The adequacy of demonstration of conformity based on performance evaluation, bench testing and pre-clinical evaluation in the absence of clinical data must be duly substantiated. The NB must review the manufacturer’s justification, the adequacy of data presented and whether or not conformity is demonstrated. Nevertheless, a clinical evaluation is still required and the above information and an evidenced justification should be presented as the clinical evaluation for the device in question.

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A1. Demonstration of Equivalence Pursuant to Annex X of Directive MDD and Annex 7 AIMDD, the evaluation of clinical data (i.e., the clinical evaluation), where appropriate taking account of any relevant harmonized standards, must follow a defined and methodologically sound procedure based on: 1. either a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, where: • there is demonstration of equivalence of the device to which the data relates; and • the data adequately demonstrate compliance with the relevant ERs. 2. or a critical evaluation of the results of all clinical investigations made. 3. or a critical evaluation of the combined clinical data provided from 1 and 2. Clinical, technical, and biological characteristics shall be taken into consideration for the demonstration of equivalence: a. Clinical: • used for the same clinical condition (including when applicable similar severity and stage of disease, same medical indication); • used for the same intended purpose; • used at the same site in the body; • used in a similar population (this may relate to age, gender, anatomy, physiology, possibly other aspects); • not foreseen to deliver significantly different performances (in the relevant critical performances such as the expected clinical effect, the specific intended purpose, the duration of use, etc.). b. Technical: • be of similar design; • used under the same conditions of use; • have similar specifications and properties (e.g., physicochemical properties such as type and intensity of energy, tensile strength, viscosity, surface characteristics, wavelength, surface texture, porosity, particle size, nanotechnology, specific mass, atomic inclusions such as nitrocarburizing, oxidability); • use similar deployment methods (if relevant); • have similar principles of operation and critical performance requirements. c. Biological: Use the same materials or substances in contact with the same human tissues or body fluids. Exceptions can be foreseen for devices in contact with intact skin and minor components of devices; in these cases, risk analysis results may allow the use of similar materials taking into account the role and nature of the similar material. Different aspects of equivalence and compliance to different ERs can be affected by materials. Evaluators should consider biological safety (e.g., in compliance to ISO 10993) as well as other aspects necessary for a comprehensive demonstration of equivalence. A justification explaining the situation should be provided for any difference.

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For assuming equivalence: • Equivalence can only be based on a single device [14]. • All three characteristics (clinical, technical, biological) need to be fulfilled. • Similar means that no clinically significant difference in the performance and safety of the device would be triggered by the differences between the device under evaluation and the device presumed to be equivalent. • The differences between the device under evaluation and the device presumed to be equivalent need to be identified, fully disclosed, and evaluated; explanations should be given why the differences are not expected to significantly affect the clinical performance and clinical safety of the device under evaluation. • The manufacturer should investigate if the medical device presumed to be equivalent has been manufactured via a special treatment (e.g., a surface modification, a process that modifies material characteristics); if this is the case, the treatment could cause differences in respect to technical and biological characteristics; this should be taken into account for the demonstration of equivalence and documented in the CER. • If measurements are possible, clinically relevant specifications and properties should be measured both in the device under evaluation and the device presumed to be equivalent, and presented in comparative tabulations. • Comparative drawings or pictures should be included in order to compare shapes and sizes of elements that are in contact with the body. • The manufacturer is expected to: o Include the supporting non-clinical information (e.g., pre-clinical study reports) in the technical documentation of the device; and o In the CER, summarize the information and cite its location in the technical documentation; • For the evaluation of the technical characteristics, devices that achieve the same therapeutic result by different means cannot be considered equivalent. • For the evaluation of the biological characteristics: o When a detailed chemical characterization of materials in contact with the body is needed, ISO 10993-18 Annex C can be used to show toxicological equivalence but this is just a part of the evaluation of the biological criteria. o Sourcing and manufacturing procedures may adversely affect impurity profiles; analytical methods chosen to characterize medical devices should appropriately take into consideration knowledge concerning expected impurity profiles (tests may have to be repeated when production methods or sourcing are changed). o It may be necessary to show from histopathological studies that the same host response is achieved in vivo in the intended application and the intended duration of contact. o For animal tests, differences between species may limit the predictive value of the test; the choice of the test and its predictive value should be justified. o Abrasion, if relevant, and host response to particles may also need to be considered.

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• The only clinical data that are considered as relevant are the data obtained when the equivalent device is a CE-marked medical device used in accordance with its intended purpose as documented in the IFU. A2. When Should Additional Clinical Investigations be Carried Out? a. How should manufacturers and evaluators decide if there is sufficient clinical evidence? When clinical data are required in order to draw conclusions as to the conformity of a device to the ERs, the data need to be in line with current knowledge/the state of the art, be scientifically sound, cover all aspects of the intended purpose, and all products/models/sizes/settings foreseen by the manufacturer. If gaps are present that cannot be addressed by other means, clinical investigations should be planned and carried out. b. Considerations: Implants and high-risk devices, those based on technologies where there is little or no experience, and those that extend the intended purpose of an existing technology (i.e., a new clinical use) are most likely to require clinical investigation data. For compliance with Annex X Section 1.1.a MDD and Annex 7 AIMDD, clinical investigations with the device under evaluation are required for implantable and class III devices unless it can be duly justified to rely on existing clinical data alone. The need for clinical investigations depends on the ability of the existing data to adequately address the benefit/risk profile, claims, and side-effects in order to comply with the applicable ERs. Clinical investigations may therefore also be required for other devices, including for devices in class I and class IIa, and for class IIb devices that are not implantable. When deciding if additional clinical investigations need to be carried out, the manufacturer should perform a detailed gap analysis. The gap analysis should determine whether the existing data are sufficient to verify that the device is in conformity with all the ERs pertaining to clinical performance and clinical safety. Special attention should be given to aspects such as: • New design features, including new materials; • New intended purposes, including new medical indications, new target populations (age, gender, etc.); • New claims the manufacturer intends to use; • New types of users (e.g., lay persons); • Seriousness of direct and/or indirect risks; • Contact with mucosal membranes or invasiveness; • Increasing duration of use or numbers of re-applications; • Incorporation of medicinal substances; • Use of animal tissues (other than in contact with intact skin); • Issues raised when medical alternatives with lower risks or more extensive benefits to patients are available or have become newly available [15];

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Issues raised when new risks are recognized (including due to progress in medicine, science, and technology); • Whether the data of concern are amenable to evaluation through a clinical investigation, etc. Data on the safety and performance of other devices and alternative therapies, including benchmark devices and equivalent devices, should be used to define the state of the art or identify hazards due to substances and technologies. This will allow the clinical data requirements to be established more precisely in relation to the intended purpose of a device. Precision in this analysis and the choice of selected medical indications and target populations may reduce the amount of clinical data needed from additional clinical investigations.

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A3. Device Description – Typical Contents The description should be detailed enough to allow for a valid evaluation of the state of compliance with ERs, the retrieval of meaningful literature data and if applicable, the assessment of equivalence to other devices described in the scientific literature: • Name, models, sizes, components of the device, including software and accessories; • Device group to which the device belongs (e.g., biological artificial aortic valve); • Whether the device is being developed/undergoing initial CE-marking/is CEmarked; • Whether the device is currently on the market in Europe or in other countries, since when, number of devices placed on the market; • Intended purpose of the device: o Exact medical indications (if applicable); o Name of disease or condition/clinical form, stage, severity/symptoms or aspects to be treated, managed or diagnosed; o Patient populations (adults/children/infants, other aspects); o Intended user (use by health care professional/lay person); o Organs/parts of the body/tissues or body fluids contacted by the device; o Duration of use or contact with the body; o Repeat applications, including any restrictions as to the number or duration of reapplications; o Contact with mucosal membranes/invasiveness/implantation; o Contraindications; o Precautions required by the manufacturer; o Single use/reusable; o Other aspects. • General description of the medical device including: o A concise physical and chemical description; o The technical specifications, mechanical characteristics; o Sterility; o Radioactivity; o How the device achieves its intended purpose; o Principles of operation; o Materials used in the device with focus on materials coming in contact (directly or indirectly) with the patient/user, description of body parts concerned; o Whether it incorporates a medicinal substance (already on the market or new), animal tissues, or blood components, the purpose of the component; o Other aspects. • Whether the device is intended to cover medical needs that are otherwise unmet/ if there are medical alternatives to the device/if the device is equivalent to an existing device, with a description of the situation and any new features. • If the device is intended to enter the market based on equivalence:

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• • •

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Name, models, sizes, settings components of the device presumed to be equivalent, including software and accessories; Whether equivalence has already been demonstrated. Intended performance, including the technical performance of the device intended by the manufacturer, the intended clinical benefits, claims regarding clinical performance and clinical safety that the manufacturer intends to use. For devices based on predecessor devices: Name, models, sizes of the predecessor device, whether the predecessor device is still on the market, description of the modifications, date of the modifications. The current version number or date of the information materials supplied by the manufacturer (label, IFU, available promotional materials and accompanying documents possibly foreseen by the manufacturer).

A4. Sources of Literature There are different sources of clinical literature that can be searched for clinical evaluation. A comprehensive search strategy is required, normally involving multiple databases. The search strategy should be documented and justified. Important sources include the following: a. Scientific Literature Databases: • MEDLINE or PubMed can provide a good starting point for a search. However, with possibly incomplete coverage of European Journals and reduced search features, comprehensiveness may not necessarily be guaranteed. • Additional databases may need to be used to ensure adequate coverage of devices and therapies in use in Europe, to identify relevant clinical trials and publications of user experience, and to facilitate searches by device name and manufacturer (e.g., EMBASE/Excerpta Medica, the Cochrane CENTRAL trials register, etc.). • Information coverage and search features available in scientific databases can change with time. Criteria for selecting adequate databases therefore need to be defined and reevaluated on a regular basis. b. Internet Searches: Searches provide important data; examples include information on: • Harmonized standards and other standards applicable to the device in question and containing information on clinical performance and clinical safety. • Field safety corrective actions for the equivalent and/or other devices. These can be found on manufacturer’s web sites, internet sites of European Competent authorities, the U.S. Food and Drug Administration (FDA), possibly other sites. • Implant registry reports. • Documents available in systematic review databases (e.g., the Cochrane Database of Systematic Reviews, Prospero international prospective register of systematic reviews).

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•

Expert documents produced by professional medical associations that are important for assessment of current knowledge/the state of the art, including clinical practice guidelines and consensus statements. • Meta-analyzes and reviews of health technology assessment (HTA) institutes and networks. • Identification of studies via the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov. c. Non-Published Data: These are important for many devices and retrieval of such data should be considered, including for monitoring of any changes, e.g.: • The label and IFU of the equivalent device (if equivalence is claimed by the manufacturer) and/or of benchmark devices and other devices. • Data provided to manufacturers from implant registries. • Data presented at congresses. Citations referenced in scientific literature can be important and should be screened. Literature found to be relevant is likely to cite other literature that is of direct interest to the manufacturer. Additionally, it may be necessary to retrieve some of the referenced literature in order to appraise the scientific quality of a document. A5. Literature Search and Literature Review Protocol, Key Elements The output of the literature search and literature review are: • Literature on the device in question and the equivalent device. Note: If the manufacturer holds own clinical data for the device in question (e.g., own premarket clinical investigations, PMCF Studies, other PMS data), the literature is considered together with those data for consistent appraisal and overall analysis. • A review of the current knowledge/the state of the art needed for the proper conduct of the appraisal and analysis of the clinical data of the device under evaluation and the equivalent device (i.e., applicable standards and guidance documents, information on the medical conditions that are relevant to the clinical evaluation, therapeutic/management/diagnostic options available for the intended patient population, etc.). The literature collected may relate directly to the device in question (e.g., publications of clinical investigations of the device in question that have been performed by third parties, its side effects or complications, incidence reports) and/or to equivalent device, benchmark devices, other devices and medical alternatives available to the intended patient population. The literature search and literature review protocol should address the background to and the objective of the review, specifying the literature review questions and the methods for identification, selection, collection, and appraisal of the relevant publications needed to address them. It should include the literature search methodology (literature search protocol).

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The selection of literature should be objective and justified, i.e., include all relevant data, both favorable and unfavorable. With respect to the clinical evaluation, it is important that the clinical evaluators are able to assess the degree to which the selected papers reflect the intended application/use of the device. Objective, non-biased, systematic search and review methods should be used. Examples are: • PICO (patient characteristics, type of intervention [17], control, and outcome queries). • Cochrane handbook for systematic reviews of interventions. • PRISMA (The preferred reporting items for systematic reviews and meta-analyzes) statement. • MOOSE proposal (meta-analysis of observational studies in epidemiology). The protocol should specify the elements described below, addressing the background, objective, and methods for identification, selection, and collection of the relevant publications to address the literature review questions. A5.1. Background to the Literature Search and the Literature Review This section documents the importance of and rationale for the literature review and includes, but is not limited to: • Device name/model. • Importance of literature review to risk management process. The literature review will provide data on current interventions [18] for the intended patient population (state of the art) in order to give input to the assessments of acceptable benefit/risk profiles, what is currently considered as providing a high level of protection of health and safety and what are considered acceptable sideeffects. • Previous literature reviews. • Importance of review to risk management process. • Previous literature searches conducted by the manufacturer. • If including equivalent or benchmark devices, name, and model of the devices. • The CER will need to establish equivalence to the device under evaluation or the relevance of benchmark devices to the clinical evaluation. A5.2. Objective This section documents the research question(s), which should be consistent with the scope of the clinical evaluation and carefully constructed using a process (e.g., PICO): • Population(s)/disease(s) or condition(s); • Intervention(s); • Comparator group(s)/control(s); • Outcome(s)/endpoint(s).

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The inputs for the review question(s) (e.g., PICO) are the device description and the intended performance of the device including any claims on clinical performance and clinical safety which the manufacturer wants to use. Also, information from the risk management process is needed as an input. A5.3. Methods The methods section of the protocol documents the plans for literature search, study selection, data collection, and analysis methods. It defines the literature search strategy and the inclusion/exclusion criteria for the documents found. The protocol should include: • The literature search methodology. The purpose of a literature search protocol is to plan the search before execution. It should be developed and executed by persons with expertise in information retrieval, having due regard to the scope of the clinical evaluation set out by the manufacturer. The involvement of information retrieval experts will help to optimize literature retrieval to identify all relevant published literature. The importance of a literature search protocol is for critical appraisal of the methods. The search strategy should be based on carefully constructed review questions. • The sources of data that will be used and a justification for their choice (see Appendix A4, Sources of literature). • The extent of any searches of scientific literature databases (the database search strategy). • Attempts to identify all published literature. • Which electronic databases are to be searched, with justification. • The extent of any Internet searching and searching non-published information, including the search strategy and justification. • Exact search terms and any limits. • Limits for start and end dates of each search. • The selection/criteria (such as inclusion/exclusion criteria) to be applied to published literature and justification for their choice. • Strategies for addressing the potential for duplication of data across multiple publications. • Strategies for avoiding retrieving publications of data generated and already held by the manufacturer. • The data collection plan that defines data management practices to ensure data integrity during extraction (e.g., quality control/second review of extracted data by additional reviewer). • The appraisal plan, which defines the methods for appraising each publication, including the relevance of the data to the intended clinical use and the methodological quality of the data. • The analysis plan, which defines the methods for analyzing the data including data processing and transformation. Any deviations from the literature search protocol should be noted in the literature search report.

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A6. Appraisal of Clinical Data – Examples of Studies That Lack Scientific Validity for Demonstration of Adequate Clinical Performance and/or Clinical Safety a. Lack of Information on Elementary Aspects: This includes reports and publications that omit disclosure of: • the methods used; • the identity of products used; • numbers of patients exposed; • what the clinical outcomes were; • all the results the clinical study or investigation planned to investigate; • undesirable side-effects that have been observed; • confidence intervals/calculation of statistical significance; • if there are intent-to-treat and per protocol populations: definitions and results for the two populations. b. Numbers too Small for Statistical Significance: Includes publications and reports with inconclusive preliminary data, inconclusive data from feasibility studies, anecdotal experience, hypothesis papers and unsubstantiated opinions. c. Improper Statistical Methods: This includes: • Results obtained after multiple subgroup testing, when no corrections have been applied for multiple comparisons. • Calculations and tests based on a certain type of distribution of data (e.g., Gaussian distribution with its calculations of mean values, standard deviations, confidence intervals, t-tests, others tests), while the type of distribution is not tested, the type of distribution is not plausible, or the data have not been transformed. Data such as survival curves, e.g., implant survival, patient survival, symptomfree survival, are generally unlikely to follow a Gaussian distribution. d. Lack of Adequate Controls: In the following situations, bias or confounding are probable in single arm-studies and in other studies that do not include appropriate controls: • when results are based on subjective endpoint assessments (e.g., pain assessment). • when the endpoints or symptoms assessed are subject to natural fluctuations (e.g., regression to the mean when observing patients with chronic diseases and fluctuating symptoms, when natural improvement occurs, when the natural course of the disease in a patient is not clearly predictable). • when effectiveness studies are conducted with subjects that are likely to take or are foreseen to receive effective co-interventions (including over-the-counter medication and other therapies). • when there may be other influencing factors (e.g., outcomes that are affected by variability of the patient population, of the disease, of user skills, of infrastructure available for planning/intervention/aftercare, use of prophylactic medication, other factors).

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when there are significant differences between the results of existing publications, pointing to variable and ill controlled influencing factors. In the situations described above, it is generally not adequate to draw conclusions based on direct comparisons with external or historic data (such as drawing conclusions by comparing data from a clinical investigation with device registry data or with data from published literature). Different study designs may allow direct comparisons and conclusions to be drawn in these situations, such as randomized controlled design, cross-over design, or split-body design. e. Improper Collection of Mortality and Serious Adverse Events Data: Demonstration of adequate benefits and safety is sometimes based on mortality data or occurrence of other serious outcomes that limit a subject’s ability to live in his home and be available for follow-up contacts. In this type of study: • Consent of the subjects for contacting reference persons/institutions for retrieval of medical information should be obtained during recruitment; when subjects can no longer be found, outcomes should be investigated with the reference persons/ institutions. • The consequences of missing data on the results should be analyzed (e.g., with a sensitivity analysis); alternatively, when patients can no longer be found and their outcomes cannot be identified, they should be considered to meet the SAE endpoint under investigation (e.g., the mortality endpoint of a study). In mortality studies (and other studies addressing serious outcomes) procedures for investigating serious patient outcomes, numbers of subjects lost to followup, reasons why subjects leave the study, and the results of sensitivity analysis should be fully disclosed in reports and publications. f. Misinterpretation by the Authors: Includes conclusions that are not in line with the results section of the report or publication, such as: • Reports and publications not correctly addressing lack of statistical significance/ confidence intervals that encompass the null hypothesis; • Effects too small for clinical relevance. g. Illegal Activities: Includes clinical investigations not conducted in compliance with local regulations. Clinical investigations are generally expected to be designed, conducted, and reported in accordance with EN ISO 14155 or to a comparable standard, and in compliance with local regulations and the Declaration of Helsinki.

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A7. Analysis of the Clinical Data – Compliance to Specific Essential Requirements (ERs) While this appendix describes the needs for the clinical evaluation (MDD ER1, ER3, ER6; AIMDD ER1, ER2, ER5), there may be additional essential requirement(s) that need support of sufficient clinical evidence for the conformity assessment. A7.1. Conformity Assessment with Requirement on Safety (MDD ER1/ AIMDD ER1) The information materials supplied by the manufacturer (including label, IFU, available promotional materials including accompanying documents possibly foreseen by the manufacturer), should be reviewed to ensure they are consistent with the relevant clinical data appraised in stage 2 and that all the hazards, information on risk mitigation and other clinically relevant information have been identified appropriately. Input from the risk management and the use of standards: • Risk management documents should determine if all identified hazards are fully covered by harmonized standards or other relevant standards or if there are gaps needed to be covered by clinical data. • Risk management documents should determine if all identified risks relating to patient treatment, method of operation of the device or risks relating to usability have been minimized or if there are question regarding clinical risks that need to be solved. • Harmonized standards are generally expected to be applied in full in order to confer a presumption of conformity. • If technical developments provide a higher level of safety than current harmonized standards, then the higher level of safety should be prioritized in order to meet the ERs on reducing the risks as far as possible, that risks must be compatible with a high level of protection of health and safety, and that side effects must be acceptable (MDD ER2 and ER3 and ER6; AIMDD ER1 and ER5). Examples: • Electrical hazards should be covered by compliance to EN 60601-1 and applicable collateral standards regarding medical electrical equipment, so that the device will not compromise the safety and health of patients or users. Under these circumstances, residual risks regarding electrical hazards are acceptable and additional clinical data are not needed unless negative issues are detected during PMS activities. • Harmonized standards on usability (EN 62366 and if applicable EN 60601-1-6) are expected to be applied to ensure that usability aspects are taken into consideration during the device development. However, they do not give guidance on a detailed level of design, while usability aspects are known to cause or contribute to a large portion of incidents. Therefore, clinical data may be needed to prove that the risk of use error, due to the ergonomic features of the device and the environment in which the device is intended to be used, has been reduced as far as possible.

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A7.2. Conformity Assessment with Requirement on Acceptable Benefit/Risk Profile (MDD ER1/AIMDD ER1) It is expected: • that the clinical evaluation demonstrates that any risks which may be associated with the intended purpose are minimized and acceptable when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety. • that the IFU correctly describe the intended purpose of the device as supported by sufficient clinical evidence. • that the IFU contain correct information to reduce the risk of use error, information on residual risks and their management as supported by sufficient clinical evidence (e.g., handling instructions, description of risks, warnings, precautions, contraindications, instructions for managing foreseeable unwanted situations). a. Evaluation of the Description of the Intended Purpose of the Device: The information materials supplied by the manufacturer (including label, IFU, available promotional materials including accompanying documents possibly foreseen by the manufacturer) should be reviewed. The evaluators should evaluate if the description provided by the manufacturer correctly identifies those medical conditions and target groups for which conformity with the relevant ERs has been demonstrated through sufficient clinical evidence. When reading the IFU, there should be no uncertainty for users as to when a given medical condition or medical indication or target population is covered by the CE marking or when it falls entirely under the user’s own responsibility (off label use). b. Evaluation of the Device’s Benefits to the Patient: Positive impacts of a device on the health of an individual should be meaningful (relevant for the patient) and measurable. The nature, extent, probability, and duration of benefits should be considered. Benefits may include: • Positive impact on clinical outcome (such as reduced probability of adverse outcomes, e.g., mortality, morbidity; or improvement of impaired body function); • The patient’s quality of life (significant improvements, including by simplifying care or improving the clinical management of patients, improving body functions, providing relief from symptoms); • Outcomes related to diagnosis (such as allowing a correct diagnosis to be made, provide earlier diagnosis of diseases or specifics of diseases, or identify patients more likely to respond to a given therapy); • Positive impact from diagnostic devices on clinical outcomes; or • Public health impact (such as to the ability of a diagnostic medical device to identify a specific disease and therefore prevent its spread, to identify phases, stages, location, severity or variants of disease, predict future disease onset). c. Quantification of Benefit(s) to the Patients: Defining specified endpoints is indispensable for setting up clinical investigations and properly performing the identification, appraisal, and analysis of the clinical data.

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•

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Benefit(s) are often evaluated along a scale or according to specific endpoints or criteria (types of benefits), or by evaluating whether a pre-identified health threshold was achieved. The change in subjects’ condition or clinical management as measured on that scale, or as determined by an improvement or worsening of the endpoint, determines the magnitude of the benefit(s) in subjects. Variation in the magnitude of the benefit across a population may also be considered. • The clinical relevance of these changes should be discussed and justified. • Ideally, these parameters should be directly clinically relevant. • In certain cases, benefits can be assumed when validated surrogate endpoints are met (such as obtaining certain results with laboratory tests or measurements of anatomical or physiological properties). • Based on the current state of medical knowledge, the evaluators shall justify and document the clinical relevance of endpoints used for the clinical evaluation of a device and demonstrate the validity of all surrogate endpoints (if surrogate endpoints have been used). The probability of the patient experiencing one or more benefit(s) is another important aspect of evaluating benefits and the clinical performance of a device. • Based on the clinical data provided and on a sound statistical approach, a reasonable prediction of the proportion of “responders” out of the target group or subgroups should be made. • The data may show that a benefit may be experienced only by a small proportion of patients in the target population, or, on the other hand, that a benefit may occur frequently in patients throughout the target population. It is also possible that the data will show that different patient subgroups are likely to experience different benefits or different levels of the same benefit. • If the subgroups can be identified, the device may be indicated for those subgroups only. • In some cases, however, the subgroups may not be identifiable. Magnitude and probability of clinical benefits will have to be put together when weighing benefits against risks. • A large benefit experienced by a small proportion of subjects may raise different considerations than does a small benefit experienced by a large proportion of subjects. For example, a large benefit, even if experienced by a small population, may be significant enough to outweigh risks, whereas a small benefit may not, unless experienced by a large population of subjects. The duration of effect(s) (i.e., how long the benefit can be expected to last for the patient, if applicable to the device). • The duration should be characterized (for example as a statistical distribution) on the basis of sound clinical data and appropriate statistical approaches. • PMCF will be decisive to refine and corroborate reasonable predictions over time.

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The mode of action may play an important role: Some treatments are curative, whereas, some may need to be repeated frequently over the patient’s lifetime. • To the extent that it is known, the duration of a treatment’s effect may directly influence how its benefit is defined. Treatments that must be repeated over time may introduce greater risk, or the benefit experienced may diminish each time the treatment is repeated. • The evaluation of the duration of effect should take into consideration current knowledge/the state of the art and available alternatives. d. Evaluation of the Clinical Risks of Devices: The risk management documents are expected to identify the risks associated with the device and how such risks have been addressed. The clinical evaluation is expected to address the significance of any risks that remain after design risk mitigation strategies have been employed by the manufacturer. PMS reports are compiled by the manufacturer and often include details of the device’s regulatory status (countries in which the device is marketed and date of commencement of supply), regulatory actions undertaken during the reporting period (e.g., recalls, notifications), a tabulation of incidents (particularly serious adverse events/incidents, including deaths, stratified into whether the manufacturer considers them to be device-related or not) and estimates of the incidence of incidents. Post-marketing data about incidents are generally more meaningful when related to usage but caution is needed. The extent of user reporting in the medical devices vigilance system may vary considerably between countries, users, and type of incident. Considerable under-reporting by users is expected. However, the analyzes of data within these reports may, for some devices, provide reasonable assurance of both clinical safety and performance. It may be helpful to provide a table summarizing device-related incidents, paying particular attention to serious adverse events/incidents, with comments on whether observed device related incidents are predictable on the basis of the mode of action of the device. To demonstrate the extent of the probable risk(s)/harm(s), the following factors – individually and in the aggregate – should be addressed: • Nature severity, number, and rates of harmful events associated with the use of the device: o Device-Related Serious Adverse Events/Incidents: Those events that may have been or were attributed to the use of the device and produce an injury or illness that is life threatening, results in permanent impairment or damage to the body, or requires medical or surgical intervention to prevent permanent harm to the body. o Device-Related Non-Serious/Non-Reportable Harmful Events: Those events that may have been or were attributed to the use of the device and that do not meet the criteria for classification as a device-related serious adverse events/ incidents. o Procedure-Related Incidents: Harm to the patient that results from use of the device but is not caused by the device itself. For example, anesthetic-related complications associated with the implantation of a device.

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• •

• o o o

•

•

e.

•

•

o

– – – o

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Probability of a harmful event: The proportion of the intended population that would be expected to experience a harmful event; whether an event occurs once or repeatedly may be factored into the measurement of probability. Duration of harmful events (i.e., how long the adverse consequences last): Some devices can cause temporary, minor harm; some devices can cause repeated but reversible harm; and other devices can cause permanent, debilitating injury. The severity of the harm should be considered along with its duration. Risk from false-positive or false-negative results for diagnostic medical devices: if a diagnostic device gives a false-positive result, the patient might, for example, receive an unnecessary treatment and incur all the risks that accompany that treatment, or might be incorrectly diagnosed with a serious disease. if a diagnostic device gives a false-negative result, the patient might not receive an effective treatment (thereby missing out on the benefits that treatment would confer), or might not be diagnosed with the correct disease or condition. other risks associated with false-positives and false-negatives. It is also important to look at the totality of the harmful events associated with the device. The number of different types of harmful events that can potentially result from using the device and the severity of their aggregate effect has to be considered. When multiple harmful events occur at once, they have a greater aggregate effect. Comment specifically on any clinical data that identifies hazards not previously considered in the risk management documentation, outlining any additional mitigation required (e.g., design modification, amendment of information materials supplied by the manufacturer such as inclusion of contraindications in the IFU). Evaluation of Acceptability of the Benefit/Risk Profile: Evaluate if the clinical data on benefits and risks are acceptable for all medical conditions and target populations covered by the intended purpose when compared with the current considered for some populations and/or medical conditions. The current knowledge/state of the art therefore needs to be identified and defined, possibly also relevant benchmark devices and medical alternatives available to the target population. Typically, documentation of the clinical background shall include the following information: Clinical background: Information on the clinical condition(s) to be treated, managed, or diagnosed; Prevalence of the condition(s); Natural course of the condition(s). Other devices, medical alternatives available to the target population, including evidence of clinical performance and safety:

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Historical treatments; Medical options available to the target population (including conservative, surgical, and medicinal); – Existing devices, benchmark devices. • Sufficient detail of the clinical background is needed so that the state of the art can be accurately characterized in terms of clinical performance, and clinical safety profile. The selection of clinical data that characterizes the state of the art should be objective and not selective of data on the basis of being favorable for the device under evaluation. Information should be provided on alternative approaches that have been used or considered and their benefits and drawbacks. Deficiencies in current therapies should be identified from a critical and comprehensive review of relevant published literature. The literature review should demonstrate if the device addresses a significant gap in healthcare provision. Where there is no such clinical need, the design solution needs to show an improved or at least equivalent benefit/risk profile compared to existing products or therapies. • If or when treatment comparability versus accepted therapy is not available at the time of placing on the market, this should be clearly described in the device IFU. • Even if a device cannot compete with an agreed first-line treatment or the best in class, it may add to the portfolio of acceptable treatments, as even a first-line treatment will likely have contraindications or non-responders. • Devices, that might not be best-in-class, might provide sufficient clinical evidence for an acceptable benefit/risk-profile for specific, defined subgroups or even superior clinical performance under specific conditions (e.g., emergency outdoor conditions). • The position within the treatment portfolio has to be specified properly in the CER and other relevant documentation. Example: A system for deep brain stimulation has a proven effectiveness for the treatment of depression. However, the implantation of electrodes in the brain is associated with major risks. Less invasive treatment options are available to patients suffering from depression. Taking into account the available treatment portfolio, the manufacturer has limited the medical indication of the device to “therapy resistant depression,” which is reflected in the IFU and in other relevant documentation. A7.3. Conformity Assessment with Requirement on Performance (MDD ER3/ AIMDD ER2) The devices must achieve the performances intended by the manufacturer. The ability of a medical device to achieve its intended purpose as claimed by the manufacturer needs to be demonstrated, including any direct or indirect medical effects on humans as well as the clinical benefit on patients resulting from the technical or functional, including diagnostic characteristics of a device, when used as intended by the manufacturer.

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Clinical performance includes any claims about clinical properties and safety of the device that the manufacturer intends to use. It is expected: • that the devices achieve their intended performances during normal conditions of use; and • that the intended performances are supported by sufficient clinical evidence. Evaluation of clinical performance can vary widely between device groups, especially between therapeutic and diagnostic devices. The following list gives examples of performance data relevant particularly to diagnostic devices: • Reproducibility of independent acquisition of images (same patient, same machine, different operator and interpreter). • Reproducibility of independent reporting of images (same patient, same machine, same images, different interpreter/analyzer). • Diagnostic sensitivity and specificity of the test for major clinical indications; positive and negative predictive values according to varying pre-test probabilities. • Comparisons of performance of new iterations of diagnostic software against previous software versions. • Normal values by age and gender, covering all groups in which the diagnostic system may be used. A7.4. Conformity Assessment with Requirement on Acceptability of Undesirable Side-Effects (MDD ER6/AIMDD ER5) Any undesirable side-effect must constitute an acceptable risk when weighed against the performances intended. In order to evaluate the acceptability of the side-effects of a device: • there needs to be clinical data for the evaluation of the nature, severity, and frequency of potential undesirable side-effects; • the clinical data should contain an adequate number of observations (e.g., from clinical investigations or PMS) to guarantee the scientific validity of the conclusions relating to undesirable side-effects and the performance of the device; • in order to evaluate if undesirable side-effects are acceptable, consideration has to be given to the state of the art, including properties of benchmark devices and medical alternatives that are currently available to the patients, and reference to objective performance criteria from applicable standards and guidance documents. If there is lack of clinical data or an insufficient number of observations, conformity with the requirement on acceptability of undesirable side-effects is not fulfilled. A reasonable probability (80%) of observing at least one event of an undesirable sideeffect when 15 subjects are studied requires a side-effect with an actual probability of 10%. If only 15 patients have been studied, from a statistical point of view, there could be serious side-effects with an actual probability of 10% that have not had a reasonable chance to be detected. The device would only be acceptable (for any type and severity of undesirable side-effects), if that magnitude is acceptable when weighted against the performance of the device and the current state of the art.

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The table below shows corresponding numbers for undesirable side-effects with an actual probability of 10%, 5% and 1%. Case 1

Case 2

Case 3

Chance of observing at least 80% 1 event (P)

80%

80%

Actual probability of event

10%

5%

1%

Number of subjects studied (n)

15

32

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The threshold proposed as acceptable for any new device will depend on the severity and detectability of side effects concerned. A8. Devices for Unmet Medical Needs – Aspects to Consider Like all medical devices, medical devices for unmet medical needs must fully comply with the ERs in order to be CE-marked. The evaluators should assess whether devices deliver clinical benefits to patients for: • medical conditions that are life threatening, or cause permanent impairment of a body function; and • for which current medical alternatives are insufficient or carry significant risks. Corresponding devices are referred to as “breakthrough products” in this Appendix. a. Breakthrough Products: In exceptional cases, major benefits may justify relatively high levels of uncertainty, and access to the market may be granted on the basis of limited clinical evidence such as: • experience available from compassionate use/humanitarian exemption programs, use of custom-made devices, results of feasibility studies; • limited long-term data. In addition to general aspects described in this MEDDEV document, the evaluators should fully disclose the situation and address the following items in the CER: • The exact intended purpose, including the medical indication (if applicable to the device), the product was developed for and whether residual risks and uncertainties or unanswered questions are considered acceptable in this indication (often a niche indication); • Explanations of why current medical alternatives are considered to be insufficient or to carry significant risks; • Explanations of the benefits delivered by the device under evaluation; • Whether the IFU clearly describe:

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§ § §

the exact intended purpose (including medical indications) and any limitations; the limited clinical experience; uncertainties or unanswered questions about residual risks and benefits to patients [19]. • The need to set up a stringent PMCF plan with information on: § The type and quality of data that needs to be generated in the post-market phase in order to further evaluate the clinical performance and clinical safety of the device; § How to generate data in a timely manner and aspects thereof, including projections on the numbers of patients that will be managed with the device per year; § In the following cases, the manufacturer should aim at including all patients in PMCF studies; § A device that carries significant risks (i.e., expected to cause serious adverse events); or § A device for rare diseases. • The need to actively update the CER when new significant information become available, and in accordance with Section 6.2.3(b) of the present document. In these exceptional cases, notified bodies should perform annual assessments of the updated CERs and the results of PMCF studies. b. Subsequent Products: Devices that enter the market subsequent to a therapeutic/diagnostic breakthrough cannot be judged by the same criteria as listed above for breakthrough devices. When performing a clinical evaluation for these devices, the following considerations should be taken into account: • when a device enters the market subsequent to a therapeutic/diagnostic breakthrough, clinical evidence is likely to have evolved rapidly since the first breakthrough device became available; • with the evolving body of evidence, entering the market with large uncertainty may no longer be legitimate; • if PMCF data are required, PMCF Studies should also be foreseen for devices that enter the market subsequent to a therapeutic/therapeutic breakthrough. A9. Clinical Evaluation Report (CER) – Proposed Table of Contents, Examples of Contents Examples of contents that are shown in the table are for illustration. The contents of the CER will vary according to the nature and history of the device under evaluation.

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Table of Contents

Examples of Contents

1. Summary

Executive summary for external purposes. This section should summarize the determination of the benefit/risk profile in the intended target groups and medical indications, and the demonstration of acceptability of that profile based on the state of the art in the medical fields concerned.

2. Scope of the clini- See Section 7 and Appendix A3. cal evaluation Identification of devices covered by this CER, products, models, sizes, software versions, accessories, their proprietary names, code names assigned during device development. Name and address of the manufacturer. Whether this clinical evaluation is submitted to the AIMDD as amended by directive 2007/47/EC, or to the MDD as amended by directive 2007/47/EC. Concise physical and chemical description, including materials. Whether the device incorporated medicinal substances (already on the market or new), tissues, or blood products. Mechanical and physicochemical characteristics; others (such as sterile vs. nonsterile, radioactivity, etc.); picture or drawing of the device. Technologies used, whether the device is based on a new technology, a new clinical application of an existing technology, or the result of incremental change of an existing technology. Description of innovative aspects of the device. Device group the device belongs to. How the device achieves its intended purpose. Positioning in relation to available treatment/management/diagnostic options. Exact description of the intended purpose as described in the device’s IFU, with exact medical indications (if applicable) and contraindications; claims made in available promotional materials. Name of disease or condition, clinical form, stage, severity, symptoms or aspects to be treated/managed/diagnosed, target patient population, target user group. Intended application of the device, single use/reusable, invasive/non-invasive, implantable, duration of use or contact with the body, maximum number of repeat applications. Identification of organs, tissues or body fluids contacted by the device. Precautions. Claims on clinical performance and clinical safety foreseen by the manufacturer. Whether the device is already CE marked, whether it is on the market, since when, in what regions, history of the device, including date of past modifications with reasons and description, sales volumes. Changes since the last report, whether the device has been modified, identification of new products, models, sizes, software, accessories, new intended purposes, new claims, new events related to the device with an impact on clinical evaluation. Identification of the sections of the CER that are concerned with the new information and have been modified. Other aspects.

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4. Device under evaluation 4.1 Type of evaluation

4.2 Demonstration of equivalence (only when equivalence is claimed)

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See Sections 8–10 and Appendices A4–A5. Identification of medical fields concerned/relevant medical conditions. Brief summary and justification of the literature search strategy applied for retrieval of information on current knowledge/the state of the art, including sources used, search questions, search terms, selection criteria applied to the output of the search, quality control measures, results, number, and type of literature found to be pertinent. Appraisal criteria used. Applicable standards and guidance documents. Description, natural course and consequences of the medical conditions concerned. Whether there are different clinical forms, stages, and severities of the conditions. Frequency in the general population, by age group, gender, ethnicity, familiar predispositions, genetic aspects. Description of available therapeutic/management/diagnostic options, historical context and developments, summary of advantages and disadvantages of the different options, benefit/risk profiles and limitations in relation to the different clinical forms, stages, and severities of the medical conditions and in relation to different target populations. Description of the benefits and risks (nature, extent, probability, duration, frequency), acceptability of undesirable side-effects and other risks (including the nature, severity, probability, and duration of acceptable harm). Hazards due to substances and technologies that could be relevant to the device under evaluation. The mechanisms of harm, clinical aspects of minimization and management of side effects and other risks. Types of users. Diverging opinions of professionals as to the use of the different medical options. Unmet medical needs.

Whether the clinical evaluation is based on: • Scientific literature currently available; and/or • Clinical investigations made; or • Whether demonstration of conformity with ERs based on clinical data is not deemed appropriate. If clinical data is not deemed appropriate, include considerations according to Section 10.3. See Appendix A1. Identification of the equivalent device and its manufacturer. Exact name, models, sizes, software versions, accessories, etc. Name of the manufacturer. Relationship to the device under evaluation (predecessor/successor, others). Regulatory status. If the device is not CEmarked, justification for the use of the data.

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Clinical Evaluations for Medical Devices Comparison of clinical, biological, and technical characteristics (see Appendix A1 for details). Justification of equivalence, description of relevant clinical, biological, and technical characteristics that affect clinical properties of the device, differences between the intended purpose of the device under evaluation and the equivalent device (indications, contraindications, precautions, target patient groups, target users, mode of application, duration of use/number of re-applications, others), type of device-body interaction. Choice, justification, and validity of parameters and models for non-clinical determination of characteristics. Identification of pre-clinical studies carried out and literature used, concise summaries of studies and literature (methods, results, conclusions of the authors), evaluation of the methodological quality of the study or document, the scientific validity of the information. Comparative tabulations for the device under evaluation versus the equivalent device showing parameters relevant to the evaluation of the three characteristics. Comparative drawings or pictures of the device and the equivalent device showing the elements in contact with the body.

Identification of differences, evaluation if differences are expected or not to influence the clinical performance and clinical safety of the device, reasons for assumptions made. Conclusions concerning equivalence. Whether the comparison carried out covers all products/models/sizes/settings/accessories and the entire intended purpose of the device under evaluation, or only certain products/models/sizes/settings/accessories, or selected aspects of the intended purpose, which ones. Conclusions whether equivalence is demonstrated or not; if it is demonstrated, confirmation that the differences are not expected to affect the clinical performance and clinical safety of the device under evaluation; description of any limitations and gaps. 4.3 Clinical data generated and held by the manufacturer

See Section 8.1. Identification of clinical data generated and held by the manufacturer.

4.4 Clinical data generated from literature

See Section 8.2 and Appendices A4–A5. Brief summary and justification of the literature search strategy applied for retrieval of clinical data, including objectives, sources used, search questions, search terms, selection criteria applied to the output of the search, quality control measures, results, number, and type of literature found to be pertinent.

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4.6 Analysis of the clinical data 4.6.1. Requirement on safety (MDD ER1/AIMDD ER1)

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See Section 9 and Appendix A6. Feasibility studies: • Pivotal clinical investigations; • PMCF studies; • Other use data. Summaries of clinical data generated and held by the manufacturer and of scientific literature found to be pertinent. Including brief summary of the studies or references (methods, results, conclusion of the authors), evaluation of their methodological quality, scientific validity of contents, relevance to the clinical evaluation, weighting attributed to the data, contents used (performance data, safety data, both) reasons for rejecting a study or document, reasons for rejecting some of its contents.

See Section 10 and Appendix A7.1. Summary of conformity assessment with requirement on safety (MDD ER1/AIMDD ER1). Analysis whether there are special design features that pose special safety concerns (e.g., presence of medicinal, human or animal components) that where identified in the device risk management documentation and that required evaluation from a clinical perspective, and whether these have been adequately addressed. Whether the risks identified in the risk management documentation and literature have been adequately addressed. Whether all the hazards and other clinically relevant information (e.g., clinical precautions for reduction of risks, clinical management of risks) have been identified appropriately. Whether the safety characteristics and intended purpose of the device requires training of the end-user or other precautions, if users foreseen are adequate, if training requirements and other precautions are described in the IFU. Whether there is full consistency between current knowledge/the state of the art, the available clinical data, the information materials supplied by the manufacturer, and the risk management documentation 4.6.2 requirement on for the device. acceptable benefit/ risk profile (MDD See Section 10 and Appendix A7.2. ER1/AIMDD ER1) Summary of conformity assessment with requirement on acceptable benefit/risk profile (MDD ER1/AIMDD ER1). Summary of the total experience with the device, including estimated numbers and characteristics of patients exposed to the device in clinical investigations, PMCF, from other user experience, and in the market; duration of follow-up. Nature, extent/severity, probability/ frequency, duration of benefits to the patients and of undesirable side-effects and other risks. For each aspect of the intended purpose, whether the benefit/risk profile including its uncertainties or unanswered questions is compatible with a high level of protection of health and safety, corresponding justifications.

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4.6.3 requirement on See Section 10 and Appendix A7.3. performance (MDD Summary of conformity assessment with requirement on performance ER3/AIMDD ER2) (MDD ER3/AIMDD ER2). Description of clinical performance. For each intended performance, extent to which evaluation of benefits is possible based on available data, limitations of the data, description of gaps, uncertainties or unanswered questions, and assumptions. Whether available data allows adequate evaluation of performance, limitations of the data, gaps, uncertainties or unanswered questions. Whether there is sufficient clinical evidence for every intended performance. 4.6.4 requirement on acceptability of side effects (MDD ER6/ AIMDD ER5)

See Section 10 and Appendix A7.4. Summary of conformity assessment with requirement on acceptability of undesirable side-effects (MDD ER6/AIMDD ER5). Whether the data available is of sufficient amount and quality for the detection of undesirable side-effects and their frequency, limitations of the data, description of gaps, uncertainties or unanswered questions, and assumptions. Whether the undesirable side-effects are acceptable and corresponding justifications.

5.Conclusions

See Section 11. Clear statement concerning compliance to ERs. Acceptability of the benefit/risk profile according to current knowledge/the state of the art in the medical fields concerned and according to available medical alternatives. Adequacy of the information materials supplied by the manufacturer, whether the intended purpose and risk reduction measures are adequate; discrepancies. Suitability of the device, including its IFU, for the intended users and usability aspects; discrepancies. Adequacy of claims foreseen by the manufacturer; discrepancies. If there is consistency between the clinical data, the information materials supplied by the manufacturer, the risk management documentation for the device under evaluation; discrepancies. Whether there is consistency between these documents and the current knowledge/the state of the art; discrepancies. Description of residual risks and uncertainties or unanswered questions, whether these are acceptable for CE-marking, how these should be followed during PMS (uncertainties regarding medium- and long-term performance, safety under wide-spread use, residual risks such as undesirable side-effects and complications occurring at rates below detection possibilities of currently available clinical data, others). Whether these are already being addressed in ongoing PMS activities, e.g., in currently ongoing PMCF studies. Whether new or additional PMS activities, including PMCF studies, should be foreseen.

6.Date of the next clinical evaluation

See Section 6.2.3. Suggested date, justification of the date.

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See Section 11. Date of the CER. Statement that the evaluators agree with the contents of the report. Dates, names, and signatures of the evaluators. Final release by the manufacturer. Date, name, and signature.

8. Qualification of the responsible evaluators

See Section 6.4.

9. References

See Section 11.

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A10. Proposed Checklist for the Release of the Clinical Evaluation Report (CER) The following aspects should be checked for the release of a CER: • Can the report be read and understood by a third party, does it provide sufficient detail for understanding the data that are available, all assumptions made and all conclusions reached? • If clinical data have been generated and are held by the manufacturer, are all data mentioned and adequately summarized in the report? • If equivalence is claimed: o is demonstration of equivalence included in the report? o does the report disclose all the differences between the device under evaluation and the equivalent device? o does it explain why the differences are not expected to affect the clinical performance and clinical safety of the device? • If the product is already in the market in Europe or elsewhere, has the latest PMS/ PMCF data been taken into consideration and has it been summarized and referenced in the report? • In respect to current knowledge/the state of the art: o has the report been updated? o is current knowledge/the state of the art summarized in the report and is it adequately substantiated by literature? o does the content of the report fully correspond to current knowledge/the state of the art? o does the report explain why the benefit/risk profile and the undesirable side-effects are acceptable in relation to current knowledge/the state of the art? • If the report covers several models/sizes/settings and/or different clinical situations, is there sufficient clinical evidence and are the report’s conclusions correct for: o all the devices? o all its sizes, models, and settings? (Including the smallest/largest size, highest/ lowest dose, etc.) o every medical indication? (As described in the IFU/not excluded with contraindications in the IFU).

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o the entire target population? (From pre term infants to old age, for males and females, etc., if not restricted in the IFU). o every form, stage, and severity of the medical condition, as applicable? (Including the most severe/most benign forms, acute/chronic stage, if not excluded in the IFU). o all intended users? (Including lay persons, if not excluded in the IFU, and any unusual user group). o the whole duration of product use, including the maximal number of repeated exposure? (as allowed by the IFU). o if there are any discrepancies as to the above, are they identified in the report’s conclusions? • Is conformity to each of the relevant ERs (AIMDD ER1,2,5/MDD ER1,3,6) clearly stated and are all discrepancies identified in the report’s conclusions? • Do the information materials supplied by the manufacturer correspond with the contents of the report and are all discrepancies identified in the report’s conclusions? • Do the report’s conclusions identify all residual risks and uncertainties or unanswered questions that should be addressed with PMS/PMCF studies? • Is the report dated? • Is the qualification of the evaluators included in the report and correct? • Does the manufacturer hold a CV and declaration of interests of each of the evaluators and are these up-to-date? A11. Information on Declarations of Interests Declarations of interests of the evaluators should be held by the manufacturer and cover relevant financial interests outside the current work as an evaluator. Declarations of interests should contain statements that clarify the extent of the declaration. For example: • The time span included (e.g., grants, sources of revenue or benefits paid or promised to be paid over the 36 months prior to the evaluation); • Whether financial interests of family members are included or not (namely spouse or partner living in the same residence as the evaluator, children, and adults for whom the evaluators are legally responsible). Typical contents: • Employment by the manufacturer; • Participation as an investigator in clinical studies of the device, or in pre-clinical testing of the device; • Ownership/shareholding possibly affected by the outcome of the evaluation;

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• Grants sponsored by the manufacturer; • Benefits such as traveling or hospitality (if beyond what is reasonably necessary

for the work as an employee or external evaluator); • Interests in connection with the manufacturing of the device or its constituents; • Interests in connection with intellectual property, such as patents, copyrights, and royalties (whether pending, issued or licensed) possibly affected by the outcome of the evaluation; • Other interests or sources of revenues possibly affected by the result of the evaluation. The declaration of interests should be dated and signed by the evaluator and the manufacturer. A12. Activities of Notified Bodies A12.1. Notified Body (NB) Assessment of Clinical Evaluation by Conformity Assessment Route The NB assessment of CERs and the supporting data presented by manufacturers is required for all medical devices. The timing and frequency of the NB reviews will vary according to the risk carried by the device, how well established the device is (see Section 6.2.3) and the conformity assessment procedure that is applied. This includes for medical devices in accordance with Directive 93/42/EEC: • An audit as part of a quality system approval procedure (Annex II, Section 3): o The NB assesses the manufacturer’s procedure for clinical evaluation, PMS plan and PMCF plan and (if applicable) results of PMCF. o As part of the representative sampling of devices [21]; for review of their technical documentation the NB assesses the CER presented for class IIa and IIb devices as presented below for a design dossier. • A design dossier (Annex II, Section 4) or type examination dossier (Annex III) assessment: o the NB assesses the data presented in the CER; o assesses the validity of the conclusions drawn by the manufacturer; and o the conformity of the device to relevant ERs. For active implantable medical devices in accordance with Directive 90/385/EEC: • A design dossier (Annex 2, Section 4) or type examination dossier (Annex 3) assessment: o the NB assesses the data presented in the CER; o assesses the validity of the CER and the conclusions drawn by the manufacturer; and o the conformity of the device to relevant ERs.

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The NB should also have documented procedures to address the review of updates to CERs during their scheduled surveillance activities and at the time of changes to or extensions of EC design-examination/EC type-examination certificates. The review should take into account aspects described in Section 6.2.3. This arises from the obligation placed on the manufacturer to actively update the clinical evaluation with data obtained from PMS, e.g., PMCF and ongoing literature reviews/surveys. In addition, notified bodies should refer to guidance, checklists, and other documents available on the assessment of clinical evaluations by notified bodies from the NB Operations Group (NBOG). These should be considered in addition to this guidance. Any such checklists are intended only as an aide memoire for assessment and should not replace the clinical evaluation assessment report (CEAR) outlined below. A12.2. Examination of a Design Dossier (Annex II.4; Annex 2.4) or of a Type Examination Dossier (Annex III; Annex 3) The NB examines the clinical evaluation documentation submitted (relevant documentation referenced in previous sections of this MEDDEV), assesses the manufacturer’s identification, appraisal, and analysis of that data, and validates the conclusions drawn by the manufacturer. In order to do so, the NB should possess enough knowledge and experience in clinical evaluation as stated in previous sections of this document. A12.2.1. Decision-Making by the Notified Body (NB) In reviewing the evaluation of clinical data submitted by the manufacturer, the NB verifies and concludes whether or not the manufacturer has adequately: • Supplied clinical evaluation documentation (as referenced in previous sections); • Followed relevant procedures (as addressed by previous sections); • Described and verified the intended characteristics and performances related to clinical aspects; • Performed an appropriate risk analysis and estimated the undesirable side-effects which are aligned with the clinical evaluation; • Involved appropriate clinical expertise in the clinical evaluation and in the compilation of the risk analysis to ensure risks and benefits associated with real clinical use are adequately defined; • Provided a solid justification as the basis for their estimations of benefits, risks, undesirable side-effects, indications, and contraindications of the device in question; • Justified the chosen route(s) of clinical data retrieval (according to previous sections); • Identified, appraised, analyzed, and assessed the clinical data (according to previous sections) and demonstrated the relevance and any limitations of the clinical data identified in demonstrating compliance with particular requirements of the Directive or cited in particular aspects of the risk analysis;

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Identified all clinical data, favorable, and unfavorable, that is relevant to the device and using an appropriately robust, reproducible, and systematic search strategy; Provided sufficient clinical evidence relating to the safety, including benefits to the patients, the clinical performance intended by the manufacturer (including any clinical claims for the device the manufacturer intends to use), design characteristics and intended purpose of the device, in order to demonstrate conformity with each of the relevant ERs; Conducted and provided a critical evaluation of relevant scientific literature and data relating to the safety, benefits, performance, design characteristics and intended purpose of the device; Demonstrated the equivalence of the device under evaluation to the device to which the data relates in all necessary areas, i.e., clinical, technical, biological, and that the data available adequately addresses conformity to each of the relevant ERs (if a critical evaluation of relevant scientific literature is provided as the only source of clinical data); Designed appropriate clinical investigations, when necessary, to address specific questions arising from the critical review of the scientific literature and address each of the relevant ERs; Provided specific justification if a specific clinical investigation was not performed for class III or implantable devices; Provided evidence that clinical investigations presented are in compliance with applicable regulatory and ethical requirements, e.g., scientific validity, ethics committee approval, competent authority approval; Provided detail of the PMS plan in place for the particular device and justified the appropriateness and adequacy of this plan; Clearly identified which areas in the clinical evaluation and related data need to be further addressed and confirmed in the post-market phase, with specific alignment to the PMCF; Justified the appropriateness of the planned PMCF; Justified and documented if PMCF is not planned as part of the PMS plan for the device; Identified the sources of clinical data which will be gathered from the manufacturer’s PMS system and PMCF; Concluded that the contents of the IFU are supported by clinical evidence (description of the intended purpose, handling instructions, type, and frequency of risks, warnings, precautions, contraindications, others) and are in line with the risk analysis and clinical evaluation;

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• Concluded on the basis of documented evidence:

a. that the risks are acceptable when weighed against the intended benefits and are compatible with a high level of protection of health and safety; b. that the intended clinical performances described by the manufacturer are achieved by the device; and c. that any undesirable side-effect constitutes an acceptable risk when weighed against the performances intended. The assessment carried out by the NB will in addition typically confirm the following aspects of the manufacturer’s clinical evaluation: • Appraisal to determine suitability and any limitations of the data presented to address the ERs in particular relating to the safety, and performance of the device as outlined in previous sections; • The validity of any justification given; • Characterization and evidence-based proof of the clinical performance of the device intended by the manufacturer and the expected benefits for the defined patient group(s); • The application of all relevant harmonized standards or appropriate justifications if not; • Identified hazards to be addressed through analysis of clinical data as described in Section 10; • The adequate estimation of the associated risks for each identified hazard by characterizing the severity of the hazard; • Estimating and characterizing the probability of occurrence of harm, impairment of health or loss of benefit of the treatment (documented and discussed based on scientifically valid clinical data); • The adequate description and estimation of the current state of the art in the corresponding medical field; • A justifiable and reasoned basis for estimation of risks and hazards. Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product, the NB is responsible for verifying the usefulness of the medicinal substance as part of the device prior to the submission of an application for scientific opinion from a medicine’s authority. For drug-device combination products and products incorporating stable human blood derivatives, where a scientific opinion from a medicinal competent authority or from the European Medicines Agency (EMA) has been sought, the NB should consider any comments or considerations raised in the medicinal clinical assessment when making its final decision on the device. In the case of devices with a human blood derivative the NB may not deliver a positive decision to issue a certificate if the EMA’s scientific opinion is unfavorable.

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A12.2.2. The Report of the Notified Body (NB) The NB should write a CEAR based on its assessment of the submitted CER and supporting documentation. If a design dossier report is applicable to the device, the CEAR may be incorporated into this report or referenced from it. The report should clearly identify the NB’s assessment, verification on each of the critical elements and overall conclusions. The CEAR at a minimum should address the NB’s assessment of manufacturer’s application relating to the following: • Device description and product specification; • Intended purpose of the device; • Classification proposed for the device; • Pre-clinical evaluation data presented by the manufacturer; • Risk analysis and risk management and alignment with the CER; • Clinical evaluation process; • Clinical evaluation report authors; • Equivalence assessment – if data from equivalent is used; • Clinical investigation plans and reports; • Justification if no clinical investigation has been performed; • Instructions for use, labeling and when necessary, the training plan for users; • Justification if no PMCF is planned; • PMS; • PMCF; • Planned frequency/criteria for updates to the clinical evaluation; • Summary of review; • Conclusion on clinical benefit/risk profile; • Conformance of the device to the relevant ERs. The CEAR should also provide details relating to the submission and NB review (including staff and experts involved in the review and the aspects assessed by each, signatures of responsible reviewers, etc.). The NB should justify and document each step of the decision-making process referred in Section A12.2.1 above. The CEAR at a minimum should include a summary of the information provided by the manufacturer relating to the following: • Record whether the clinical evaluation documentation is complete in accordance with this document and adequate to demonstrate conformance to the ERs of the relevant Directive. • Record the NB’s verification of each step of the clinical evaluation process, from the planning of the clinical evaluation, choice of route(s), identification, appraisal, analysis, and overall assessment of the clinical data, to concluding and reporting.

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Record the NB’s assessment of the clinical investigation data and/or literature review assembled, relevant procedures and compliance to relevant standards. Verify that the device has met the claimed performance/intended purpose and benefits, and that undesirable side-effects and risks have been properly evaluated. Record the NB’s assessment of the clinical safety, clinical performance and benefit/risk profile. Record the NB’s assessment of the overall conclusions drawn by the manufacturer from the clinical data presented. Record the NB’s assessment of the validity of the clinical evaluation and its steps. Record the NB’s conclusions on the clinical evaluation, documenting each step in the decision-making process as per Section A12.2.1.

A12.2.3. Clinical Data from an Equivalent Device and Other Products a. Equivalent Devices: The NB should clearly document its assessment of clinical data presented from an equivalent device as part of a clinical evaluation. This should critically review and conclude on the equivalence or not of the device under assessment to the devices presented as equivalent in terms of their technical, biological, and clinical characteristics. The relevance of each dataset from an equivalent device should be clearly evident and assessed by the NB. The NB should also assess and document the level of access to the technical and clinical data from an Equivalent device that the manufacturer has. Relevant information may be commercially sensitive/confidential and not available to the manufacturer. The NB should challenge the ability of the manufacturer to access information that are relevant to the demonstration of equivalence. Demonstration of equivalence might be difficult or impossible in case of limited access to the technical documentation of the devices. b. Other Products: For hazard identification and when assessing the benefit/risk profile of the device, the NB should consider current knowledge/the state of the art. The NB should assess the appropriateness of the use of data from benchmark devices, other devices, and medical alternatives. A12.3. Evaluation as Part of Quality System Related Procedures A12.3.1. Review of the Manufacturer’s Procedures The NB shall, as part of the review of the manufacturer’s quality system, assess the establishment, maintenance, and application of the manufacturer’s documented procedures for the evaluation of clinical data. This should cover: a. The proper assignment of responsibilities to suitably qualified persons involved in the clinical evaluation (e.g., clinical evaluator(s), information retrieval expert(s), expert(s) in clinical research). b. The integration of clinical evaluation into the quality system as a continuous process, to be specifically inter-related to, and informed by, pre-clinical evaluation and risk management.

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c.

Standard operating procedures to assure proper planning, conduct, evaluation, control, and documentation planning of the clinical evaluation, identification of clinical data (previous section), literature searching (previous section), collection of clinical experience (previous section), clinical investigation (previous section and EN ISO 14155), appraisal of clinical data (previous section), analysis of clinical data (previous section), concluding, reporting (previous section) and update of clinical evaluation, procedures, reporting, and updating based on data from the PMS system and from PMCF (MEDDEV 2.12/2 Rev. 2). d. Document control as part of overall documentation of procedures, reporting, qualifications, and technical documentation/design dossier(s). e. Identification and evaluation of undesirable side-effects and of clinical performance(s). This involves identification of known or reasonably foreseeable hazards and verification of unfavorable and favorable outcome(s), qualification of their severity/ magnitude and of their probability of occurrence. (It is part of the manufacturer’s documented risk analysis based on both favorable and unfavorable data identified as relevant in order to give a balanced view).

A12.3.2. Review of the Technical Documentation of Representative Samples The NB is required to assess the technical documentation for class IIa and class IIb devices on a representative basis. The CER should be assessed by the NB for at least one representative sample for each device subcategory for class IIa devices and at least one representative sample for each generic device group for class IIb devices. Further representative samples have to be assessed as part of the annual surveillance assessment cycle. Regarding the choice of representative sample(s) the NB will consider the novelty of the technology, similarities in design, technology, manufacturing, and sterilization methods, the intended purpose, and the results of previous relevant assessments. Assessment of representative samples includes assessment of the CER and available clinical data in accordance with the review procedure in this document rather than solely confirming that the manufacturer has a clinical evaluation procedure in place or that the CER is available. The criteria for the technical documentation assessment on a representative basis outlined in NBOG BPG 2009-4 should be applied. When performing the assessment on samples of a manufacturer’s clinical evaluation, the NB will follow the steps indicated in previous sections of this document. A CEAR should be completed and available for each device sampled and assessed.

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A12.4. Notified Body (NB) Specific Procedures and Expertise A NB should have formal procedures in place controlled by their quality system relating to the assessment of CERs and associated data provided by medical device manufacturers. These procedures should also cover the review of updates to the CER during their scheduled surveillance activities and at the time of changes to or extensions of EC design-examination/EC type-examination certificates. Notified bodies should establish and implement internal policies and procedures for the assessment of CERs and associated data in order to: • Ensure that suitable resources, especially clinical competence necessary for such assessment, are available within [24] the NB to conduct and manage assessments of clinical evaluations for the NB, normally a qualified medical doctor. Such expertise should be sufficient to conduct a complete review of the clinical data and clinical evaluation presented for a particular device, to identify and estimate the risks and benefits associated with the use of the medical devices and to identify what, if any, specific clinical expertise is required for the full assessment of the device. The assessment team should be able to assess a risk analysis, the risk management strategy performed by the manufacturer, and the scientific validity of clinical investigations and publications. The assessment team should have sufficient expertise in the device technology as the associated medical procedures. Such an assessment requires input from a qualified medical practitioner (for example physician, dentist, nurse, etc.), as appropriate for the particular device, who has clinical experience in using the device or similar devices, the pathology of the condition being treated, the usual treatment, other medical alternatives, etc. The NB clinical assessor may work with external clinical experts. The NB clinical assessor should ensure that any experts are appropriately aware of the relevant legislation, guidance, and standards and to identify specific aspects of the clinical data evaluation for their specific review. Notified bodies should have robust procedures around the recruitment, selection, training, conflict of interest and interaction with external clinical experts including clear procedures around how the expert opinion is documented and integrated with the NB assessment and considered as part of the overall certificate decision. When examining the results of clinical investigations, the assessment team shall have knowledge in planning, conduct, and interpretation of clinical investigations. All assessors should be appropriately trained and qualified. Particular attention should be drawn to training of external experts on the conformity assessment procedure(s), relevant guidance, standards, and the context of the assessment they are providing. The NB should be responsible for reviewing the opinion of these experts, taking account of their level of knowledge of the provisions of the Directives.

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The opinion of an external clinical expert may form part of the assessment conducted by the NB. The opinion and conclusions of the NB, in part based on this external opinion, should be clearly documented. The impartiality and the potential for conflict of interest of an external expert reviewer should be assessed and documented by the NB. • Review the CER and clinical data provided by the manufacturer. The NB should verify the validity of key statements made in the CER. The NB should consider: o statements based on published literature using the full text version of publications; o statements based on clinical data generated from PMS systems in particular PMCF and source verification of such data; o statements regarding equivalence to other devices using the original full text version of pre-market study reports assessing parameters of interest. o statements regarding results of own clinical investigations of the manufacturer using the original full text version of the clinical investigation plan and the clinical investigation report. The review of the NB should consider the scientific validity of the clinical data set presented as part of the clinical evaluation and decide as to whether it provides evidence that the clinical benefit outweighs all associated risks. The data presented by the manufacturer should be scientifically robust and well presented, it should be complete and clear in its reasoning and should be of sufficient quality and validity to demonstrate the conclusions which are being drawn. All clinical data relevant to the device in question, both favorable and unfavorable, should be considered, appraised, and assessed by the manufacturer and likewise by the NB. An absence of unfavorable data relating to a medical device should be carefully examined. CERs which are based on incomplete, unclear or uncertain datasets should not be accepted. CERs which are based on incomplete clinical investigations or clinical investigations which were halted or terminated earlier than their intended duration should be carefully examined and a robust justification for halting or termination should be sought. The original endpoints, objectives, and statistical basis for the manufacturer’s clinical investigation are unlikely to remain valid in circumstances when an investigation is completed prior to its original planned duration and so it is unlikely that scientific conclusions can be drawn. • Document the opinion with rationale of all experts involved. • Document the result of their assessment. This is achieved through a specific CEAR which may be part of, or may be referenced, in the overall audit report, design/type examination report (as per A12.2.2 of this document) or the report on the assessment of representative samples’ documentation. • Preserve confidentiality of the information and data received from the manufacturer, especially within the terms for contracting external experts.

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• Clearly identify how data from PMS conducted by manufacturers, vigilance, and market surveillance information from CA, PMCF data, and data from other relevant sources (e.g., clinical literature) is identified and reviewed by the NB. This should clearly describe how, when, and what criteria are used by the NB to judge when a reassessment of the benefit/risk profile of a particular device is deemed necessary.

CHAPTER

3

ESSENTIAL REQUIREMENTS (ERS) OF MEDICAL DEVICES (UNDER THE MDD 93/42 EEC)

This section of the MDD focuses on the minimum ERs for the design and manufacture of medical devices. It is aimed at ensuring the protection of the health and safety of patients, users, and third parties. For this reason, these requirements stipulate that the principles of safety should be integral to the design of the product and that the product should be suitable for its intended purpose. The ERs are defined in Annex I of the MDD. Annex 1 of the Directive lays down a series of ERs for the design, safety, and functionality of medical devices. The ERs of the MDD apply to all medical devices and cover the following: • • • • •

A general requirement for safe design; The minimization of risks from contamination; Compatibility with materials with which they are likely to come into contact; Minimization of hazards of infection and microbial contamination; Provision of sufficient accuracy (for devices with a measuring function);

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• Protection against radiation; • Adequate product marking; • Adequate user instructions. The specific details and requirements of these ERs are laid out in the directive and are further defined below: •

Excerpt from the MDD: Article 3: Essential Requirements (ERs)

Article 3 of the MDD 93/42/EEC: Essential Requirements (ERs) The devices must meet the ERs set out in Annex I which apply to them, taking account of the intended purpose of the devices concerned. Where a relevant hazard exists, devices which are also machinery within the meaning of Article 2(a) of Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery (5) shall also meet the essential health and safety requirements set out in Annex I to that Directive to the extent to which those essential health and safety requirements are more specific than the ERs set out in Annex I to this Directive.

Now let’s look at the requirements of Annex I (essential requirements) in greater detail. Annex I of the MDD 93/42/EEC: Essential Requirements (ERs) I. General Requirements 1. The devices must be designed and manufactured in such a way that, when used under the conditions and for the purposes intended, they will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their intended use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety. This shall include: • reducing, as far as possible, the risk of use error due to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety); and • consideration of the technical knowledge, experience, education, and training and where applicable the medical and physical conditions of intended users (design for lay, professional, disabled or other users). 2. The solutions adopted by the manufacturer for the design and construction of the devices must conform to safety principles, taking account of the generally acknowledged state of the art.

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In selecting the most appropriate solutions, the manufacturer must apply the following principles in the following order: • eliminate or reduce risks as far as possible (inherently safe design and construction); • where appropriate take adequate protection measures including alarms if necessary, in relation to risks that cannot be eliminated; • inform users of the residual risks due to any shortcomings of the protection measures adopted. 3. The devices must achieve the performances intended by the manufacturer and be designed, manufactured, and packaged in such a way that they are suitable for one or more of the functions referred to in Article 1 (2)(a), as specified by the manufacturer. 4. The characteristics and performances referred to in Sections 1, 2 and 3 must not be adversely affected to such a degree that the clinical conditions and safety of the patients and where applicable, of other persons are compromised during the lifetime of the device as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use. 5. The devices must be designed, manufactured, and packed in such a way that their characteristics and performances during their intended use will not be adversely affected during transport and storage taking account of the instructions and information provided by the manufacturer. 6. Any undesirable side-effect must constitute an acceptable risk when weighed against the performances intended. 6a. Demonstration of conformity with the ERs must include a clinical evaluation in accordance with Annex X. II. Requirements Regarding Design and Construction 7. Chemical, Physical, and Biological Properties 7.1.The devices must be designed and manufactured in such a way as to guarantee the characteristics and performances referred to in Section I on the ‘General requirements. Particular attention must be paid to: • the choice of materials used, particularly as regards toxicity and where appropriate, flammability; • the compatibility between the materials used and biological tissues, cells, and body fluids, taking account of the intended purpose of the device; • where appropriate, the results of biophysical or modeling research whose validity has been demonstrated beforehand. 7.2.The devices must be designed, manufactured, and packed in such a way as to minimize the risk posed by contaminants and residues to the persons involved in the transport, storage, and use of the devices and to the patients, taking account of the intended purpose of the product. Particular attention must be paid to the tissues exposed and to the duration and frequency of exposure.

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7.3. The devices must be designed and manufactured in such a way that they can be used safely with the materials, substances, and gases with which they enter into contact during their normal use or during routine procedures; if the devices are intended to administer medicinal products they must be designed and manufactured in such a way as to be compatible with the medicinal products concerned according to the provisions and restrictions governing these products and that their performance is maintained in accordance with the intended use. 7.4. Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product as defined in Article 1 of Directive 2001/83/EC and which is liable to act upon the body with action ancillary to that of the device, the quality, safety, and usefulness of the substance must be verified by analogy with the methods specified in Annex I to Directive 2001/83/ EC. For the substances referred to in the first paragraph, the NB shall, having verified the usefulness of the substance as part of the medical device and taking account of the intended purpose of the device, seek a scientific opinion from one of the CA designated by the Member States or the European Medicines Agency (EMEA) acting particularly through its committee in accordance with Regulation (EC) No 726/2004 (1) on the quality and safety of the substance including the clinical benefit/risk profile of the incorporation of the substance into the device. When issuing its opinion, the competent authority or the EMEA shall take into account the manufacturing process and the data related to the usefulness of incorporation of the substance into the device as determined by the NB. Where a device incorporates, as an integral part, a human blood derivative, the NB shall, having verified the usefulness of the substance as part of the medical device and taking into account the intended purpose of the device, seek a scientific opinion from the EMEA, acting particularly through its committee, on the quality and safety of the substance including the clinical benefit/risk profile of the incorporation of the human blood derivative into the device. When issuing its opinion, the EMEA shall take into account the manufacturing process and the data related to the usefulness of incorporation of the substance into the device as determined by the NB. Where changes are made to an ancillary substance incorporated in a device, in particular related to its manufacturing process, the NB shall be informed of the changes and shall consult the relevant medicines competent authority (i.e., the one involved in the initial consultation), in order to confirm that the quality and safety of the ancillary substance are maintained. The competent authority shall take into account the data related to the usefulness of incorporation of the substance into the device as determined by the NB, in order to ensure that the changes have no negative impact on the established benefit/risk profile of the addition of the substance in the medical device. When the relevant medicines competent authority (i.e., the one involved in the initial consultation) has obtained information on the ancillary substance, which could have an impact on the established benefit/risk profile of the addition of the substance in the medical device, it shall provide the NB with advice, whether this information has an impact on the established benefit/risk profile of the addition of the substance in the medical device or not.

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The NB shall take the updated scientific opinion into account in reconsidering its assessment of the conformity assessment procedure. 7.5. The devices must be designed and manufactured in such a way as to reduce to a minimum the risks posed by substances leaking from the device. Special attention shall be given to substances which are carcinogenic, mutagenic or toxic to reproduction, in accordance with Annex I to Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations, and administrative provisions relating to the classification, packaging, and labeling of dangerous substances. If parts of a device (or a device itself) intended to administer and/or remove medicines, body liquids or other substances to or from the body, or devices intended for transport and storage of such body fluids or substances, contain phthalates which are classified as carcinogenic, mutagenic or toxic to reproduction, of category 1 or 2, in accordance with Annex I to Directive 67/548/EEC, these devices must be labeled on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging as a device containing phthalates. If the intended use of such devices includes treatment of children or treatment of pregnant or nursing women, the manufacturer must provide a specific justification for the use of these substances with regard to compliance with the ERs, in particular of this paragraph, within the technical documentation and within the IFU, information on residual risks for these patient groups and if applicable, on appropriate precautionary measures. 7.6. Devices must be designed and manufactured in such a way as to reduce, as much as possible, risks posed by the unintentional ingress of substances into the device taking into account the device and the nature of the environment in which it is intended to be used. 8. Infection and Microbial Contamination 8.1. The devices and manufacturing processes must be designed in such a way as to eliminate or reduce as far as possible the risk of infection to the patient, user, and third parties. The design must allow easy handling and where necessary, minimize contamination of the device by the patient or vice versa during use. 8.2. Tissues of animal origin must originate from animals that have been subjected to veterinary controls and surveillance adapted to the intended use of the tissues. Notified bodies shall retain information on the geographical origin of the animals. Processing, preservation, testing, and handling of tissues, cells, and substances of animal origin must be carried out so as to provide optimal security. In particular safety with regard to viruses and other transmissible agents must be addressed by implementation of validated methods of elimination or viral inactivation in the course of the manufacturing process. 8.3. Devices delivered in a sterile state must be designed, manufactured, and packed in a non-reusable pack and/or according to appropriate procedures to ensure that they are sterile when placed on the market and remain sterile, under the storage and transport conditions laid down, until the protective packaging is damaged or opened.

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8.4. Devices delivered in a sterile state must have been manufactured and sterilized by an appropriate, validated method. 8.5. Devices intended to be sterilized must be manufactured in appropriately controlled (e.g., environmental) conditions. 8.6. Packaging systems for non-sterile devices must keep the product without deterioration at the level of cleanliness stipulated and if the devices are to be sterilized prior to use, minimize the risk of microbial contamination; the packaging system must be suitable taking account of the method of sterilization indicated by the manufacturer. 8.7. The packaging and/or label of the device must distinguish between identical or similar products sold in both sterile and non-sterile condition. 9. Construction and Environmental Properties 9.1. If the device is intended for use in combination with other devices or equipment, the whole combination, including the connection system must be safe and must not impair the specified performances of the devices. Any restrictions on use must be indicated on the label or in the IFU. 9.2. Devices must be designed and manufactured in such a way as to remove or minimize as far as is possible: • the risk of injury, in connection with their physical features, including the volume/pressure ratio, dimensional, and where appropriate ergonomic features; • risks connected with reasonably foreseeable environmental conditions, such as magnetic fields, external electrical influences, electrostatic discharge, pressure, temperature or variations in pressure and acceleration; • the risks of reciprocal interference with other devices normally used in the investigations or for the treatment given; • risks arising where maintenance or calibration are not possible (as with implants), from aging of materials used or loss of accuracy of any measuring or control mechanism. 9.3. Devices must be designed and manufactured in such a way as to minimize the risks of fire or explosion during normal use and in single fault condition. Particular attention must be paid to devices whose intended use includes exposure to flammable substances or to substances which could cause combustion. 10. Devices with a Measuring Function 10.1. Devices with a measuring function must be designed and manufactured in such a way as to provide sufficient accuracy and stability within appropriate limits of accuracy and taking account of the intended purpose of the device. The limits of accuracy must be indicated by the manufacturer. 10.2. The measurement, monitoring, and display scale must be designed in line with ergonomic principles, taking account of the intended purpose of the device. 10.3. The measurements made by devices with a measuring function must be expressed in legal units conforming to the provisions of Council Directive 80/181/ EEC (1).

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11. Protection Against Radiation 11.1. General 11.1.1. Devices shall be designed and manufactured in such a way that exposure of patients, users, and other persons to radiation shall be reduced as far as possible compatible with the intended purpose, whilst not restricting the application of appropriate specified levels for therapeutic and diagnostic purposes. 11.2. Intended Radiation 11.2.1. Where devices are designed to emit hazardous levels of radiation necessary for a specific medical purpose the benefit of which is considered to outweigh the risks inherent in the emission, it must be possible for the user to control the emissions. Such devices shall be designed and manufactured to ensure reproducibility and tolerance of relevant variable parameters. 11.2.2. Where devices are intended to emit potentially hazardous, visible, and/or invisible radiation, they must be fitted, where practicable, with visual displays and/or audible warnings of such emissions. 11.3. Unintended Radiation 11.3.1. Devices shall be designed and manufactured in such a way that exposure of patients, users, and other persons to the emission of unintended, stray or scattered radiation is reduced as far as possible. 11.4. Instructions 11.4.1. The operating instructions for devices emitting radiation must give detailed information as to the nature of the emitted radiation, means of protecting the patient and the user and on ways of avoiding misuse and of eliminating the risks inherent in installation. 11.5. Ionizing Radiation 11.5.1. Devices intended to emit ionizing radiation must be designed and manufactured in such a way as to ensure that, where practicable, the quantity, geometry, and quality of radiation emitted can be varied and controlled taking into account the intended use. 11.5.2. Devices emitting ionizing radiation intended for diagnostic radiology shall be designed and manufactured in such a way as to achieve appropriate image and/or output quality for the intended medical purpose whilst minimizing radiation exposure of the patient and user. 11.5.3. Devices emitting ionizing radiation, intended for therapeutic radiology shall be designed and manufactured in such a way as to enable reliable monitoring and control of the delivered dose, the beam type and energy and where appropriate the quality of radiation.

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12. Requirements for Medical Devices Connected to or Equipped with an Energy Source 12.1. Devices incorporating electronic programmable systems must be designed to ensure the repeatability, reliability, and performance of these systems according to the intended use. In the event of a single fault condition (in the system) appropriate means should be adopted to eliminate or reduce as far as possible consequent risks. 12.1a. For devices which incorporate software or which are medical software in themselves, the software must be validated according to the state of the art taking into account the principles of development lifecycle, risk management, validation, and verification. 12.2. Devices where the safety of the patients depends on an internal power supply must be equipped with a means of determining the state of the power supply. 12.3. Devices where the safety of the patients depends on an external power supply must include an alarm system to signal any power failure. 12.4. Devices intended to monitor one or more clinical parameters of a patient must be equipped with appropriate alarm systems to alert the user of situations which could lead to death or severe deterioration of the patient’s state of health. 12.5. Devices must be designed and manufactured in such a way as to minimize the risks of creating electromagnetic fields which could impair the operation of other devices or equipment in the usual environment. 12.6. Protection against electrical risks. Devices must be designed and manufactured in such a way as to avoid, as far as possible, the risk of accidental electric shocks during normal use and in single fault condition, provided the devices are installed correctly. 12.7. Protection against mechanical and thermal risks 12.7.1. Devices must be designed and manufactured in such a way as to protect the patient and user against mechanical risks connected with, for example, resistance, stability, and moving parts. 12.7.2. Devices must be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from vibration generated by the devices, taking account of technical progress and of the means available for limiting vibrations, particularly at source, unless the vibrations are part of the specified performance. 12.7.3. Devices must be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from the noise emitted, taking account of technical progress and of the means available to reduce noise, particularly at source, unless the noise emitted is part of the specified performance. 12.7.4. Terminals and connectors to the electricity, gas or hydraulic and pneumatic energy supplies which the user has to handle must be designed and constructed in such a way as to minimize all possible risks. 12.7.5. Accessible parts of the devices (excluding the parts or areas intended to supply heat or reach given temperatures) and their surroundings must not attain potentially dangerous temperatures under normal use.

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12.8.

Protection against the risks posed to the patient by energy supplies or substances 12.8.1. Devices for supplying the patient with energy or substances must be designed and constructed in such a way that the flow-rate can be set and maintained accurately enough to guarantee the safety of the patient and of the user. 12.8.2. Devices must be fitted with the means of preventing and/or indicating any inadequacies in the flow-rate which could pose a danger. Devices must incorporate suitable means to prevent, as far as possible, the accidental release of dangerous levels of energy from an energy and/or substance source. 12.9. The function of the controls and indicators must be clearly specified on the devices. Where a device bears instruction required for its operation or indicates operating or adjustment parameters by means of a visual system, such information must be understandable to the user and as appropriate, the patient. 13. Information Supplied by the Manufacturer 13.1. Each device must be accompanied by the information needed to use it safely and properly, taking account of the training and knowledge of the potential users, and to identify the manufacturer. This information comprises the details on the label and the data in the IFU. As far as practicable and appropriate, the information needed to use the device safely must be set out on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging. If individual packaging of each unit is not practicable, the information must be set out in the leaflet supplied with one or more devices. IFU must be included in the packaging for every device. By way of exception, no such IFU are needed for devices in Class I or IIa if they can be used safely without any such instructions. 13.2.

13.3. a.

b. c. d.

Where appropriate, this information should take the form of symbols. Any symbol or identification color used must conform to the harmonized standards. In areas for which no standards exist, the symbols and colors must be described in the documentation supplied with the device. The label must bear the following particulars: the name or trade name and address of the manufacturer. For devices imported into the Community, in view of their distribution in the Community, the label, or the outer packaging, or IFU, shall contain in addition the name and address of the authorized representative (AR) where the manufacturer does not have a registered place of business in the Community; the details strictly necessary to identify the device and the contents of the packaging especially for the users; where appropriate, the word ‘STERILE;’ where appropriate, the batch code, preceded by the word ‘LOT,’ or the serial number;

80 e. f. g. h. i. j. k. l. m. n. 13.4. 13.5.

13.6. a. b. c.

d.

e. f. g. h.

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where appropriate, an indication of the date by which the device should be used, in safety, expressed as the year and month; where appropriate, an indication that the device is for single use. A manufacturer’s indication of single use must be consistent across the Community; if the device is custom-made, the words ‘custom-made device;’ if the device is intended for clinical investigations, the words ‘exclusively for clinical investigations;’ any special storage and/or handling conditions; any special operating instructions; any warnings and/or precautions to take; year of manufacture for active devices other than those covered by (e). This indication may be included in the batch or serial number; where applicable, method of sterilization; in the case of a device within the meaning of Article 1(4a), an indication that the device contains a human blood derivative. If the intended purpose of the device is not obvious to the user, the manufacturer must clearly state it on the label and in the IFU. Wherever reasonable and practicable, the devices and detachable components must be identified, where appropriate in terms of batches, to allow all appropriate action to detect any potential risk posed by the devices and detachable components. Where appropriate, the IFU must contain the following particulars: the details referred to in Section 13.3, with the exception of (d) and (e); the performances referred to in Section 3 and any undesirable side-effects; if the device must be installed with or connected to other medical devices or equipment in order to operate as required for its intended purpose, sufficient details of its characteristics to identify the correct devices or equipment to use in order to obtain a safe combination; all the information needed to verify whether the device is properly installed and can operate correctly and safely, plus details of the nature and frequency of the maintenance and calibration needed to ensure that the devices operate properly and safely at all times; where appropriate, information to avoid certain risks in connection with implantation of the device; information regarding the risks of reciprocal interference posed by the presence of the device during specific investigations or treatment; the necessary instructions in the event of damage to the sterile packaging and where appropriate, details of appropriate methods of resterilization; if the device is reusable, information on the appropriate processes to allow reuse, including cleaning, disinfection, packaging, and where appropriate, the method of sterilization of the device to be resterilized, and any restriction on the number of reuses.

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Where devices are supplied with the intention that they be sterilized before use, the instructions for cleaning and sterilization must be such that, if correctly followed, the device will still comply with the requirements in Section I. If the device bears an indication that the device is for single use, information on known characteristics and technical factors known to the manufacturer that could pose a risk if the device were to be re-used. If in accordance with Section 13.1 no IFU are needed, the information must be made available to the user upon request. i. details of any further treatment or handling needed before the device can be used (for example, sterilization, final assembly, etc.); j. in the case of devices emitting radiation for medical purposes, details of the nature, type, intensity, and distribution of this radiation. The IFU must also include details allowing the medical staff to brief the patient on any contra-indications and any precautions to be taken. These details should cover in particular: k. precautions to be taken in the event of changes in the performance of the device; l. precautions to be taken as regards exposure, in reasonably foreseeable environmental conditions, to magnetic fields, external electrical influences, electrostatic discharge, pressure or variations in pressure, acceleration, thermal ignition sources, etc.; m. adequate information regarding the medicinal product or products which the device in question is designed to administer, including any limitations in the choice of substances to be delivered; n. precautions to be taken against any special, unusual risks related to the disposal of the device; o. medicinal substances, or human blood derivatives incorporated into the device as an integral part in accordance with Section 7.4; p. degree of accuracy claimed for devices with a measuring function; q. date of issue or the latest revision of the IFU.

Compliance to the ERs is usually shown by completion of a checklist like documentation. Manufacturers are expected to indicate which requirements are applicable and which are not applicable. In addition, they are also required to show which standards they are in compliance with as well as what supporting evidence, they have to show this. A simple template for manufacturers to use when completing their Essential Requirements is included in the appendix at the end of this volume. A downloadable version can be purchased from www.scientistssanctuary. com

CHAPTER

4

GENERAL SAFETY AND PERFORMANCE REQUIREMENTS (GSPRS) OF MEDICAL DEVICES (UNDER THE MDR 2017/745)

While compliance with the ERs is imperative for establishing conformity with the MDD and active implantable medical device directive (AIMDD, 90/385/EEC), the same applies for the GSPRs within the MDR. The main purpose of this chapter is to compare the ERs within the MDD to that of the GSPRs of the MDR. The first point to note is that the GSPRs are detailed in Annex I of the MDR and are structured into three chapters, namely: • •

Chapter I: General requirements; Chapter II: Requirements regarding design and manufacture; and • Chapter III: Requirements regarding the information supplied with the device. While there are 13 ERs in the MDD and 16 in the AIMDD, there are 23 GSPRs in the new MDR. The overall requirements have been expanded, but the scope is the same as that of the previous directives. There are a few notable exceptions. For example, clinical evaluation has moved into the

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articles section of the regulation and a few new topics have been added such as devices without a medical purpose and requirements for devices used by lay persons. In addition, some parts of the GSPR now have increased emphasis and more detailed requirements so as to allow for more thorough alignment with harmonized standards and industry guidance. Some numbering and organizational changes have taken place, the requirements for risk and labeling have been expanded, there are new areas of emphasis as per standards and industry guidance, and many “state of the art” requirements from harmonized standards have been incorporated directly into the Regulation’s GSPRs. Let’s take a closer look at some of the detail of the GSPR: 1. GSPR 1: Performance and Safety: GSPR 1 generally corresponds to MDD ER 1 with majority of the text being the same. This requirement states that the devices shall be ‘designed and manufactured in such a way’ that safety of patients and users shall not be compromised. As with ER 1 in the directives, this is under the normal conditions of use. The concept of ‘performance’ is also brought in from the MDD ER 3. Design and construction of the device should conform to safety principles, taking into account the ‘generally acknowledged state of the art’ as required in to MDD ER 2. Risks relating to ergonomic features and consideration of the use environment which was previously present in MDD ER 1 have now moved to GSPR 5. 2. GSPR 2: Reduction of Risks: The GSPR 2–5 all relate to risk management. GSPR 2 is a new statement addressing the requirement to reduce risks as far as possible without adversely affecting the riskbenefit ratio. 3. GSPR 3: Risk Management System: GSPR 3 is a new requirement which more explicitly defines the requirements of risk management as aligned with EN ISO 14971. 4. GSPR 4: Risk Control Measures and Residual Risks: GSPR 4 generally corresponds to ER 2 in the existing MDD and covers the requirements that both, the overall residual risks and the residual risk associated with each hazard is evaluated and judged to be acceptable, with respect to the benefits. While this is already an expectation of the harmonized standard, this will now be explicitly included in the Regulation. Furthermore, there is also a requirement that the manufacturer ‘shall inform users of any residual risks.’ 5. GSPR 5: Risks Related to Use: GSPR 5 corresponds to the latter

General Safety and Performance Requirements (GSPRs) of Medical Devices ...

6.

7.

8. 9.

10. 11.

85

part of ER 1 in the MDD and addresses the reduction of risks relating to use error. Usability or human factors are addressed such that the risk of use error shall be reduced as far as possible. GSPR 6: Device Lifetime: GSPR 6 defines requirements for the characteristics and device performance over the lifetime of the device as indicated. The device characteristics and performance shall not be adversely impacted to such a degree that health or safety of a patient or user would be compromised, when under the stresses of ‘normal conditions of use.’ Device performance must not be adversely impacted when the device ‘has been properly maintained in accordance with the manufacturer’s instructions.’ Reasonably foreseeable maintenance or storage errors may be considered as part of use risk evaluation, but in some cases, impacts to performance cannot be prevented when maintenance and storage are not per the manufacturer’s instructions. GSPR 7: Packaging, Transport, Storage: This requirement outlines the basics for device packaging, transportation, and storage. This requirement can be linked to ER 5 in the MDD. The regulation provides examples of potential temperature and humidity fluctuations which are commonly considered by manufacturers during transportation simulations and storage where necessary. GSPR 8: Risk-Benefit Ratio: Here an updated definition of the ‘risk-benefit ratio’ is provided. It now includes ‘all known and foreseeable risks,’ and states that the risks ‘shall be minimized.’ GSPR 9: Devices Without a Medical Purpose: Devices without a medical purpose are excluded from the scope of the MDD but are included in the MDR. GSPR 9 clarifies how to apply the ‘risk-benefit’ and ‘performance’ requirements for those devices without a medical purpose or medical benefit. GSPR 10: Chemical, Physical, and Biological Properties: The requirements of GSPR 10 are broadly related to biological safety with more focus on the areas of specific substances of concern. GSPR 11: Infection and Microbial Contamination: The requirements of GSPR 11 are generally similar to that of MDD ER 8 and relate to infection and microbial contamination. This includes risk of infection, design for reuse, devices with a specific microbial state, devices delivered sterile, validation for sterile devices, environmental controls, packaging for non-sterile devices and labeling for sterile state.

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12. GSPR 12: Devices Incorporating a Medicinal Product, Substances Absorbed or Locally Dispersed: GSPR 12 deals with the requirements for medicinal products or substances which are absorbed or locally dispersed in the body. Medicinal substances were previously addressed in MDD ER 7.4. It should be noted that the scope of GSPR 12 has significantly changed under MDR with a broader scope with regards to the definition of what is included along with the medicinal considerations which now includes ‘substances or combinations of substances that are absorbed by or locally dispersed in the human body.’ 13. GSPR 13: Devices Incorporating Materials of Biological Origin: Materials of biological origin within the MDR has expanded a great deal from what was originally included in the MDD. These requirements generally correspond to MDD ER 7.4 and 8.2 and address tissues, cells or derivatives of human origin. 14. GSPR 14: Construction of Devices and Interaction with Their Environment: GSPR 14 corresponds to ER 9 in the MDD as well as ER 10.2 for ergonomic principles and deals with the construction of devices and interaction with their environment. Specifically, it focuses on use in combination, risks of interaction with the environment, risks of fire or explosion, design for adjustment, calibration, and maintenance; design for compatibility, measurement, monitoring or display scales and design and manufacture for safe disposal. 15. GSPR 15: Devices with a Diagnostic or Measuring Function: GSPR 15 of the MDR (in comparison to the MDD) deals with ‘diagnostic devices’ which has been added to the scope of the requirement. Manufacturers should consider the ‘precision’ of the device and measurements from measuring devices are still required to be expressed in legal units as per Directive 80/181/EEC. 16. GSPR 16: Protection Against Radiation: These requirements in GSPR 16 generally correspond to parts of ER 11 in the MDD and covers protection against radiation. This includes general requirements for intended and unintended radiation as well as ionizing radiation. 17. GSPR 17: Electronic Programmable Systems and Software: GSPR 17 defines the requirements for electronic programmable systems and software considered to be a medical device. The specific wording of the Regulation now includes ‘software that are devices in themselves’ more explicitly in the scope of these requirements. Information security are also included.

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18. GSPR 18: Active Devices and Devices Connected to Them: GSPR 18 defines particular requirements for active devices and connected devices with a large portion of the requirement corresponding to subparts of ER 12 in the MDD. 19. GSPR 19: Particular Requirements for Active Implantable Devices: GSPR 19 defines the requirements for active implantable devices. The requirements can be generally linked to ERs in the current AIMDD however as the MDD and AIMDD requirements have now been merged into the single MDR, many of the requirements for active implantable devices have moved and are listed here. This includes particular risks to be reduced for active implantable devices, device compatibility and reliability of energy, identification of devices and components and identification codes. 20. GSPR 20: Protection Against Mechanical and Thermal Risks: The requirements in GSPR 20 can be directly correlated to ER 12.7 in the MDD. This includes errors that could be made in fitting or refitting parts. This is usually covered as manufacturers align to the current standards and usability requirements. 21. GSPR 21: Protection Against the Risks Posed to the Patient or User by Devices Supplying Energy or Substances: GSPR 21 corresponds to ERs 12.8.1, 12.8.2 and 12.9 in the MDD and deals with protection against the risks posed to the patient or user by devices supplying energy or substances. There is some minor rewording of the requirement however the intent is unchanged. 22. GSPR 22: Protection Against the Risks Posed by Medical Devices Intended by the Manufacturer for Use by Lay Persons: Specific requirements for devices used by lay persons are new in the MDR. GSPR 22 outlines the requirements and considerations for the device’s instructions, variation in user technique, risks of error and injury, and verification of device function by the user. 23. GSPR 23: Label and Instructions for Use (IFU): GSPR 23 deals with product labels and IFU in which the text and requirements for labels and IFUs are greatly expanded as compared with both Directives. This includes the general requirements for information supplied by the manufacturer, label requirements as well as sterile package label requirements and requirements pertaining to the IFU. A simple template for manufacturers to use when completing their General Safety and Performance Requirements document is included in the appendix at the end of this volume. A downloadable version can be purchased from www.scientistssanctuary.com

CHAPTER

5

CLAIMING EQUIVALENCE BETWEEN MEDICAL DEVICES

Equivalence is defined as the process of demonstrating that two or more devices are similar such that there are no clinically relevant differences in their safety and clinical performance when on the market. The idea of claiming equivalence has been around for years. In Europe, medical device manufacturers with products on the market have used clinical data from devices that are already on the market to confirm the clinical safety and performance of their own devices. This is known as claiming equivalence whereby the device already on the market whose clinical evidence is being used is known as the equivalent device. Using clinical data and clinical evidence from these equivalent devices allows manufacturers to save time and avoid the need for carrying out their own clinical investigations. The guidance document MEDDEV 2.7/1 rev 4, released in 2016, identified clear criteria to establish equivalence and the new MDR has since reinforced these criteria. The MDR (Annex XIV, Part A) establishes that, in order to demonstrate equivalence in relation to other devices, three characteristics must be considered when demonstrating equivalence: technical, biological, and clinical. These characteristics shall be investigated and differences

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between devices should be disclosed. To harmonize and align the requirements between the MEDDEV guidance document and the MDR, a new guidance document was released in 2020 known as “MDCG 2020-5 Clinical Evaluation – Equivalence.” We will look at this guidance document in further detail. In addition, the MDR specifies that: “It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence.” If a manufacturer cannot demonstrate sufficient levels of access to presumed equivalent device data, equivalence cannot be claimed for the purpose of clinical evaluation. Furthermore, an equivalence claim can only work if the device in question is shown to be clinically, technically, and biologically equivalent to another device on the market which is already CE marked. Manufacturers should note that it won’t work if claiming equivalence is to a device that is not CE-marked under the MDR. We will look at the MDCG 2020-5 Guidance document in greater detail below.

CHAPTER

6

MDCG 2020-5: CLINICAL EVALUATION – EQUIVALENCE: A GUIDE FOR MANUFACTURERS AND NOTIFIED BODIES

The MDCG Guidance document was put together as a result of contributions from national CA and various other stakeholders to guide industry on what the best practice is when claiming equivalence. 1. Introduction This guidance document is not legally binding. It has been put together following contribution from national CA, industry, and relevant stakeholders and it should therefore be recognized as best practice. The Regulation (EU) 2017/745 on medical devices, hereafter referred to as the MDR, provides a possibility to use clinical data related to an equivalent device in the clinical evaluation required for a device under conformity assessment. Whilst carrying out a clinical investigation is the most direct way to generate clinical data concerning the safety and performance of medical devices for the purpose of CE marking, clinical data can also be sourced from: • Clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated; • Reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated.

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Equivalence shall be demonstrated according to the MDR requirements. The European Commission has published a guide on clinical evaluation under the directives 93/42/EEC and 90/385/EEC; MEDDEV 2.7/1 Rev. 4. This MEDDEV guide should be used also during the process of demonstrating equivalence under the MDR. However, it has been recognized that some of the requirements set out in MEDDEV 2.7/1 Rev. 4 are not fully aligned with the MDR and that further guidance to address the differences would be of benefit to industry and other stakeholders. Only the text of the MDR is legally binding. In cases of divergence between the MEDDEV 2.7/1 Rev. 4, this MDCG guidance and the MDR shall take precedence. This MDCG guidance does not introduce any new requirements. The demonstration of equivalence does not remove the requirement to always conduct a clinical evaluation in accordance with the MDR. It is the demonstration of equivalence that allows the manufacturer to let clinical data from an equivalent device enter the clinical evaluation process of the device in question for the purpose of confirmation of conformity with relevant GSPRs. There may also be other sources of clinical data than from an equivalent device to include in the process of clinical evaluation.

The guidance document further defines the scope such that it covers the demonstration of equivalence that is based on data relating to a device that is already on the market. This is further highlighted below: 2. Scope This MDCG guidance covers the demonstration of equivalence, based on data pertaining to an already existing device on the market, for the purpose of CE-marking under the MDR. One of the purposes of this document is to highlight the differences between the MDR and the MEDDEV 2.7/1 Rev. 4 specifically with regards to equivalence. It is also intended to provide additional guidance and support a harmonized approach to the demonstration of equivalence across the EU. In addition, non-exhaustive guidance and references have been provided with respect to device considerations for medical devices incorporating an ancillary medicinal product. This MDCG guidance also covers products without an intended medical purpose listed in Annex XVI of the MDR.

When claiming equivalence according to the MDCG 2020-5 Guidance document, it stipulates that the technical, biological, and clinical characteristics should be considered. These general characteristics are also described in the MEDDEV 2.7/1 document, the MDCG 2020-5 guidance document is aligned more with the requirements of the MDR. There are some differences in criteria between the MDR and the MEDDEV 2.7/1 document and these are highlighted below:

CHAPTER

7

DIFFERENCES IN TECHNICAL, BIOLOGICAL, AND CHEMICAL CHARACTERISTICS

•

TECHNICAL CHARACTERISTICS MDR, Annex XIV Part A (3)

Technical characteristics

MEDDEV 2.7/1 Rev 4, Appendix A1

The device is of similar design; is • • used under similar conditions of use; has similar specifications and properties including physicochem- • ical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength, and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and critical performance requirements. • •

be of similar design; used under the same conditions of use; have similar specifications and properties (e.g., physicochemical properties such as type and intensity of energy, tensile strength, viscosity, surface characteristics, wavelength, surface texture, porosity, particle size, nanotechnology, specific mass, atomic inclusions such as nitrocarburizing, oxidability); use similar deployment methods (if relevant); and have similar principles of operation and critical performance requirements.

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The above excerpt shows that the MDR requires that technical characteristics be taken into consideration for the demonstration of equivalence. This includes showing that the device in question and the device presumed to be equivalent are “used under similar conditions of use.” The MEDDEV 2.7/1 Rev. 4, on the other hand, specifies use under the same conditions with regard to technical characteristics. The conditions of use shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance between the device in question and the device presumed to be equivalent. Furthermore, difference examples are given for specifications and properties of the device when considering technical characteristics across the two definitions. The guidance document states that this list of examples is not to be treated as an exhaustive list when considering the demonstration of equivalence to another device. Refer to below extract: a.

b.

The MDR requires that technical characteristics shall be taken into consideration for the demonstration of equivalence including that the device in question and the device presumed to be equivalent are “used under similar conditions of use.” MEDDEV 2.7/1 Rev. 4, however, specifies use under the same conditions with regard to technical characteristics [11]. The conditions of use shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance between the device in question and the device presumed to be equivalent. For further guidance on the assessment of ‘similar,’ see also Section 4 of this document. Different examples are given for specifications and properties of the device when considering technical characteristics across the two definitions. These are examples only and are to be considered as such. They must not be interpreted as an exhaustive list of specifications and properties of technical characteristics when considering equivalence to another device. Note however that the MDR specifically points out that software algorithms shall be similar in the device presumed to be equivalent. This includes software algorithms in software driving or influencing the use of a device, and in software intended to be used alone. It is the functional principle of the software algorithm, as well as the clinical performance(s) and intended purpose(s) of the software algorithm, that shall be considered when demonstrating the equivalence of a software algorithm. It is not reasonable to demand that equivalence is demonstrated for the software code, provided it has been developed in line with international standards for safe design and validation of medical device software.

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Software solely intended for the configuration of a device (e.g., presentation on a graphical user interface, etc.), and not related to any medical purpose [14] (e.g., diagnosis, treatment, etc.), does not need to be similar when considering equivalence as long as it can be justified to not negatively affect the usability, safety or clinical performance.

•

BIOLOGICAL CHARACTERISTICS

Biological characteristics

MDR, Annex XIV Part A (3)

MEDDEV 2.7/1 Rev 4, Appendix A1

The device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachable

Use the same materials or substances in contact with the same human tissues or body fluids. Exceptions can be foreseen for devices in contact with intact skin and minor components of devices; in these cases, risk analysis results may allow the use of similar materials taking into account the role and nature of the similar material.

It should be noted that the MDR requires biological characteristics to take into account the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact, and with similar release characteristics of substances, including degradation products and leachable as the device equivalence is being claimed against. This distinction between same and similar is made to account for variations in processing, design, and the use environment which may introduce small changes despite the same raw materials. Refer to below extract: a.

Manufacturers must consider the additional text in the MDR and adequately specify all applicable characteristics. The exceptions, outlined in the MEDDEV 2.7/1 rev 4, to not use the same materials are NOT acceptable under the MDR. The MDR requires that biological characteristics shall be taken into consideration for the demonstration of equivalence, i.e., the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact, and with similar release characteristics of substances, including degradation products and leachable, as the presumed equivalent device. The distinction between “same materials or substances” and “similar release characteristics of substances” is made to account for the fact that processing, design, and the use environment may introduce small changes even when the raw materials are the same.

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Processing can make materials more susceptible to degradation by changing properties of the material and/or by inducing different stresses. For example, small changes in pH or oxidative stress can increase or decrease release characteristics. For this reason, it is the final device that shall be assessed. b. The principles outlined in ISO 10993 series of standards for the biological evaluation of medical devices can be adopted, in particular the ISO 10993-1 for a risk-based approach to biological evaluation and also for material characterization. In addition, the ISO 10993-18 which covers chemical characterization of materials can be adopted to specify the identity of materials and to estimate the type and quantity of leachable from the final device. Annex C of this standard addresses biological equivalence. The ISO 10993-17 includes principles on the toxicological risk assessment of leachable. Leachables may include degradation products or other substances from the materials or substances that the device is made of, but also other constituents for example residuals from the manufacturing process or sterilization, any contaminations, etc. Therefore, for the consideration of equivalence, it is the properties and characteristics of the final device that shall be taken into account. For degradable materials, ISO 10993, Parts 13, 14 and 15 address the identification and quantification of degradation products. Note, that there may be further parts in the ISO 10993 series of standards that are relevant for the device in question. c.

The MDR has additional requirements for devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed in the human body. For the consideration of equivalence, the substances shall be the same. Those devices are not medicinal products, but for the conformity assessment they shall comply with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions. This means that for the demonstration of equivalence under the MDR, those aspects shall also be taken into consideration. Note that the requirement that the NB shall seek a scientific opinion from a competent authority for medicinal products or the EMA, for the device or its products of metabolism, that are systemically absorbed by the human body in order to achieve their intended purpose, on the compliance with the relevant requirements laid down in Annex I to Directive 2001/83/EC, always applies for the device under evaluation even if equivalence has been demonstrated under the MDR. d.

The demonstration of equivalence may also concern medical devices with an ancillary medicinal substance, for example drug-eluting stents or heparin bonded central venous catheters.

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The MDR requires that biological characteristics shall be taken into consideration for the demonstration of equivalence, including that the device in question and the device presumed to be equivalent, use “the same materials or substances in contact with the same human tissues or body fluids.” This applies also to the medicinal substance and any related excipients/coatings. Excipients/coatings may potentially have a significant effect for example on the release characteristics of the medicinal substance intended only for a local effect from a stent, and thereby a significant effect on the clinical performance. In all cases, concerning the device under evaluation, the NB shall: • verify the usefulness of the substance as part of the device, taking account of the intended purpose of the device; and • seek a scientific opinion from a competent authority for medicinal products or the EMA to ensure that the quality, safety, and benefit/risk of using the ancillary medicinal product, including whether the manufacturing process have been adequately assessed. Note that medical devices with an ancillary medicinal substance are class III devices. In cases where a manufacturer intends to claim equivalence to a device not manufactured by him, the MDR requires that the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis. Manufacturers cannot claim equivalence of a device with an ancillary medicinal substance to a device without an ancillary medicinal substance and vice versa. For example, the manufacturer of a heparin coated catheter shall not claim equivalence to a drug-free catheter even if both catheters are otherwise identical. Similarly, manufacturers shall not claim equivalence of the ancillary medicinal substance to a ‘standalone’ medicinal substance.

•

CLINICAL CHARACTERISTICS MDR, Annex XIV Part A (3) MEDDEV 2.7/1 Rev 4, Appendix A1

Chemical characteristics

The device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy, and physiology; has the same kind of user; has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose.

• used for the same clinical condition (including when applicable similar severity and stage of disease, same medical indication); • used for the same intended purpose; • used at the same site in the body; • used in a similar population (this may relate to age, gender, anatomy, physiology, possibly other aspects); • not foreseen to deliver significantly different performances (in the relevant critical performances such as the expected clinical effect, the specific intended purpose, the duration of use, etc.).

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The MDCG 2020-5 guidance document further defines that for manufacturers to compare clinical characteristics, the device should have the same kind of user. This could be a healthcare professional or lay user. Refer to extract below: a.

b.

The MDR additionally requires that, for manufacturers to compare clinical characteristics, the device shall have the same kind of user. The MDR clearly points out that a user means any healthcare professional or lay person who uses a device, and that a lay person means an individual who does not have formal education in a relevant field of healthcare or medical discipline. Manufacturers must therefore take into consideration whether the intended user’s competence or knowledge can have any implication for the safety, clinical performance and outcome when considering equivalence between the device in question and the presumed equivalent device. For example, a device intended for professional use and a device intended for home use, but for the same clinical condition or purpose, may have a different safety and performance profile due to the environment in which they are intended to be used. The MDR does not explicitly state that the medical device needs to be used for the same medical indication, gender, and duration of use as the equivalent device. However, it is understood that in general, this is covered by the MDR requirement that both devices should be used for the same clinical condition or purpose including similar severity and stage of disease and also have similar relevant critical performance which is also outlined in the MEDDEV 2.7/1 Rev. 4. This is supported by the definitions in the MDR of the ‘intended purpose,’ and the ability of the device to achieve its intended purpose by the ‘clinical performance’ including measurable ‘clinical benefit.’

CHAPTER

8

DEMONSTRATION OF EQUIVALENCE

The MDCG 2020-5 guidance document compares the text between the MDR 2017/745 and MEDDEV 2.7/1 Rev 04. Refer below: MDR, Annex XIV Part A (3)

MEDDEV 2.7/1 Rev. 4, Appendix A1

The characteristics listed in the first paragraph shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification.

For assuming equivalence, – all three characteristics (clinical, technical, biological) need to be fulfilled; – similar means that no clinically significant difference in the performance and safety of the device would be triggered by the differences between the device under evaluation and the device presumed to be equivalent.

The guidance document refers to a number of prerequisites that shall be fulfilled to demonstrate equivalence. This includes: •

Comparison of technical, biological, and clinical characteristics and consideration of similarity such that there is no clinically significant difference in the safety and performance of the device.

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•

A manufacturer of a medical device shall not claim equivalence to a product without an intended medical purpose. • Manufacturers can identify more than one equivalent device to the device under evaluation. Each device must show equivalence to the device under evaluation for all the listed technical, biological, and clinical characteristics. • Manufacturers shall not use different parts of different devices to claim equivalence to the device under evaluation. • The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant GSPRs. • Considerations of equivalence shall be based on proper scientific justifications. Technical, biological, and clinical characteristics shall be duly investigated and documented. Any differences between the two devices should be fully disclosed. • Equivalence can be claimed to a device that is not CE-marked, provided all relevant MDR requirements regarding equivalence and clinical evaluation can be met. This is further explained in the table below: The below is an extract from the MDCG 2020-5 regarding claiming equivalence: a. The overall considerations of equivalence shall conclude whether the listed technical, biological, and clinical characteristics in the MDR are similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Note that some of the listed characteristics in the MDR shall be the same, not only similar. The corresponding wording from MEDDEV 2.7/1 Rev. 4 is presented for information above. Consideration must be given to the characteristics mentioned above and a gap analysis should be conducted by the manufacturer to evaluate any clinically significant difference(s). Modifications of a device may be implemented for a variety of reasons. If the differences have been introduced to address specific safety and/or performance issues it shall be duly justified, that there would be no clinically significant difference in the safety and clinical performance other than the intended improvements related to the specific issue that triggered the modification/difference. For all modifications and concomitant claims of equivalence, there must be no additional risks or potential of negatively altered performance related to the introduced modifications.

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b. Manufacturers may identify more than one equivalent device to the device under evaluation, but each device shall be equivalent to the device under evaluation in all the listed technical, biological, and clinical characteristics. Equivalence to each device shall be fully investigated, described, and demonstrated in the CER. This means that manufacturers shall not use different parts of different devices to claim equivalence to the device under evaluation. The MEDDEV 2.7/1 Rev. 4 is in line with this approach. In exceptional cases, a deviation from this principle may be considered. There may be device systems comprised of several more or less “stand alone” devices, where it may be justified to consider equivalence of a device in the system to a presumed equivalent device in a device system already on the market (by the same manufacturer) provided that all technical, biological, and clinical characteristics are same/similar [32], and that the devices in the system do not affect the safety and performance of each other. This should be duly investigated and documented both on the level of potential interference between the devices in the system, as well as on the overall safety and clinical performance of the device system. c. Regarding the clinical evaluation, the MDR requires that the manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant GSPRs. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose. In addition, considerations of equivalence shall be based on proper scientific justification. This implies that technical, biological, and clinical characteristics shall be duly investigated and documented. The manufacturer is expected to fully identify and disclose any differences between the two devices. Pre-clinical data for the consideration of equivalence should allow a scientifically sound evaluation of technical and biological characteristics. Examples of data sources: • Data from the technical documentation of a manufacturer’s own presumed equivalent device (specifications, test-results, chemical/physical/biological analyzes, data from pre-clinical investigations, etc.). • Data published in the scientific literature, e.g., animal or other pre-clinical data The assessment of whether any differences in characteristics would result in clinically significant difference in safety and clinical performance shall also be duly substantiated and based on proper scientific justification. This assessment may be supported by, e.g., clinical data from the scientific literature, common specifications (CS), harmonized standards or other established technical specifications. Furthermore, for the assessment of safety, a risk-based approach is expected, both for the identification of characteristics that may affect safety as well as for the final assessment of equivalence regarding safety. It is important for the consideration of equivalence that pre-clinical data and any clinical data relate to the actual device under evaluation, and to a defined generation/ version of the actual device considered for equivalence, bearing in mind that there may be significant differences between different generations of the other device. If a manufacturer is not able to demonstrate sufficient levels of access to the data relating to the presumed equivalent device and needed for the consideration of equivalence claims cannot be made for the purpose of conformity assessment.

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d. The MDR notes specific requirements in addition to the demonstration of equivalence in order not to perform a clinical investigation which must be taken into account. A manufacturer of implantable devices and class III devices shall perform clinical investigations except if the device has been designed by modifications of a device already marketed by the same manufacturer and equivalence can be demonstrated according to the MDR. In this context, a marketed device is considered to be a device already placed on the market and CE marked with respect to either the MDR or the directives 93/42/EEC or 90/385/EEC. The CE marking should still be valid, should be based on an updated clinical evaluation, and the benefit/risk ratio for this device should be favorable. For a manufacturer of implantable devices and class III devices claiming equivalence to an already marketed device not manufactured by him, in addition to the requirements in MDR Article 61(4), the manufacturer must have a contract in place that allows full access to the technical documentation on an ongoing basis. Furthermore, the MDR also requires that the original clinical evaluation of the equivalent device has been performed in compliance with the requirements of the MDR. This implies that the presumed equivalent device is certified under the MDR. As such, it will not be possible to claim equivalence to a device certified with respect to the Directives 93/42/EEC or 90/385/EEC. e. For devices other than implantable devices and class III devices and where the manufacturer wants to claim equivalence, MDR Article 61(3) is applicable. This requirement does not specify whether the device is presumed to be marketed within the EU. Therefore, it will be possible to claim equivalence to a device certified with respect to the Directives 93/42/EEC or 90/385/EEC or the MDR. However, exceptions can be considered, and equivalence claimed to a device that is not CE-marked, provided all relevant MDR requirements regarding equivalence and clinical evaluation can be met. This includes − that the manufacturer shall have sufficient levels of access to the data relating to devices with which they are claiming equivalence. In the circumstance that the presumed equivalent device is from another manufacturer, there is no MDR requirement of a contract between the manufacturers for regulating the access to the technical documentation. − that clinical investigations were conducted in accordance with international guidelines [42] − that the clinical data meet the requirements of the MDR, and a justification is provided whether the clinical data are transferrable to the European population. The regulatory status of the presumed equivalent device should be disclosed. See MEDDEV 2.7/1 Rev. 4 Appendix A1 for further guidance. f. In case of products without an intended medical purpose listed in MDR Annex XVI clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified. An analogous device, in this context, is understood as a medical device which is similar in terms of functioning and risks profile and has a medical purpose. To duly justify reliance on existing clinical data from an analogous medical device, the principles of demonstration of equivalence should be applied with the acceptance that the device under evaluation will only have an esthetic or another non-medical purpose whereas the analogous device has a medical purpose. The general requirement to demonstrate a clinical benefit shall be understood as a requirement to demonstrate the performance of the device.

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In addition, since the CS for the products without an intended medical purpose may have requirements related to the clinical evaluation regarding safety these requirements must be taken into consideration when demonstrating equivalence and concluding whether there would be no clinically significant difference in the safety. There shall be no significant difference in the safety and performance between the product and the presumed analogous medical device.

Note: A template of an equivalence table is presented in the appendix section below. Ready-to-use templates can be purchased and downloaded from https://scientistssanctuary.com/ Simplified diagram showing how to determine if a device is comparable:

CHAPTER

9

USE OF DATA FROM SIMILAR DEVICES

It is also possible to use data from what the regulation refers to as similar devices. These devices are those belonging to the same generic device group. The MDR defines this as a set of devices having the same or similar intended purposes allowing them to be classified in a generic manner not reflecting specific characteristics. This perspective can be used in cases where equivalence cannot be demonstrated under the MDR. Common ways to show this includes: • • • •

•

Ensuring that the risk management system is comprehensive by identifying relevant hazards and clinical risks; Demonstrating state of the art; Identifying any design features in similar devices that pose special performance or safety concerns; Providing input for clinical investigation design or post-market clinical follow-up design, and the post-market surveillance system; Identification of relevant clinical outcome parameters for the intended clinical benefits. This can be based on published clinical data pertaining to the similar device(s);

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•

Defining minimum requirements for a quantified clinical benefit that is considered clinically relevant, and/or to identify acceptable occurrence rates of risks and adverse events.

CHAPTER

10

HOW TO CONDUCT A LITERATURE REVIEW?

Conducting a successful clinical evaluation depends on the manufacturer’s ability to find suitable data and appraise it in a way that shows the devices safety, efficacy, and performance. Preparing a suitable literature review can be a fairly time-consuming task. The clinical evaluation can be based on both, direct, and indirect data. Direct data is data that has been generated by the device itself. This can include data from pilot studies, case studies and clinical trials. This can also include data from registries and that which is publicly available but in relation to the device itself. It can also include data from the manufacturers QMS which is often generated after the device is on the market, such as PMS activities, risk management and documented non-conformances. On the other hand, indirect clinical data includes data that has been generated by a device which the manufacturer claims equivalence too. The literature review should have two main goals namely: (1) literature on the device in question and the device which equivalence is claimed against; and (2) a review of the current knowledge and state-of-the-art necessary for appraising and analyzing the clinical data from the literature obtained.

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Ideally when preparing the clinical evaluation, a clinical evaluation literature review protocol should be prepared. The literature review needs to be a systematic process. The MEDDEV 2.7.1 Rev 4 includes annexures which detail a list of what should be included in the search protocol. Common points include: • • •

Defining the objectives of the literature evaluation; Defining specific terms that will be used in the search; Defining which sources of information will be used for searches such as PubMed, MEDLINE or Embase; • Setting up the search such that both titles and abstracts for the articles are obtained. Having a systematic approach to appraising data is important, as often literature searches turn up hundreds of results. The systematic approach should help identify which data to use and which ti discard. Ideally, suitability, applicability, population, and quality should be considered. This is elaborated on below: Suitability: It is based on the device in question or the equivalent device. ii. Applicability: It is about other devices that use the same technology. iii. Population: It is the population similar to the population we believe our device will treat? iv. Quality: It is the literature published in a peer reviewed journal? What kind of study is it? Quality of data is important and the MEDDEV 2.7.1 Rev 4 defines various points to be considered when analyzing quality of data. This includes: i.

• • • • • •

Methods, patient populations, side effects, clinical outcomes; Statistically significant/insignificant data and statistical methods; A lack of adequate controls which may lead to bias or confusion; Improper collection of mortality and serious adverse events data; Misinterpretation of data by authors; Illegal activities such as clinical investigations that were not conducted in compliance with local regulations. A weighting should be applied to relevant data that is most relevant to the device – a higher weighting should be applied to high quality data and a lower weighting should be applied to less relevant data. Often such data

How to Conduct a Literature Review?

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appraisals should be performed by an individual with a specialized skill set such as a clinical evaluator or a statistician. Once the data has been gathered and appraised, the next step is to determine whether or not it demonstrates compliance with clinical performance and safety requirements and document this. The report should include enough information to show a reviewer how the search was done and what appraisal and analysis criteria were used.

CHAPTER

11

WHEN TO UPDATE YOUR CER?

Preparing the CER is often just beginning of the CER’s lifecycle. In general, a CER needs to be updated anywhere from annually to up to every five years. The CER should also be updated when new information is received from PMS activities that could result in change some of the clinical outcomes. Often the frequency of update depends on the risk class of the device and how well established the device is.

CHAPTER

12

WHAT IS A CLINICAL EVALUATION PLAN?

The clinical evaluation plan forms a road map for conducting the clinical evaluation process. It includes the scope, methodological, and systematic process on how to proceed and reach a conclusion on the clinical evaluation which is then documented in a CER. The following are some of the major requirements to be considered in the Clinical Evaluation Plan: • • • • • •

Identification of the GSPRs that require the support of the clinical data (Annex I of the MDR 2017/745); Intended purpose of the device; Intended target groups with indications and contraindications; Various aspects required for the analysis and the conformity assessment of the clinical data; Intended clinical benefits with relevant and specified criteria relating to clinical outcomes; Methods to be used for the evaluation of qualitative and quantitative details of clinical safety with reference to the determination of residual risks and side effects;

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•

Identification of the criteria to be used to determine the acceptability of the benefit-risk ratio for various indications and for the intended purpose of the device, based on state of the art; • If any specific components such as the use of medicinal substances, non-viable animal or human tissues are incorporated in the medical device, then how to address the related risk to benefit ratio must be identified; • An indication of the technique followed for the collection of clinical data for the clinical evaluation; • Clinical development plan with clear indications of the milestones and descriptions of potential acceptance criteria for each progression; • Levels of clinical evidence required for the demonstration of the conformity assessment of the general safety and performance requirement. Below are some guidance documents to further help with preparing the clinical evaluation: • • • • •

MEDDEV 2.7.1 Rev. 4 – as discussed in detail above; MDCG 2020-1 – refer to relevant chapter below; MDCG 2020-5 – as discussed in detail above; MDCG 2020-6 – refer to relevant chapter below; MDCG 2020-13 – refer to relevant chapter below.

CHAPTER

13

POST-MARKET CLINICAL FOLLOW-UP (PMCF)

Post-market clinical follow up (PMCF) is the active collection of clinical experience or clinical data on a medical device after it has been released to the market. For this reason, PMCF is often defined as a continuous process whereby the manufacturer will maintain and update their clinical information and PMS plan and reports. This can include extended followups with patients from the pre-market investigation, initiating new clinical investigations, or review of data collected from patients previously exposed to the device. This type of on-going studies aims to reduce any risks that still may be associated with the device in question as well as any other significant changes that may occur to the device itself or its defined intended uses. PMCF is often considered as a continuous process which essentially updates the clinical evaluation in a holistic manner. Often this is addressed in the manufacturers PMS plan and can be used to collect additional clinical data to address any remaining uncertainties about a device. PMCF studies may also be used to address new concerns showing as a result of post-market adverse events being reported around the device.

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The process should start by the implementation of a PMCF plan. This plan should specify the methods and procedures which the manufacturer has set up, to proactively collect and evaluate clinical data from devices that have already been placed on the market or put into service. The aim of the PMCF plan is to: •

Confirm the safety and performance including the clinical benefit (if applicable) of the device throughout its expected lifetime; • Identify the previously unknown side effects; • Monitor identified side-effects and contraindications; • Identify and analyze emergent risks on the basis of factual evidence; • Ensure continued acceptability of the benefit-risk ratio, referred to in Sections 1 and 9 of Annex I in the MDR; • Identify possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct. The findings of a PMCF shall be analyzed by the manufacturer who shall document the results in a PMCF evaluation report. This report shall form part of the CER and essentially the technical documentation. A Medical Device Coordination Group (MDCG) Document was released to guide manufacturers and notified bodies on the correct template for a PMCF. This document is entitled MDCG 2020-7: Post-market Clinical Follow-up Plan Template: A Guide for Manufacturers and Notified Bodies and was released in April 2020. The purpose of the template provided was to guide manufacturers in complying with the requirements of the new MDR (2017/745) with respect to compiling a PMCF plan and presenting this information in an organized manner, while also making it easier for notified bodies and/or CA to find the information. The contents of the plan will usually be assessed by the NB and this assessment will also include the manufacturers procedures and documentation as well as the justification for not carrying out a PMCF.

APPENDICES

Simple Templates for Manufacturers to Use •

Template of an Equivalence Table

Equivalence Table: This table can be used for comparison of a device with a presumed equivalent device that is already marketed device Technical characteristics

Device 1 This is the device under clinical evaluation (Add any description of characteristics and reference to specifying documents)

Device 2 This device is already being marketed (Add any description of characteristics and reference to specifying documents)

Identified differences or conclusion that there are no differences in the characteristics

Device is of a similar design

–

–

–

Used under similar conditions of use

–

–

–

Similar specifications and properties including physiochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength, and software algorithms

–

–

–

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Uses similar deployment methods where relevant

–

–

–

Has similar principles of operation and critical performance requirements

–

–

–

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)

Clinically significant difference Yes/No

Summary

Biological Characteristics

Device 1 This is the device under clinical evaluation (Add any description of characteristics and reference to specifying documents)

Device 2 This device is already being marketed (Add any description of characteristics and reference to specifying documents)

Identified differences or conclusion that there are no differences in the characteristics

Uses the same materials or substances in contact with the same human tissues or body fluids

–

–

–

Similar kind and duration of – contact with the same human tissues or body fluids

–

–

Similar release characteristics of substances including degradation products and leachable

–

–

–

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)

Summary

Clinically significant difference Yes/No

Appendices

119

Clinical Characteristics

Device 1 This is the device under clinical evaluation (Add any description of characteristics and reference to specifying documents)

Device 2 This device is already being marketed (Add any description of characteristics and reference to specifying documents)

Identified differences or conclusion that there are no differences in the characteristics

Same clinical condition or purpose, including similar severity and stage of disease

–

–

–

Same site in the body

–

–

–

Similar population, including as regards age, anatomy, and physiology

–

–

–

Same kind of user

–

–

–

Similar relevant critical performance in view of the expected clinical effect for a specific intended purpose

–

–

–

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)

Clinically significant difference Yes/No

Summary

Simple easy to use templates and guides can be downloaded from https:// scientistssanctuary.com/. •

Template of a Clinical Evaluation Plan: This plan should be later updated by the post-market clinical follow-up to include new search criteria for the literature search.

120 1.

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Related Documents: • SOP clinical evaluation; • Clinical evaluation report. Product Details: • Name: • Version: • UDI Details: Responsibilities: Describe the roles of people who will be doing the Clinical Evaluation. 2. Scope of the Clinical Evaluation 2.1. Device Description Write the device description here. This should include the intended use. 2.2. Clinical Benefits, Outcome Parameters Describe the clinical benefits you expect from your product. Define how you’ll measure the clinical benefits. Describe the product claims as stated by MEDDEV 2/7.1 Rev. 4. 2.3. Clinical Safety, Methods for Analysis Describe your safety parameters. Describe methods that will be used to prove that your product fulfills those safety parameters. 2.4. Acceptability of Benefit-Risk Ratio Define your benefits and safety parameters and why the benefit outweighs the risks. 3. Type of Evaluation Describe the type of Clinical Evaluation being done – are you claiming equivalence to an already-certified/CE marked device? Describe your methodology for searching for such devices. 4. Literature Search 4.1. Literature Search Methods • Describe your literature search methods; • Common databases include PubMed, Google Scholar, Cochrane, Embase); • Describe the keywords you’ll be using; • Describe how you plan to document it; • Describe the adequacy of search terms (it should be sufficiently broad to establish benchmarks, determine the general state of the art, determine potential risk, adverse events, undesirable side-effects, etc.); • Acceptability of inclusion and exclusion criteria; • Both favorable and unfavorable data should be included; • Strategies for avoiding duplication of data should be identified; • Literature search and review protocols should be identified; • Any deviations from the manufacturer’s literature search protocol.

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121

4.2. Literature Appraisal Criteria • Describe your criteria for clinical data which you deem acceptable for your clinical evaluation; • Information should be relevant; • Additional hard criteria (like requirements for the study design, etc.), should also be included; • Weighing of information from multiple studies should be included; • Equivalence of the described device literature should be considered. 4.3. Additional Databases • Additional databases that can be used include: • Clinical trials: clinicaltrail.gov, DRKS, WHO, ANZCTR • Adverse events: EUDAMED, FDA MAUDE, FDA Medical Device Recalls

•

Template of a Simplified PMCF Plan PMCF plan number: PMCF plan date: PMCF plan version: Link to clinical evaluation report: Scope of this PMCF:

Revision History Revision Revision Date

Description of Change

Manufacturers Contact Details Legal manufacturer name: Address: SRN: Personal responsible for regulatory compliance: Email: Phone: Fax: Authorized representative/agent: Address:

Revised By

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Contact person: Email: Phone: Fax: Medical Device Description and Specification Product or trade name: Model and type: General description of the device: Intended purpose: Intended users: Basic UDI-DI: Intended patient population: Clinical condition to be diagnosed, prevented, treated, etc., by the medical device: Indications: Contraindications: Warnings: List and description of any variants and/or configurations covered by this plan: List of any accessories covered by this plan: Certificate number (if available) Other codes (i.e., CND codes): Class: Classification rule: Expected lifetime: Is this a novel device? Explanation of any novel features: Link to clinical literature/evidence around the novelty of the device?

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123

Activities Related to PMCF (This section should highlight any specific methods and procedures)

• • • • • •

Description of activities that will be conducted post-market. Description of methods and procedures used in this PMCF. Aim of each activity described. Rationale for appropriateness of the chosen methods to achieve objectives. Known limitations of the planned activities. Timelines of activities (define quarterly or at least annually). For each activity: • Define where the need for conducting the PMCF activity is coming from (i.e., requested from the NB, CER requirement, PMS, risk management report, previous PMCF report, etc.) • Provide the description of activity. • General or specific procedure/method Define the aim of the activity: • To confirm the safety of the medical device; • To confirm the performance of the medical device; • To identify previously unknown side effects; • To monitor the identified side effects and contraindications; • To identify and analyze emergent risks; • To ensure the continued acceptability of the benefit-risk ratio; • To identify the possible systematic misuse or off-label use of the device. Describe the different procedures which will be used as part of the PMCF: • Screening of scientific literature; • Screening of other sources of clinical data; • Post-market studies; • Collecting data from registries; • Surveys from health care professionals; • Surveys from patients/users; • Review of case reports which may reveal misuse/off label use. Describe the rationale for the appropriateness of the chosen methods/procedures: • Justification for sample size, timescales, and endpoints; • Justification of the study design and why it is sufficient to ensure representative patient populations; • Statistical justification for the expected quality of outcomes including justification for why this is satisfactory in light of the residual risks.

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Summary Table of Different PMCF Activities Foreseen by the Manufacturer Activity No.

Description of Activity

Aim of Activity

Rationale and Know Limitations of the Activity

Timelines of the Activity

Reference to Relevant Parts of Technical Documentation

• Include references to relevant information from the CER and risk management file which need to be analyzed, followed up on and evaluated;

• If there is no relevant information from the CER and/or the risk management file to be considered, the manufacturers must mention this.

Evaluation of Clinical Data Relating to Equivalent or Similar Devices In this section, the manufacturer shall: • Gather information regarding equivalent/similar devices for which clinical data will be further evaluated and presented in the PMCF; • Source PMCF data intended to demonstrate continuing safety and performance; • Use data from equivalent/similar devices for example to update the information relating to state of the art, to identify and further assess relevant safety outcomes; • Be consistent with the selected devices throughout the technical documentation; • Indicate whether the selected devices are demonstrated to be equivalent or is a similar device (for each device listed, a clear reference to the relevant parts of the CER can be made). Summary Evaluation of Clinical Data Relating to Equivalent or Similar Devices Product Name of Equivalent/Similar Device

Intended Purpose

Intended Users

Intended Patient Population

Medical Condition

Indication

Reference to Clinical Data Evaluation in the CER

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125

Reference to Any Applicable Common Specifications, Harmonized Standards or Applicable Guidance Documents The manufacturer should: • List any common specifications to comply with (title, date, version); • List any harmonized standards to comply with (title, date, version); • List any guidance documents to comply with (title, date, version). Estimated Date of the PMCF Evaluation Report This section should address when the manufacturer plans to have the first report ready. The timelines shall be defined quarterly or at least yearly.

Simple easy to use templates and guides can be downloaded from https:// scientistssanctuary.com/. • Template of a Simplified PMCF Evaluation Report The manufacturer shall analyze the findings coming from the activities of the PMCF plan and document the results in the PMCF Evaluation Report. This shall form part of the CER and the technical documentation. The conclusions of the PMCF evaluation report shall be taken into consideration and eventually lead to an update of the CER, the risk management file, the PMS plan and the Summary of Safety and Clinical Performance documentation. Post-market Clinical Follow-Up (PMCF) Plan Corresponding to the Present Evaluation Report PMCF plan number and version: Post-market Clinical Follow-Up (PMCF) Evaluation Report PMCF report number: PMCF report date: PMCF report version: Revision History Revision Revision Date

Description of Change

Revised By

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Manufacturers Contact Details Legal manufacturer name: Address: SRN: Personal responsible for regulatory compliance: Email: Phone: Fax: Authorized representative (if applicable): Address: Contact person: Email: Phone: Fax: Medical Device Description and Specification Refer to Section B from the PMCF Plan, if there are no changes. If there are changes from the PMCF Plan, please fill in the different requested fields highlighting those changes. Product or trade name: Model and type: General description of the device: Intended purpose: Intended users: Basic UDI-DI: Intended patient population: Clinical condition to be diagnosed, prevented, treated, etc., by the medical device: Indications: Contraindications: Warnings: List and description of any variants and/or configurations covered by this plan: List of any accessories covered by this plan: Certificate number (if available) Other codes (i.e., CND codes): Class:

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Classification rule: Expected lifetime: Is this a novel device? Explanation of any novel features: Link to clinical literature/evidence around the novelty of the device? Section C: Activities Undertaken Related to PMCF In this section, the manufacturer should report all the activities described in Section C of the PMCF plan which have been performed, all the collected clinical data obtained from those completed activities, as well as any justification of deviations from the plan. The discussion shall include the analysis of the findings, whether positive or negative and also the potential impact on the different documents (such as the CER, risk management file, Summary of Safety and Clinical Performance) initially reviewed during the conformity assessment. It is expected for each activity performed, there should be a description in different subsections. This should be related to the type of activities and for each subsection, a description about the quality of data collected. For each subsection: • Description of activities that was conducted; • Description of methods and procedures used; • Rationale for appropriateness of the chosen methods to achieve objectives; • Known limitations of the activities taken; • Aims of the activities should be described; • Description of the different procedures undertaken; • Description of the rationale for the appropriateness of the chosen methods/procedures. Section D: Evaluation of Clinical Data Relating to Equivalent or Similar Devices In this section, the manufacturer shall report all the clinical data collected relating to an equivalent device or selected similar device(s), provide an analysis and conclusions, and whether changes of the state of the art, or newly identified hazards would have an impact on the devices benefit-risk determination, the clinical evaluation and/or the PMCF plan. Product name of the equivalent/similar device

Results discussed

References used to get the results (publications, part of the technical documentation from this equivalent/similar device)

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Section E: Impact of the Results on the Technical Documentation In this section, the manufacturer shall discuss the aggregate results coming from each PMCF activity planned and performed, described in Section C, but also results coming from equivalent and/or similar device, described in Section D, which are considered to impact the technical documentation and at least the following documents shall be considered: i. Clinical Evaluation Report (Date and Version): No relevant information from the CER have been considered. If applicable, it is expected from manufacturer to describe why some information that might have an impact on the CER have not been considered. Relevant information analyzed and monitored. Analysis of the outcome is to be reported in the updated CER. ii. Risk Management File (Date and Version): No relevant information from the risk management file have been considered. If applicable, it is expected from manufacturer to describe why some information that might have an impact on the risk management file have not been considered. Relevant information analyzed and monitored. Analysis of the outcome is to be reported in the updated risk management file Section F: Reference to Any Common Specifications, Harmonized Standards or Guidance Documents Applied In this section the manufacturer should point out whether the collected clinical data related to the device in question still confirms adherence to applied CS and/ or applied harmonized standards, and/or guidance listed in the PMCF plan. Common specification(s) applied (Title, date, and version) Harmonized standard(s) applied (Title, date, and version) Guidance(s) followed (Title, date, and version) Section G: Conclusions In this section, it is expected that the manufacturer shall provide an overall conclusion of the findings and relate them to the aims of the PMCF plan. The conclusions shall be taken into account in the following clinical evaluation and in the risk management. Finally, this conclusion shall highlight if any need for preventive and/or corrective measures has been identified. The conclusion may also give input to the next PMCF plan.

Simple easy to use templates and guides can be downloaded from https:// scientistssanctuary.com/.

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•

129

Simplified Template of a Clinical Evaluation Report

• •

Summary of the report Scope of the clinical evaluation report General details Device description Device classification Intended use Contraindications Warnings Precautions Device status Identification of changes • Clinical background, current knowledge and state of the art Clinical background Current knowledge and state of the art • Device under evaluation Type of evaluation Demonstration of equivalence Data generated and held by the manufacturer Post-market surveillance Post-market clinical follow up Relevant pre-clinical follow up Relevant pre-clinical studies Biocompatibility testing (biological and clinical equivalence) Bench testing (technical and clinical equivalence) Electrical safety Software verification and validation Data retrieved from literature Summary and appraisal of clinical data Analysis of the clinical data Requirement on safety Requirement on acceptable benefit/risk profile Requirement on performance Requirement on the acceptability of undesired side effects • Clinical evaluation report conclusion • Date of next clinical evaluation • Qualification of the responsible Evaluator • Dates and signatures • References

Simple easy to use templates and guides can be downloaded from https:// scientistssanctuary.com/.

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Appendix 1: Template for an Essential Requirements (ERs) Checklist (Under MDD) No.

Essential Requirements (ERs)

1.

A or N/A

Relevant Standards

Evidence Showing Compliance

Comment

General Requirements: – The devices must be designed and manufactured in such a way that, when used under the conditions and for the purposes intended, they will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their intended use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety. This shall include: • reducing as far as possible, the risk of use error due to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety); and • consideration of the technical knowledge, experience, education, and training, and where applicable the medical and physical conditions of intended users (design for lay, professional, disabled or other users).

–

–

–

2.

The solutions adopted by the manufacturer for – the design and construction of the devices must conform to safety principles, taking account of the generally acknowledged state of the art. In selecting the most appropriate solutions, the manufacturer must apply the following principles in the following order: • eliminate or reduce risks as far as possible (Inherently safe design and construction). • where appropriate take adequate protection measures including alarms if necessary, in relation to risks that cannot be eliminated. • Inform users of the residual risks due to any shortcomings of the protection methods adopted.

–

–

–

3.

The devices must achieve the performance in- – tended by the manufacturer and be designed, manufactured, and packaged in such a way that they are suitable for one or more of the functions referred to in Article 1(2) (a) as specified by the manufacturer

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–

–

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4.

The characteristics and performances referred – to in Sections 1, 2 and 3 must not be adversely affected to such a degree that the clinical condition and safety of the patients and where applicable, of other persons are compromised during the lifetime of the device as Indicated by the manufacturer, when the device Is subjected to the stresses which can occur during normal conditions of use.

–

–

–

5.

The devices must be designed, manufactured, and packed in such a way that their characteristics and performances during their intended use will not be adversely affected during transport and storage taking account of the instructions and information provided by the manufacturer.

–

–

–

–

6.

Any undesirable side effects must constitute an acceptable risk when weighed against the performances Intended.

–

–

–

–

Demonstration of conformity with the ERs must include a clinical evaluation in accordance with Annex X.

–

–

–

–

7.

Requirements regarding design and construction Chemical, physical, and biological properties

–

–

–

–

7.1

The devices must be designed and manufactured in such a way as to guarantee the characteristics and performances referred to in Section I on the “General requirements.” Particular attention must be paid to: • the choice of materials used, particularly as regards toxicity and where appropriate flammability; • the compatibility between the materials used and biological tissues, cells, and body fluids, taking account of the intended purpose of the device; • where appropriate, the results of biophysical or modeling research whose validity has been demonstrated beforehand.

–

–

–

–

7.2

The devices must be designed, manufactured, – and packed in such a way as to minimize the risk posed by contaminants and residues to the persons involved in the transport, storage, and use of the devices and to the patients, taking account of the intended purpose of the product. Particular attention must be paid to the tissues exposed and the duration and frequency of the exposure.

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–

–

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7.3

The devices must be designed and manufac- – tured in such a way that they can be used safely with materials, substances, and gases with which they enter into contact during normal use or during routine procedures; if the devices are Intended to administer medicinal products they must be designed and manufactured in such a way as to be compatible with the medicinal products concerned according to the provisions and restrictions governing those products and that their performance is maintained in accordance with the Intended use.

–

–

–

7.4

Where a device incorporates, as an integral – part, a substance which, if used separately, may be considered to be a medicinal product as defined in Article 1 of Directive 2001/83/EC and which is liable to act upon the body with action ancillary to that of the device, the quality, safety, and usefulness of the substance must be verified by analogy with the methods specified in Annex I of Directive 2001/83/EC. For the substances referred to in the first paragraph, the NB shall, having verified the usefulness of the substance as part of the medical device and taking account of the intended purpose of the device, seek a scientific opinion from one of the CA designated by the Member States or the European Medicines Agency (EMEA) acting particularly through its committee in accordance with Regulation (EC) No. 726/2004 (*) on the quality and safety of the substance including the clinical benefit/risk profile of the incorporation of the substance into the device. When issuing its opinion, the competent authority or the EMEA shall take into account the manufacturing process and the data related to the usefulness of the incorporation of the substance into the device as determined by the NB.

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–

–

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133

7.4

Where a device incorporates, as an integral – part, a human blood derivative, the NB shall, having verified the usefulness of the substance as part of the medical device and taking into account the purpose of the device, seek a scientific opinion from the EMEA, acting particularly through its committee, on the quality and safety of the substance including the clinical benefit/risk profile of the incorporation of the human blood derivative into the device. When issuing its opinion, the EMEA shall take into account the manufacturing process and the data related to the usefulness of incorporation of the substance into the device as determined by the NB. Where changes are made to an ancillary substance incorporated in a device, in particular related to its manufacturing process, the NB shall be informed of the changes and shall consult the relevant medicines competent authority (i.e., the one involved in the initial consultation), in order to confirm that the quality and safety of the ancillary substance are maintained. The competent authority shall take into account the data related to the usefulness of incorporation of the substances into the device as determined by the NB, in order to ensure that the changes have no negative impact on the established benefit/risk profile of the addition of the substance in the medical devices.

–

–

–

7.4

(*) Regulation (EC) No. 725/2994 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ L 136, 30.4.2004, p. 1). Regulation as last amended by Regulation (EC) No. 1901/2006.

–

–

–

–

7.4

When the relevant medicines competent au- – thority (i.e., the one involved in the initial consultation) has obtained information on the ancillary substance, which could have an impact on the established benefit/risk profile of the addition of the substance in the medical device, it shall provide the NB with advice, whether this information has an impact on the established benefit/risk profile of the addition of the substance in the medical device or not. The NB shall take the updated scientific opinion into account in reconsidering its assessment of the conformity assessment procedure.

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–

–

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7.5

The devices must be designed and manufac- – tured in such a way as to reduce to a minimum the risks posed by substances leaking from the device. Special attention shall be given to substances which are carcinogenic, mutagenic or toxic to reproduction, in accordance with Annex I to Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations, and administrative provisions relating to the classification, packaging, and labeling of dangerous substances. If parts of a device (or a device itself) intended to administer and/or remove medicines, body liquids or other substances to or from the body, or devices intended for transport or storage of such body fluids or substances, contain phthalates which are classified as carcinogenic, mutagenic or toxic to reproduction, of category 1 or 2, in accordance with Annex I of Directive 67/548/EEC, these devices must be labeled on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging as a device containing phthalates. If the intended use of such devices includes treatment of children or treatment of pregnant or nursing women, the manufacturer must provide a specific justification for the use of these substances with regard to compliance with the ERs, in particular of this paragraph, within the technical documentation and within the IFU, information on residual risks for these patient groups and if applicable, 0n appropriate precautionary measures. (*) OJ 196, 16.8.1967, p 1. Directive as last amended by Directive 2006/121/EC of the European Parliament and of the Council (OJ) L 396, 30.12.2006, p. 850

–

–

–

7.6

The devices must be designed and manufac- – tured in such a way as to reduce as much as possible, risks posed by the unintentional ingress of substances into the device taking into account the device and the nature of the environment in which it Is intended to be used.

–

–

–

8.

Infection and microbial contamination

–

–

–

–

8.1

The devices and their manufacturing processes – must be designed in such a way as to eliminate or reduce as far as is possible the risk of infection to the patient, user, and third parties. The design must allow easy handling and where necessary, minimize contamination of the device by the patient or vice versa during use.

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–

–

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135

8.2

Tissues of animal origin must originate from – animals that have been subjected to veterinary controls and surveillance adapted to the intended use of the tissues. Notified Bodies shall retain information on the geographical origin of the animals. Processing, preservation, testing, and handling of tissues, cells, and substances of animal origin must be carried out so as to provide optimal security. In particular safety with regard to viruses and other transmissible agents must be addressed by implementation of validated methods of elimination or viral inactivation in the course of the manufacturing process.

–

–

–

8.3

Devices delivered in a sterile state must be designed, manufactured, and packed in a nonreusable pack and/or according to appropriate procedures to ensure they are sterile when placed on the market and remain sterile, under the storage and transport conditions laid down, until the protective packaging is damaged or opened.

–

–

–

–

8.4

Devices delivered in a sterile state must have been manufactured and sterilized by an appropriate, validated method.

–

–

–

–

8.5

Devices intended to be sterilized must be manufactured in appropriately controlled (e.g., environmental) conditions.

N/A

–

–

–

8.6

Packaging systems for non-sterile devices must keep the product without deterioration in the level of cleanliness stipulated and if the devices are to be sterilized prior to use, minimize the risk of microbial contamination. The packaging system must be suitable taking account of the method of sterilization indicated by the manufacturer.

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–

–

–

8.7

The packaging and/or label of the device must distinguish between identical or similar products sold in both sterile and non-sterile condition.

–

–

–

–

9.

Construction and environmental Properties

–

–

–

–

9.1

If the device is intended for use in combination – with other devices or equipment, the ‘whole combination, including the connection system must be safe and must not impair the specified performance of the devices. Any restrictions on use must be indicated on the label or in the Instruction for Use.

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–

–

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9.2

Devices must be designed and manufactured in – such a way as to remove or minimize as far as possible: the risk of injury in connection with their physical features [1] including the volume pressure ratio, dimensional, and ‘where appropriate the ergonomic features, risks connected with reasonably foreseeable environmental conditions, such as magnetic fields external electrical influences, electrostatic discharge, pressure, temperature or variations in pressure and acceleration, the risks of reciprocal interference with other devices normally used in the investigations or for the treatment given, risks arising where maintenance or calibration are not possible (as with implants) from aging of the materials used or loss of accuracy of any measuring or control mechanism.

–

–

–

9.3

Devices must be designed and manufactured in – such a way as to minimize the risks of fire or explosion during normal use and in single fault condition. Particular attention must be paid to devices ‘whose intended use includes exposure to flammable substance ‘which could cause combustion.

–

–

–

10.

Devices with a measuring function

–

–

–

–

10.1

Devices with a measuring function must be de- – signed and manufactured in such a way as to provide sufficient accuracy and stability ‘within appropriate limits of accuracy and taking account of the Intended purpose of the device. The limits of accuracy must be indicated by the manufacturer.

–

–

–

10.2

The measurement, monitoring, and display – scale must be designed In line ‘with ergonomic principles, taking account of the intended purpose of the device.

–

–

–

10.3

The measurements made by devices ‘with a measuring function must be expressed in legal units conforming to the provisions of Council Directive 8OII8IIEEC, as last amended by Directive 89/17/EC.

–

–

–

–

11.

Protection against radiation

–

–

–

–

11.1

General Devices shall be designed and manufacturer such that exposure of patients, users, and other persons to radiation shall be reduced as far as possible compatible ‘with the intended purpose, whilst not restricting the application of appropriate specified levels for therapeutic and diagnostic purposes.

–

–

–

–

11.2

Intended radiation

–

–

–

–

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137

11.2.1

Where devices are designed to emit hazardous – levels of radiation necessary for a specific medical purpose the benefit of ‘which Is considered to outweigh the risks inherent in the emission, it must be possible for the user to control the emissions. Such devices shall be designed and manufactured to ensure reproducibility and tolerance of relevant variable parameters.

–

–

–

11.2.2

Where devices are intended to emit potentially – hazardous, visible, and/or invisible radiation, they must be fitted, ‘where practicable, ‘with visual displays and/or audible warnings of such emissions.

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–

–

11.3

Unintended Radiation – Devices shall be designed and manufactured in such a way that exposure of patients, users, and other persons to the emission of unintended, stray or scattered radiation must be reduced as far as possible.

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–

–

11.4

Instructions – The operating instructions for devices emitting radiation must give detailed information as to the nature of the emitted radiation, means of protecting the patient and the user and on ways of avoiding misuse and of eliminating the risks inherent in installation.

–

–

–

11.5

Ionizing radiation

–

–

–

–

11.5.1

Devices Intended to emit ionizing radiation – must be designed and manufactured in such a way as to ensure that, ‘where practicable, the quantity, geometry, and quality of radiation emitted can be varied and controlled taking account of the Intended uses.

–

–

–

11.5.2

Devices emitting ionizing radiation intended – for diagnostic radiology shall be designed and manufactured in such a way, as to achieve appropriate Image and/or output quality for the intended medical purpose whilst minimizing radiation exposure of the patient and user.

–

–

–

11.5.3

Devices emitting ionizing radiation, intended – for therapeutic radiology shall be designed and manufactured in such a way as to enable reliable monitoring and control of the delivered dose, the beam type and energy and ‘where appropriate the quality of the radiation.

–

–

–

12.

Requirements for medical devices connected to – or equipped with an energy source.

–

–

–

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Clinical Evaluations for Medical Devices

12.1

Devices incorporating electronic programmable systems must be designed to ensure the repeatability. Reliability and performance of these systems according to their intended use. In the event of a single fault condition (in the system) appropriate means should be adopted to eliminate or reduce as far as possible consequent risks.

–

–

–

–

a. For devices which incorporate software or which are medical software in themselves, the software must be validated according to the state of the art taking into account the principles of development lifecycle, risk management, validation, and verification. 12.2

Devices ‘where the safety of the patients depends on an internal power supply must be equipped ‘with a means of determining the state of the power supply.

–

–

–

–

12.3

Devices where the safety of the patient depends – on an external power supply must Include an alarm system to signal any power failure.

–

–

–

12.4

Devices Intended to monitor one or more clini- – cal parameters of a patient must be equipped ‘with appropriate alarm systems to alert the user of situations ‘which could lead to death or severe deterioration of the patient’s state of health.

–

–

–

12.5

Devices must be designed and manufactured in such a way as to minimize the risks of creating electromagnetic fields ‘which could impair the operation of other devices or equipment in the usual environment

–

–

–

–

12.6

Protection Against Electrical Risks – Devices must be designed and manufactured in such a way as to avoid, as far as possible, the risk of accidental electric shocks during normal use and in single fault condition, provided that the devices are Installed correctly.

–

–

–

12.7

Protection against mechanical and thermal risk

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–

–

–

12.7.1

The devices must be designed and manufac- – tured in such a way as to protect the patient and user against mechanical risks connected ‘with, for example, resistance, stability, and moving parts.

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–

–

12.7.2

The devices must be designed and manufac- – tured in such a way as to reduce to the lowest possible level the risks arising from vibration generation by the devices, taking account of technical progress and of the means available for limiting vibrations, particularly at source, unless the vibrations are part of the specified performance.

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–

–

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12.7.3

The devices must be designed and manufac- – tured in such a way as to reduce to the lowest possible level the risks arising from the noise emitted [1] taking account of technical progress end of the means available to reduce noise [1] particularly at source [9] unless the noise emitted Is part of the specified performance.

–

–

–

12.7.4

The terminals and connections to the electricity – gas or hydraulic and pneumatic energy supplies which the user has to handle must be designed and constructed in such a way as to minimize all possible risks.

–

–

–

12.7.5

Accessible parts of devices (excluding any parts or areas intended to supply heat or reach given temperatures) and their surroundings must not attain potentially dangerous temperatures under normal use.

–

–

–

–

12.8

Protection against the risks posed to the patient – by energy supplies or substances

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–

–

12.8.1

Devices for supplying the patient with energy – or substances must be designed and constructed in such a way that the flow rate can be set and maintained accurately enough to guarantee the safety of the patient and the user.

–

–

–

12.8.2

Devices must be fitted with the means of pre- – venting and/or indicating any inadequacies in the flow-rate, which could pose a danger. Devices must incorporate suitable means to prevent, as far as possible, the accidental release of dangerous levels of energy from an energy and/or substance source

–

–

–

12.9

The function of the controls and indicators must be clearly specified on the devices. Where a device beans instructions required for its operation or indicates operating or adjustment parameters by means of a visual system, such information must be understandable to the user and as appropriate, the patient

–

–

–

–

13.

Information supplied by the manufacturer

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–

–

–

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Clinical Evaluations for Medical Devices

13.1

Each device must be accompanied by the in- – formation needed to use it safely and properly, taking account of the training and knowledge of the potential user, and to identify the manufacturer. This information comprises the details on the label and the data in the IFU. As far as practicable and appropriate, the information needed to use the device safely must be set out on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging. If individual packaging of each unit is not practicable, the information must be set out in the leaflet supplied with one or more devices. IFU must be included in the packaging for every device. By way of exception, no such instruction leaflet is needed for devices in Class I or Class IIa if they can be used completely safely without any such instructions.

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–

–

13.2

Where appropriate this information should – take the form of symbols. Any symbol or identification color used must conform to the harmonized standards. In areas for which no standards exist, the symbols and colors must be described in the documentation supplied with the device.

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–

–

13.3

The label must bear the following particulars:

–

–

–

–

a.

The name or trade name and address of – the manufacturer. For devices imported into the Community, in view of their distribution in the Community, the label, or the outer packaging, or the IFU, shall contain in addition the name and address of the authorized representative where the manufacturer does not have a registered place of business in the Community;

–

–

–

b.

The details strictly necessary to identify – the device and the contents of the packaging especially for the users;

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–

–

c.

where appropriate the word “STERILE”

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–

–

–

d.

where appropriate, the batch code preceded by the word “LOT” or the serial number.

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–

–

–

e.

where appropriate an indication of the – date by which the device should be used, in safety, expressed as the year and month.

–

–

–

f.

where appropriate, an indication that the device is for single use. A manufacturer’s indication of single use must be consistent across the community.

–

–

–

–

g.

if the device is custom-made, the words “custom made device.”

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–

–

–

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141

h. if the device is intended for clinical investigations, the words “exclusively for clinical investigations.”

–

–

–

–

i. any special storage and/or handling conditions.

–

–

–

–

j. any special operating instructions.

–

–

–

–

k. any warnings and/or precautions to take.

–

–

–

–

l. year of manufacture of active devices other than those covered by (e). This indication may be included in the batch or serial number.

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–

–

–

m. where applicable, method of sterilization.

–

–

–

–

n. in the case of a device within the meaning of – Article 1(4a), an indication that the device contains a human blood derivative.

–

–

–

13.4

If the Intended purpose of the device is not obvious to the user, the manufacturer must clearly state it on the label and in the instruction leaflet.

–

–

–

–

13.5

Wherever reasonable and practicable, the devices and detachable components must be identified, where appropriate in terms of batches, to allow all appropriate action to detect any potential risk posed by the devices and detachable components.

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–

–

–

13.6

Where appropriate, the IFU must contain the following particulars:

–

–

–

–

a. the details referred to in 13.3 with the exception of (d) and (e)

–

–

–

–

b. the performances referred to in Section 3 and any undesirable side effects

–

–

–

–

c. If the device must be installed with or con- – nected to other medical devices or equipment in order to operate as required for its intended purpose, sufficient details of its characteristics to identify the correct devices or equipment to use in order to obtain a safe combination.

–

–

–

d. all the information needed to verify whether – the device is properly installed and can operate correctly and safely, plus details of the nature and frequency of the maintenance and calibration needed to ensure that the devices operate properly and safely at all times.

–

–

–

e. where appropriate, information to avoid certain risks in connection with implantation of the device.

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–

–

–

142

Clinical Evaluations for Medical Devices f. information regarding the risks of reciprocal interference posed by the presence of the device during specific investigations or treatment.

–

–

–

–

g. the necessary instructions in the event of damage to the sterile packaging and where appropriate, details of appropriate methods of re-sterilization.

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–

–

–

h. if the device is reusable, information on the – appropriate processes to allow reuse, including cleaning, disinfection, packaging, and where appropriate, the method of sterilization of the device to be re-sterilized, and any restriction on the number of reuses. Where devices are supplied with the intention that they be sterilized before use, the instructions for cleaning and sterilization must be such that, if correctly followed, the device will still comply with the requirements in Section 1.

–

–

–

i. details of any further treatment or handling – needed before the device can be used (for example, sterilization, final assembly, etc.).

–

–

–

j. in the case of devices emitting radiation for medical purposes, details of the nature, type, intensity, and distribution of this radiation.

–

–

–

–

k. The instruction for use must also include – details allowing the medical staff to brief the patient on any contra-indications and any precautions to be taken. These details should cover in particular: • precautions to be taken in the event of changes in the performance of the device.

–

–

–

l. The instruction for use must also include – details allowing the medical staff to brief the patient on any contra-indications and any precautions to be taken. These details should cover in particular: • precautions to be taken as regards exposure, in reasonably foreseeable environmental conditions, to magnetic fields, external electrical influences, electrostatic discharge, pressure or variations in pressure, acceleration, thermal ignition sources, etc.

–

–

–

If the device bears an indication that the device is for single use, information on known characteristics and technical factors known to the manufacturer that could pose a risk if the device were to be re-used. If in accordance with Section 13.1 no IFU are needed, the information must be made available to the user upon request.

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143

m. The instruction for use must also include – details allowing the medical staff to brief the patient on any contra-indications and any precautions to be taken. These details should cover in particular: • adequate information regarding the medicinal products which the device in question is designed to administer, including any limitations in the choice of substances to be delivered.

–

*

–

n. The instruction for use must also include – details allowing the medical staff to brief the patient on any contra-indications and any precautions to be taken. These details should cover in particular: • precautions to be taken against any special unusual risks related to the disposal of the device.

–

–

–

o. The instruction for use must also include – details allowing the medical staff to brief the patient on any contra-indications and any precautions to be taken. These details should cover in particular: • medicinal substances incorporated into the device as an integral part in accordance with Section 7.4.

–

–

–

p. The instruction for use must also include – details allowing the medical staff to brief the patient on any contra-indications and any precautions to be taken. These details should cover in particular: • degree of accuracy claimed for devices with a measuring function.

–

–

–

q. Date of issue or the latest revision of the IFU.

–

–

–

–

Simple easy to use templates and guides to completing an Essential Requirements checklist can be downloaded from https://scientistssanctuary. com/.

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Clinical Evaluations for Medical Devices

Appendix 2: Template for a General Safety and Performance Requirements (GSPRs) checklist (under MDR) No.

Essential Requirements (ERs)

A or N/A

1.

General Requirements – Devices shall achieve the performance intended by their manufacturer and shall be designed and manufactured in such a way that, during normal conditions of use, they are suitable for their intended purpose. They shall be safe and effective and shall not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art.

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2.

The requirement in this Annex to reduce risks as far as possible means the reduction of risks as far as possible without adversely affecting the benefit-risk ratio.

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Relevant Evidence Comment Standards Showing Compliance

Appendices 3.

Manufacturers shall establish, imple- – ment, document, and maintain a risk management system. Risk management shall be understood as a continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating. In carrying out risk management manufacturers shall: a. establishes and document a risk management plan for each device; b. identifies and analyze the known and foreseeable hazards associated with each device; c. estimates and evaluate the risks associated with, and occurring during, the intended use and during reasonably foreseeable misuse; d. eliminates or control the risks referred to in point (c) in accordance with the requirements of Section 4; e. evaluates the impact of information from the production phase and in particular, from the post-market surveillance system, on hazards and the frequency of occurrence thereof, on estimates of their associated risks, as well as on the overall risk, benefit-risk ratio and risk acceptability; and f. based on the evaluation of the impact of the information referred to in point (e), if necessary, amend control measures in line with the requirements of Section 4.

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4.

– Risk control measures adopted by manufacturers for the design and manufacture of the devices shall conform to safety principles, taking account of the generally acknowledged state of the art. To reduce risks, Manufacturers shall manage risks so that the residual risk associated with each hazard as well as the overall residual risk is judged acceptable. In selecting the most appropriate solutions, manufacturers shall, in the following order of priority: a. eliminates or reduce risks as far as possible through safe design and manufacture; b. where appropriate, take adequate protection measures, including alarms if necessary, in relation to risks that cannot be eliminated; and c. provides information for safety (warnings/precautions/contra-indications) and where appropriate, training to users. Manufacturers shall inform users of any residual risks.

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5.

In eliminating or reducing risks – related to use error, the manufacturer shall: a. reduces as far as possible the risks related to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety); and b. give consideration to the technical knowledge, experience, education, training, and use environment, where applicable, and the medical and physical conditions of intended users (design for lay, professional, disabled or other users)

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Appendices 6.

The characteristics and performance – of a device shall not be adversely affected to such a degree that the health or safety of the patient or the user and where applicable, of other persons are compromised during the lifetime of the device, as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use and has been properly maintained in accordance with the manufacturer’s instructions.

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7.

Devices shall be designed, manu– factured, and packaged in such a way that their characteristics and performance during their intended use are not adversely affected during transport and storage, for example, through fluctuations of temperature and humidity, taking account of the instructions and information provided by the manufacturer.

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8.

All known and foreseeable risks, and any undesirable side-effects, shall be minimized and be acceptable when weighed against the evaluated benefits to the patient and/or user arising from the achieved performance of the device during normal conditions of use.

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9.

For the devices referred to in Annex – XVI, the general safety requirements set out in Sections 1 and 8 shall be understood to mean that the device, when used under the conditions and for the purposes intended, does not present a risk at all or presents a risk that is no more than the maximum acceptable risk related to the product’s use which is consistent with a high level of protection for the safety and health of persons.

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10.

Chemical, physical, and biological properties

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10.1

Devices shall be designed and manufactured in such a way as to ensure that the characteristics and performance requirements referred to in Chapter I are fulfilled. Particular attention shall be paid to:

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a.

the choice of materials and substances used, particularly as regards toxicity and where relevant, flammability;

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b.

the compatibility between the materials and substances used and biological tissues, cells, and body fluids, taking account of the intended purpose of the device and where relevant, absorption, distribution, metabolism, and excretion;

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c.

the compatibility between the different parts of a device which consists of more than one implantable part;

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d.

the impact of processes on material properties;

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e.

where appropriate, the results of biophysical or modeling research the validity of which has been demonstrated beforehand;

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f.

the mechanical properties of the materials used, reflecting, where appropriate, matters such as strength, ductility, fracture resistance, wear resistance and fatigue resistance;

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g.

surface properties; and

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h.

the confirmation that the device meets any defined chemical and/ or physical specifications.

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Appendices 10.2

Devices shall be designed, manufac– tured, and packaged in such a way as to minimize the risk posed by contaminants and residues to patients, taking account of the intended purpose of the device, and to the persons involved in the transport, storage, and use of the devices. Particular attention shall be paid to tissues exposed to those contaminants and residues and to the duration and frequency of exposure.

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10.3

– Devices shall be designed and manufactured in such a way that they can be used safely with the materials and substances, including gases, with which they enter into contact during their intended use; if the devices are intended to administer medicinal products they shall be designed and manufactured in such a way as to be compatible with the medicinal products concerned in accordance with the provisions and restrictions governing those medicinal products and that the performance of both the medicinal products and of the devices is maintained in accordance with their respective indications and intended use.

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10.4

Substances

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10.4.1

Design and manufacture of devices Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues, that may be released from the device.

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Clinical Evaluations for Medical Devices Devices, or those parts thereof or those materials used therein that: • are invasive and come into direct contact with the human body; • (re)administer medicines, body liquids or other substances, including gases, to/from the body; or • transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body, shall only contain the following substances in a concentration that is above 0.1% weight by weight (w/w) where justified pursuant to Section 10.4.2.

10.4.2

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– a. substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), of category 1A or 1B, in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the European Parliament and of the Council (1), or

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b. substances having endocrine-dis- – rupting properties for which there is scientific evidence of probable serious effects to human health and which are identified either in accordance with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council (2) or, once a delegated act has been adopted by the Commission pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 of the European Parliament and the Council (3), in accordance with the criteria that are relevant to human health amongst the criteria established therein.

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Justification regarding the presence of CMR and/or endocrine-disrupting substances

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Appendices

10.4.3

The justification for the presence of such substances shall be based upon: a. an analysis and estimation of potential patient or user exposure to the substance;

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b. an analysis of possible alternative substances, materials or designs, including, where available, information about independent research, peer-reviewed studies, scientific opinions from relevant scientific committees and an analysis of the availability of such alternatives;

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– c. argumentation as to why possible substance and/or material substitutes, if available, or design changes, if feasible, are inappropriate in relation to maintaining the functionality, performance, and the benefit-risk ratios of the product; including taking into account if the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials; and

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d. where applicable and available, the latest relevant scientific committee guidelines in accordance with Sections 10.4.3 and 10.4.4.

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Guidelines on phthalates

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10.4.4

10.4.5

Clinical Evaluations for Medical Devices For the purposes of Section 10.4, the Commission shall, as soon as possible and by 26 May 2018, provide the relevant scientific committee with a mandate to prepare guidelines that shall be ready before 26 May 2020. The mandate for the committee shall encompass at least a benefit-risk assessment of the presence of phthalates which belong to either of the groups of substances referred to in points (a) and (b) of Section 10.4.1. The benefit-risk assessment shall take into account the intended purpose and context of the use of the device, as well as any available alternative substances and alternative materials, designs or medical treatments. When deemed appropriate on the basis of the latest scientific evidence, but at least every five years, the guidelines shall be updated.

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Guidelines on other CMR and endocrine-disrupting substances

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Subsequently, the Commission – shall mandate the relevant scientific committee to prepare guidelines as referred to in Section 10.4.3. Also, for other substances referred to in points (a) and (b) of Section 10.4.1, where appropriate.

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Labeling

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Appendices Where devices, parts thereof or materials used therein as referred to in Section 10.4.1 contain substances referred to in points (a) or (b) of Section 10.4.1. In a concentration above 0.1% weight by weight (w/w), the presence of those substances shall be labeled on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging, with the list of such substances. If the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials, information on residual risks for those patient groups and if applicable, on appropriate precautionary measures shall be given in the IFU.

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10.5

Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by the unintentional ingress of substances into the device taking into account the device and the nature of the environment in which it is intended to be used.

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10.6

Devices shall be designed and manu- – factured in such a way as to reduce as far as possible the risks linked to the size and the properties of particles which are or can be released into the patient’s or user’s body, unless they come into contact with intact skin only. Special attention shall be given to nanomaterials.

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11.

Infection and microbial contamination

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11.1

– Devices and their manufacturing processes shall be designed in such a way as to eliminate or to reduce as far as possible the risk of infection to patients, users, and where applicable, other persons. The design shall: a. reduces as far as possible and appropriate the risks from unintended cuts and pricks, such as needle stick injuries; b. allows easy and safe handling; c. reduces as far as possible any microbial leakage from the device and/or microbial exposure during use; and d. prevents microbial contamination of the device or its content such as specimens or fluids.

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11.2

Where necessary devices shall be de- – signed to facilitate their safe cleaning, disinfection, and/or re-sterilization.

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11.3

Devices labeled as having a specific microbial state shall be designed, manufactured, and packaged to ensure that they remain in that state when placed on the market and remain so under the transport and storage conditions specified by the manufacturer.

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11.4

Devices delivered in a sterile state – shall be designed, manufactured, and packaged in accordance with appropriate procedures, to ensure that they are sterile when placed on the market and that, unless the packaging which is intended to maintain their sterile condition is damaged, they remain sterile, under the transport and storage conditions specified by the manufacturer, until that packaging is opened at the point of use. It shall be ensured that the integrity of that packaging is clearly evident to the final user.

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Appendices 11.5

Devices labeled as sterile shall be processed, manufactured, packaged, and sterilized by means of appropriate, validated methods.

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11.6

Devices intended to be sterilized shall – be manufactured and packaged in appropriate and controlled conditions and facilities.

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11.7

Packaging systems for non-sterile devices shall maintain the integrity and cleanliness of the product and where the devices are to be sterilized prior to use, minimize the risk of microbial contamination; the packaging system shall be suitable taking account of the method of sterilization indicated by the manufacturer.

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11.8

The labeling of the device shall distinguish between identical or similar devices placed on the market in both a sterile and a non-sterile condition additional to the symbol used to indicate that devices are sterile.

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12

Devices incorporating a substance considered to be a medicinal product and devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body.

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12.1

In the case of devices referred to in – the first subparagraph of Article 1(8), the quality, safety, and usefulness of the substance which, if used separately, would be considered to be a medicinal product within the meaning of point (2) of Article 1 of Directive 2001/83/EC, shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC, as required by the applicable conformity assessment procedure under this Regulation.

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12.2

Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed in the human body shall comply, where applicable and in a manner limited to the aspects not covered by this Regulation, with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions, as required by the applicable conformity assessment procedure under this Regulation.

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13

Devices incorporating materials of biological origin

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13.1

For devices manufactured utilizing derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable covered by this Regulation in accordance with point (g) of Article 1(6), the following shall apply: a. donation, procurement, and testing of the tissues and cells shall be done in accordance with Directive 2004/23/ EC; b. processing, preservation, and any other handling of those tissues and cells or their derivatives shall be carried out so as to provide safety for patients, users, and where applicable, other persons. In particular, safety with regard to viruses and other transmissible agents shall be addressed by appropriate methods of sourcing and by implementation of validated methods of elimination or inactivation in the course of the manufacturing process; c. the traceability system for those devices shall be complementary and compatible with the traceability and data protection requirements laid down in Directive 2004/23/EC and in Directive 2002/98/EC.

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Appendices 13.2

For devices manufactured utilizing tissues or cells of animal origin, or their derivatives, which are nonviable or rendered non-viable the following shall apply: a. where feasible taking into account the animal species, tissues, and cells of animal origin, or their derivatives, shall originate from animals that have been subjected to veterinary controls that are adapted to the intended use of the tissues. Information on the geographical origin of the animals shall be retained by manufacturers.

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13.3

For devices manufactured utilizing non-viable biological substances other than those referred to in Sections 13.1 and 13.2, the processing, preservation, testing, and handling of those substances shall be carried out so as to provide safety for patients, users, and where applicable, other persons, including in the waste disposal chain. In particular, safety with regard to viruses and other transmissible agents shall be addressed by appropriate methods of sourcing and by implementation of validated methods of elimination or inactivation in the course of the manufacturing process.

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b. sourcing, processing, pres- – ervation, testing, and handling of tissues, cells, and substances of animal origin, or their derivatives, shall be carried out so as to provide safety for patients, users, and where applicable, other persons. In particular safety with regard to viruses and other transmissible agents shall be addressed by implementation of validated methods of elimination or viral inactivation in the course of the manufacturing process, except when the use of such methods would lead to unacceptable degradation compromising the clinical benefit of the device.

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Clinical Evaluations for Medical Devices c. in the case of devices – manufactured utilizing tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012 the particular requirements laid down in that Regulation shall apply.

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14

Construction of devices and interaction with their environment

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14.1

– If the device is intended for use in combination with other devices or equipment the whole combination, including the connection system shall be safe and shall not impair the specified performance of the devices. Any restrictions on use applying to such combinations shall be indicated on the label and/or in the IFU. Connections which the user has to handle, such as fluid, gas transfer, electrical or mechanical coupling, shall be designed and constructed in such a way as to minimize all possible risks, such as misconnection.

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14.2

Devices shall be designed and manufactured in such a way as to remove or reduce as far as possible: a. the risk of injury, in connection with their physical features, including the volume/pressure ratio, dimensional, and where appropriate ergonomic features.

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b.

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risks connected with reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, temperature, variations in pressure and acceleration or radio signal interferences.

Appendices c. the risks associated with the use of the device when it comes into contact with materials, liquids, and substances, including gases, to which it is exposed during normal conditions of use.

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d. the risks associated with the possible negative interaction between software and the IT environment within which it operates and interacts.

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e. the risks of accidental ingress of substances into the device.

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– g. risks arising where maintenance or calibration are not possible (as with implants), from aging of materials used or loss of accuracy of any measuring or control mechanism.

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14.3

Devices shall be designed and manufactured in such a way as to minimize the risks of fire or explosion during normal use and in single fault condition. Particular attention shall be paid to devices the intended use of which includes exposure to or use in association with flammable or explosive substances or substances which could cause combustion.

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14.4

Devices shall be designed and manufactured in such a way that adjustment, calibration, and maintenance can be done safely and effectively.

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14.5

Devices that are intended to be operated together with other devices or products shall be designed and manufactured in such a way that the interoperability and compatibility are reliable and safe.

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the risks of reciprocal interference with other devices normally used in the investigations or for the treatment given; and

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14.6

Any measurement, monitoring or display scale shall be designed and manufactured in line with ergonomic principles, taking account of the intended purpose, users, and the environmental conditions in which the devices are intended to be used.

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14.7

Devices shall be designed and manufactured in such a way as to facilitate their safe disposal and the safe disposal of related waste substances by the user, patient or other person. To that end, manufacturers shall identify and test procedures and measures as a result of which their devices can be safely disposed after use. Such procedures shall be described in the IFU.

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Devices with a diagnostic or measuring function

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15.1

Diagnostic devices and devices with a – measuring function, shall be designed and manufactured in such a way as to provide sufficient accuracy, precision, and stability for their intended purpose, based on appropriate scientific and technical methods. The limits of accuracy shall be indicated by the manufacturer.

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15.2

The measurements made by devices – with a measuring function shall be expressed in legal units conforming to the provisions of Council Directive 80/181/EEC (1).

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16

Protection against radiation

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16.1.

General – a. Devices shall be designed, manufactured, and packaged in such a way that exposure of patients, users, and other persons to radiation is reduced as far as possible, and in a manner that is compatible with the intended purpose, whilst not restricting the application of appropriate specified levels for therapeutic and diagnostic purposes.

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Appendices b. The operating instructions for – devices emitting hazardous or potentially hazardous radiation shall contain detailed information as to the nature of the emitted radiation, the means of protecting the patient and the user, and on ways of avoiding misuse and of reducing the risks inherent to installation as far as possible and appropriate. Information regarding the acceptance and performance testing, the acceptance criteria, and the maintenance procedure shall also be specified.

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Intended radiation

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a. Where devices are designed to emit hazardous, or potentially hazardous, levels of ionizing and/or non-ionizing radiation necessary for a specific medical purpose the benefit of which is considered to outweigh the risks inherent to the emission, it shall be possible for the user to control the emissions. Such devices shall be designed and manufactured to ensure reproducibility of relevant variable parameters within an acceptable tolerance.

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b. Where devices are intended to emit hazardous, or potentially hazardous, ionizing, and/or nonionizing radiation, they shall be fitted, where possible, with visual displays and/or audible warnings of such emissions.

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16.3

Devices shall be designed and manu- – factured in such a way that exposure of patients, users, and other persons to the emission of unintended, stray or scattered radiation is reduced as far as possible. Where possible and appropriate, methods shall be selected which reduce the exposure to radiation of patients, users, and other persons who may be affected.

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16.4

Ionizing radiation

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Clinical Evaluations for Medical Devices a.

Devices intended to emit ionizing radiation shall be designed and manufactured taking into account the requirements of the Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionizing radiation.

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Devices intended to emit ionizing radiation shall be designed and manufactured in such a way as to ensure that, where possible, taking into account the intended use, the quantity, geometry, and quality of the radiation emitted can be varied and controlled, and if possible, monitored during treatment.

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c.

Devices emitting ionizing radiation intended for diagnostic radiology shall be designed and manufactured in such a way as to achieve an image and/or output quality that are appropriate to the intended medical purpose whilst minimizing radiation exposure of the patient and user.

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d.

Devices that emit ionizing radiation and are intended for therapeutic radiology shall be designed and manufactured in such a way as to enable reliable monitoring and control of the delivered dose, the beam type, energy, and where appropriate, the quality of radiation.

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Electronic programmable systems — devices that incorporate electronic programmable systems and software that are devices in themselves.

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Appendices 17.1

Devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, shall be designed to ensure repeatability, reliability, and performance in line with their intended use. In the event of a single fault condition, appropriate means shall be adopted to eliminate or reduce as far as possible consequent risks or impairment of performance.

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17.2

For devices that incorporate software or for software that are devices in themselves, the software shall be developed and manufactured in accordance with the state of the art taking into account the principles of development life cycle, risk management, including information security, verification, and validation.

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17.3

Software referred to in this section – that is intended to be used in combination with mobile computing platforms shall be designed and manufactured taking into account the specific features of the mobile platform (e.g., size, and contrast ratio of the screen) and the external factors related to their use (varying environment as regards level of light or noise).

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17.4

Manufacturers shall set out minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorized access, necessary to run the software as intended.

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18

Active devices and devices connected – to them.

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18.1.

For non-implantable active devices, in the event of a single fault condition, appropriate means shall be adopted to eliminate or reduce as far as possible consequent risks.

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18.2.

Devices where the safety of the patient depends on an internal power supply shall be equipped with a means of determining the state of the power supply and an appropriate warning or indication for when the capacity of the power supply becomes critical. If necessary, such warning or indication shall be given prior to the power supply becoming critical.

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Devices where the safety of the patient depends on an external power supply shall include an alarm system to signal any power failure.

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18.4.

Devices intended to monitor one or – more clinical parameters of a patient shall be equipped with appropriate alarm systems to alert the user of situations which could lead to death or severe deterioration of the patient’s state of health.

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18.5.

Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks of creating electromagnetic interference which could impair the operation of the device in question or other devices or equipment in the intended environment.

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18.6.

Devices shall be designed and manu- – factured in such a way as to provide a level of intrinsic immunity to electromagnetic interference such that is adequate to enable them to operate as intended.

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18.7.

Devices shall be designed and manufactured in such a way as to avoid, as far as possible, the risk of accidental electric shocks to the patient, user or any other person, both during normal use of the device and in the event of a single fault condition in the device, provided the device is installed and maintained as indicated by the manufacturer.

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Appendices 18.8.

Devices shall be designed and manufactured in such a way as to protect, as far as possible, against unauthorized access that could hamper the device from functioning as intended.

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19

Particular requirements for active implantable devices

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19.1.

Active implantable devices shall be designed and manufactured in such a way as to remove or minimize as far as possible: a. risks connected with the use of energy sources with particular reference, where electricity is used, to insulation, leakage currents and overheating of the devices; b. risks connected with medical treatment, in particular those resulting from the use of defibrillators or high-frequency surgical equipment; and c. risks which may arise where maintenance and calibration are impossible, including: • excessive increase of leakage currents; • aging of the materials used; • excess heat generated by the device; • decreased accuracy of any measuring or control mechanism.

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19.2.

Active implantable devices shall be designed and manufactured in such a way as to ensure • if applicable, the compatibility of the devices with the substances they are intended to administer; and • the reliability of the source of energy.

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19.3.

Active implantable devices and if appropriate, their component parts shall be identifiable to allow any necessary measure to be taken following the discovery of a potential risk in connection with the devices or their component parts.

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19.4.

Active implantable devices shall bear a code by which they and their manufacturer can be unequivocally identified (particularly with regard to the type of device and its year of manufacture); it shall be possible to read this code, if necessary, without the need for a surgical operation.

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20

Protection against mechanical and thermal risks

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Devices shall be designed and manufactured in such a way as to protect patients and users against mechanical risks connected with, for example, resistance to movement, instability, and moving parts.

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20.2.

Devices shall be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from vibration generated by the devices, taking account of technical progress and of the means available for limiting vibrations, particularly at source, unless the vibrations are part of the specified performance.

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20.3.

Devices shall be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from the noise emitted, taking account of technical progress and of the means available to reduce noise, particularly at source, unless the noise emitted is part of the specified performance.

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20.4.

Terminals and connectors to the electricity, gas or hydraulic and pneumatic energy supplies which the user or other person has to handle, shall be designed and constructed in such a way as to minimize all possible risks.

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Appendices 20.5.

Errors likely to be made when fitting – or refitting certain parts which could be a source of risk shall be made impossible by the design and construction of such parts or, failing this, by information given on the parts themselves and/or their housings. The same information shall be given on moving parts and/or their housings where the direction of movement needs to be known in order to avoid a risk.

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20.6.

– Accessible parts of devices (excluding the parts or areas intended to supply heat or reach given temperatures) and their surroundings shall not attain potentially dangerous temperatures under normal conditions of use.

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21.

Protection against the risks posed to the patient or user by devices supplying energy or substances

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21.1

Devices for supplying the patient – with energy or substances shall be designed and constructed in such a way that the amount to be delivered can be set and maintained accurately enough to ensure the safety of the patient and of the user.

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21.2.

Devices shall be fitted with the means – of preventing and/or indicating any inadequacies in the amount of energy delivered or substances delivered which could pose a danger. Devices shall incorporate suitable means to prevent, as far as possible, the accidental release of dangerous levels of energy or substances from an energy and/or substance source.

–

–

–

21.3.

The function of the controls and indicators shall be clearly specified on the devices. Where a device bears instruction required for its operation or indicates operating or adjustment parameters by means of a visual system, such information shall be understandable to the user and as appropriate, the patient.

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–

–

–

167

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Clinical Evaluations for Medical Devices

22.

Protection against the risks posed by medical devices intended by the manufacturer for use by lay persons

–

–

–

–

22.1

Devices for use by lay persons shall – be designed and manufactured in such a way that they perform appropriately for their intended purpose taking into account the skills and the means available to lay persons and the influence resulting from variation that can be reasonably anticipated in the layperson’s technique and environment. The information and instructions provided by the manufacturer shall be easy for the lay person to understand and apply.

–

–

–

22.2.

Devices for use by lay persons shall be designed and manufactured in such a way as to: • ensure that the device can be used safely and accurately by the intended user at all stages of the procedure, if necessary after appropriate training and/or information; • reduce, as far as possible and appropriate, the risk from unintended cuts and pricks such as needle stick injuries; and • reduce as far as possible the risk of error by the intended user in the handling of the device and if applicable, in the interpretation of the results.

–

–

–

–

22.3

Devices for use by lay persons shall, – where appropriate, include a procedure by which the lay person: • can verify that, at the time of use, the device will perform as intended by the manufacturer; and • if applicable, is warned if the device has failed to provide a valid result.

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–

–

Requirements regarding the information supplied with the device

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–

–

–

Label and instructions for use

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–

–

–

23.

Appendices 23.1.

– General requirements regarding the information supplied by the manufacturer. Each device shall be accompanied by the information needed to identify the device and its manufacturer, and by any safety and performance information relevant to the user, or any other person, as appropriate. Such information may appear on the device itself, on the packaging or in the IFU, and shall, if the manufacturer has a website, be made available and kept up to date on the website, taking into account the following: a. The medium, format, content, legibility, and location of the label and IFU shall be appropriate to the particular device, its intended purpose and the technical knowledge, experience, education or training of the intended user(s). In particular, IFU shall be written in terms readily understood by the intended user and where appropriate, supplemented with drawings and diagrams.

–

–

–

b. The information required on the – label shall be provided on the device itself. If this is not practicable or appropriate, some or all of the information may appear on the packaging for each unit, and/or on the packaging of multiple devices.

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–

–

c. Labels shall be provided in a human-readable format and may be supplemented by machinereadable information, such as radio-frequency identification (‘RFID’) or bar codes.

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–

–

–

d. IFU shall be provided together with devices. By way of exception, IFU shall not be required for class I and class IIa devices if such devices can be used safely without any such instructions and unless otherwise provided for elsewhere in this section.

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–

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–

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23.2.

Clinical Evaluations for Medical Devices e.

Where multiple devices are – supplied to a single user and/or location, a single copy of the IFU may be provided if so agreed by the purchaser who in any case may request further copies to be provided free of charge.

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–

–

f.

IFU may be provided to the – user in non-paper format (e.g., electronic) to the extent, and only under the conditions, set out in Regulation (EU) No 207/2012 or in any subsequent implementing rules adopted pursuant to this Regulation.

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–

–

g.

Residual risks which are required – to be communicated to the user and/or other person shall be included as limitations, contraindications, precautions or warnings in the information supplied by the manufacturer.

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–

–

h.

Where appropriate, the informa- – tion supplied by the manufacturer shall take the form of internationally recognized symbols. Any symbol or identification color used shall conform to the harmonized standards or CS. In areas for which no harmonized standards or CS exist, the symbols and colors shall be described in the documentation supplied with the device.

–

–

–

Information on the label shall bear all of the following particulars: a. the name or trade name of the device;

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–

–

–

b.

the details strictly necessary for a user to identify the device, the contents of the packaging and where it is not obvious for the user, the intended purpose of the device;

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–

–

–

c.

the name, registered trade name or registered trade mark of the manufacturer and the address of its registered place of business;

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–

–

–

Appendices d.

if the manufacturer has its – registered place of business outside the Union, the name of the authorized representative and address of the registered place of business of the authorized representative;

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–

–

e.

– where applicable, an indication that the device contains or incorporates: a medicinal substance, including a human blood or plasma derivative; or tissues or cells, or their derivatives, of human origin; or tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012;

–

–

–

f.

where applicable, information labeled in accordance with Section 10.4.5.

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–

–

–

g.

the lot number or the serial number of the device preceded by the words LOT NUMBER or SERIAL NUMBER or an equivalent symbol, as appropriate;

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–

–

–

h.

the UDI carrier referred to in Ar- – ticle 27(4) and Part C of Annex VII;

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–

–

i.

an unambiguous indication of t the time limit for using or implanting the device safely, expressed at least in terms of year and month, where this is relevant;

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–

–

–

–

–

–

–

• • •

j.

where there is no indication of the date until when it may be used safely, the date of manufacture. This date of manufacture may be included as part of the lot number or serial number, provided the date is clearly identifiable;

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Clinical Evaluations for Medical Devices k. an indication of any special storage and/or handling condition that applies;

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–

–

–

l.

–

–

–

–

m. warnings or precautions to be taken that need to be brought to the immediate attention of the user of the device, and to any other person. This information may be kept to a minimum in which case more detailed information shall appear in the IFU, taking into account the intended users;

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–

–

–

n. if the device is intended for single use, an indication of that fact. A manufacturer’s indication of single use shall be consistent across the Union;

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–

–

–

o. if the device is a single-use de– vice that has been reprocessed, an indication of that fact, the number of reprocessing cycles already performed, and any limitation as regards the number of reprocessing cycles;

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–

–

p. if the device is custom-made, the words ‘custom-made device;’

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–

–

–

q. an indication that the device is a – medical device. If the device is intended for clinical investigation only, the words ‘exclusively for clinical investigation;’

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–

–

–

–

–

–

r.

if the device is supplied sterile, an indication of its sterile state and the sterilization method;

in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body, the overall qualitative composition of the device and quantitative information on the main constituent or constituents responsible for achieving the principal intended action;

Appendices

23.3

23.4.

s. for active implantable devices, the serial number, and for other implantable devices, the serial number or the lot number.

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–

–

–

Information on the packaging which maintains the sterile condition of a device (‘sterile packaging’)

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–

–

–

The following particulars shall appear – on the sterile packaging: a. an indication permitting the sterile packaging to be recognized as such; b. a declaration that the device is in a sterile condition; c. the method of sterilization; d. the name and address of the manufacturer; e. a description of the device; f. if the device is intended for clinical investigations, the words ‘exclusively for clinical investigations,’ g. if the device is custom-made, the words ‘custom-made device,’ h. the month and year of manufacture; i. an unambiguous indication of the time limit for using or implanting the device safely expressed at least in terms of year and month; and j. an instruction to check the IFU for what to do if the sterile packaging is damaged or unintentionally opened before use.

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–

Information in the IFU

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–

–

–

The IFU shall contain all of the following particulars: a. the particulars referred to in points (a), (c), (e), (f), (k), (l), (n) and (r) of Section 23.2;

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–

–

b. the device’s intended purpose with – a clear specification of indications, contra-indications, the patient target group or groups, and of the intended users, as appropriate;

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–

173

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Clinical Evaluations for Medical Devices c. where applicable, a specification of the clinical benefits to be expected.

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–

–

–

d. where applicable, links to the – summary of safety and clinical performance referred to in Article 32;

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–

–

e. the performance characteristics of – the device;

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–

f.

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–

–

–

–

–

–

h. specifications the user requires – to use the device appropriately, e.g., if the device has a measuring function, the degree of accuracy claimed for it;

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–

–

i.

details of any preparatory treatment or handling of the device before it is ready for use or during its use, such as sterilization, final assembly, calibration, etc., including the levels of disinfection required to ensure patient safety and all available methods for achieving those levels of disinfection;

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–

–

j.

any requirements for special facilities, or special training, or particular qualifications of the device user and/or other persons;

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–

–

–

where applicable, information allowing the healthcare professional to verify if the device is suitable and select the corresponding software and accessories;

g. any residual risks, contra-indications, and any undesirable sideeffects, including information to be conveyed to the patient in this regard;

Appendices – k. the information needed to verify whether the device is properly installed and is ready to perform safely and as intended by the manufacturer, together with, where relevant: • details of the nature, and frequency, of preventive and regular maintenance, and of any preparatory cleaning or disinfection; • identification of any consumable components and how to replace them; • information on any necessary calibration to ensure that the device operates properly and safely during its intended lifetime; and • methods for eliminating the risks encountered by persons involved in installing, calibrating or servicing devices;

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–

if the device is supplied sterile, instructions in the event of the sterile packaging being damaged or unintentionally opened before use;

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–

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–

m. if the device is supplied nonsterile with the intention that it is sterilized before use, the appropriate instructions for sterilization;

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–

–

–

n. if the device is reusable, information on the appropriate processes for allowing reuse, including cleaning, disinfection, packaging, and where appropriate, the validated method of re-sterilization appropriate to the Member State or Member States in which the device has been placed on the market. Information shall be provided to identify when the device should no longer be reused, e.g., signs of material degradation or the maximum number of allowable reuses;

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–

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l.

175

176

Clinical Evaluations for Medical Devices o. an indication, if appropriate, – that a device can be reused only if it is reconditioned under the responsibility of the manufacturer to comply with the GSPRs;

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–

–

– p. if the device bears an indication that it is for single use, information on known characteristics and technical factors known to the manufacturer that could pose a risk if the device were to be re-used. This information shall be based on a specific section of the manufacturer’s risk management documentation, where such characteristics and technical factors shall be addressed in detail. If in accordance with point (d) of Section 23.1, no IFU are required, this information shall be made available to the user upon request;

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–

–

q. for devices intended for use – together with other devices and/or general-purpose equipment: • information to identify such devices or equipment, in order to obtain a safe combination, and/or • information on any known restrictions to combinations of devices and equipment;

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–

r.

–

–

–

•

•

if the device emits radiation for – medical purposes: detailed information as to the nature, type, and where appropriate, the intensity and distribution of the emitted radiation; the means of protecting the patient, user, or other person from unintended radiation during use of the device;

Appendices s.

•

•

•

•

•

•

information that allows the user – and/or patient to be informed of any warnings, precautions, contraindications, measures to be taken and limitations of use regarding the device. That information shall, where relevant, allow the user to brief the patient about any warnings, precautions, contra-indications, measures to be taken and limitations of use regarding the device. The information shall cover, where appropriate: warnings, precautions, and/or measures to be taken in the event of malfunction of the device or changes in its performance that may affect safety; warnings, precautions, and/or measures to be taken as regards the exposure to reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, or temperature; warnings, precautions, and/or measures to be taken as regards the risks of interference posed by the reasonably foreseeable presence of the device during specific diagnostic investigations, evaluations, or therapeutic treatment or other procedures such as electromagnetic interference emitted by the device affecting other equipment; if the device is intended to administer medicinal products, tissues or cells of human or animal origin, or their derivatives, or biological substances, any limitations or incompatibility in the choice of substances to be delivered; warnings, precautions, and/or limitations related to the medicinal substance or biological material that is incorporated into the device as an integral part of the device; and precautions related to materials incorporated into the device that contain or consist of CMR substances or endocrine-disrupting substances, or that could result in sensitization or an allergic reaction by the patient or user;

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–

177

178

Clinical Evaluations for Medical Devices t. in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body and that are absorbed by or locally dispersed in the human body, warnings, and precautions, where appropriate, related to the general profile of interaction of the device and its products of metabolism with other devices, medicinal products and other substances as well as contra-indications, undesirable side-effects and risks relating to overdose;

–

–

–

–

u. in the case of implantable devices, – the overall qualitative and quantitative information on the materials and substances to which patients can be exposed;

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–

–

v. warnings or precautions to be taken in order to facilitate the safe disposal of the device, its accessories and the consumables used with it, if any. This information shall cover, where appropriate: infection or microbial hazards such as explants, needles or surgical equipment contaminated with potentially infectious substances of human origin, and physical hazards such as from sharps. If in accordance with the point (d) of Section 23.1 no IFU are required, this information shall be made available to the user upon request;

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–

–

–

w. for devices intended for use by lay persons, the circumstances in which the user should consult a healthcare professional;

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–

–

–

x. for the devices covered by this Regulation pursuant to Article 1(2), information regarding the absence of a clinical benefit and the risks related to use of the device;

–

–

–

–

Appendices y. date of issue of the IFU or, if they have been revised, date of issue and identifier of the latest revision of the IFU;

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–

–

–

z. a notice to the user and/or patient that any serious incident that has occurred in relation to the device should be reported to the manufacturer and the competent authority of the Member State in which the user and/or patient is established;

–

–

–

–

aa. information to be supplied to the patient with an implanted device in accordance with Article 18;

–

–

–

–

ab.for devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorized access, necessary to run the software as intended.

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–

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–

179

Simple easy to use templates and guides to completing a General Safety and Performance Requirements checklist can be downloaded from https:// scientistssanctuary.com/.

BIBLIOGRAPHY

1.

2.

3.

4.

5.

Application of Risk Management to Medical Devices, (2007). International Organization for Standardization (ISO 14971:2007 Standard). https://www.iso.org/obp/ui/#iso:std:iso:14971:ed-2:v2:en (accessed on 23 August 2022). Clinical investigations, (2010). Global Harmonization Task Force (GHTF/SG5/ N3:2010). http://www.imdrf.org/docs/ghtf/final/sg5/ technical-docs/ghtf-sg5-n3-clinical-investigations-100212.pdf (accessed on 17 March 2020). EU Council Directive 93/42/EEC, (1993). Concerning Medical Devices. http://www.imdrf.org/docs/ghtf/archived/sg4/technical-docs/ghtfsg4-guidelinesauditing-qms-part-1-general-requirements-080827.pdf (accessed on 23 August 2022). Issakov, A., (1994). Service and maintenance in developing countries. In: Van, G. C. W. D., (ed.), Medical Devices: International Perspectives on Health and Safety (pp. 21–28). Elsevier, Amsterdam. Loh & Boumans, (2018). Understanding Europe’s New Medical Devices Regulation (MDR 2017/745): New Requirements, Key Changes and Transition Strategies for Device Companies. Emergo White Paper.

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6. 7. 8. 9.

10.

11.

12.

13.

14.

15.

16.

Clinical Evaluations for Medical Devices

MDCG 2020-1 Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software. MDCG 2020-13 Clinical Evaluation Assessment Report Template. MDCG 2020-5 Clinical Evaluation – Equivalence: A Guide for Manufacturers and Notified Bodies. MDCG 2020-6 Regulation (EU) 2017/745: Clinical evidence needed for medical devices previously CE marked under Directives 93/42/ EEC or 90/385/EEC. A Guide for Manufacturers and Notified Bodies. MEDDEV 2.7/1 (Rev 04) - Clinical Evaluation: A Guide for Manufacturers and Notified Bodies Under Directives 93/42/EEC and 90/385/EEC. Medical Device Regulations: Global Overview and Guiding Principles, (2003). Geneva: World Health Organization. http://www.who.int/ medical_devices/publications/en/MD_Regulations.pdf (accessed on 23 August 2022). MHRA (Medicines and Healthcare products Regulatory Agency) Medical Device Alert: DePuy ASR acetabular cups used in hip resurfacing arthroplasty and total hip replacement. MDA/2010/044. 25 May 2010. 2010a. Official Journal of the European Union: Commission Communication in the Framework of the Implementation of the Council Directive 93/ 42/ EEC Concerning Medical Devices (Publication of titles and references of harmonised standards under Union harmonisation legislation). Text with EEA relevance: (2017/C 389/03). Official Journal of the European Union: Commission Implementing Decision (EU) 2020/437 of 24 March 2020 on the Harmonised Standards for Medical Devices Drafted in Support of Council Directive 93/42/EEC. Principles of conformity assessment for medical devices (2012). Global Harmonization Task Force, (GHTF/SG1/N78:2012). http:// www.imdrf.org/docs/ghtf/final/sg1/technical-docs/ghtf-sg1-n78-2012conformity-assessment-medicaldevices-121102.pdf (accessed on 23 August 2022). Principles of medical devices classification, (2012). Global Harmonization Task Force; (GHTF/SG1/N77:2012). http://www. imdrf.org/docs/ghtf/final/sg1/technicaldocs/ghtf-sg1-n77-2012-

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principles-medical-devices-classification-121102.pdf (accessed on 23 August 2022). 17. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/ EEC. 18. WHO Good Regulatory Practices: Guidelines for National Regulatory Authorities for Medical Products. Geneva: World Health Organization (Under development, 2017).

INDEX

A Absorption 96 active implantable medical device directive 83 analogous device 102 analogous medical device 102, 103 authorized representative (AR) 79 B biological tissues 73 biostatistics 16 body fluids 73, 75, 95, 97 C claiming equivalence 89, 90 Clinical evaluation 1 Clinical Evaluation Report (CER) 1 clinical investigation 1, 91 clinical performance 89 common specifications (CS) 101 Competent Authorities (CA) 4 D device packaging 85 Device performance 85

Devices emitting ionizing radiation 77 Direct data 107 distribution 96 E education 72 Electrical hazards 45 electricity 78 electronic programmable systems 86 Equivalence 89, 90 equivalent device 89, 90 essential requirements (ERs) 1 European Medicines Agency (EMA) 64 excretion 96 F Food

and Drug Administration (FDA) 39 G

gap analysis 100 general safety and performance requirements (GSPRs) 1 good clinical practice (GCP) 5

186

Clinical Evaluations for Medical Devices

O

graphical user interface 95 H health technology assessment (HTA) 40 I indirect clinical data 107 indirect data 107 Information security 86 interaction 96 International Clinical Trials Registry Platform (ICTRP) 40 in vitro diagnostic (IVD) devices 4 J justification 99, 101, 102 L literature review 107, 108 Literature searching 19, 20 M marketed device 102 medical device 1, 2 Medical Device Coordination Group (MDCG) 116 medical device directives (MDD) 3 medical device software 94 medical software 78 metabolism 96 microbial contamination 85 N nanotechnology 34 nitrocarburizing 34 notified bodies operations group (NBOG) 33 notified body (NB) 2

oxidability 34 oxidative stress 96 P Packaging systems 76 performance 84, 85 Pivotal data 26 post-market surveillance (PMS) 1 pre-market investigation 115 Q quality management system (QMS) 13 R radiation 86 raw materials 95 risk-based approach 101 risk management 1, 107 S search protocol 108 software algorithms 93, 94 software code 94 surface texture 34 T tensile strength 34 toxicity 96 toxicological risk assessment 96 transportation 85 V verification testing 1 viscosity 34 W wavelength 34