Clinical Evaluation and Investigation of Medical Devices under the new EU-Regulation E-Book

Wolfgang Ecker

• Herausgeber: Books on Demand
• Kategorie: Fachliteratur
• Sprache: Englisch

Veröffentlichungsjahr: 2020

Beschreibung

"The concept of clinical evaluation and the framework for clinical investigations have been significantly enforced within the new EU-Medical Device Regulation (MDR). This book provides in-depth and practice-oriented guidance on the systematic identification and generation of clinical data through clinical investigations and other relevant sources. It addresses the needs of all stakeholders, be it manufacturers, notified bodies or competent authorities, when they have to plan, perform or assess clinical evaluations and investigations for medical devices on the way to conformity assessment and CE marking. It is a valuable tool of qualification for clinicians and related experts when preparing for a role of a clinical evaluator in the field, either when serving any of the stakeholders or when trying to make their own involvement stand out in start-ups, spin-offs or other development projects or in counselling services." Dr. Tom Melvin, Co-Chair, Clinical Investigation and Evaluation Working Group

Leseprobe

Acknowledgements

We want to thank Cornelia Hoflehner for her continuous support on this project, for her outstanding engagement and for her great patience during the creation of this book.

Wolfgang Ecker

Thanks his former national, EU/EEA and GHTF colleagues for interesting discussions and especially his wife Sigrid for continuous support.

Gerold Labek

Many thanks to Wolfgang Ecker and numerous colleagues from regulatory bodies in Europe and IMDRF for their critical review on concepts and ideas to realize new requirements in real world processes. I also would like to thank colleagues from more than 40 universities and research centers in Europe, Ankara and Jerusalem for their support in projects to study limitations in the value of clinical data and procedures to assure safety and performance of medical devices for patients.

Tarquin Mittermayr

Many thanks to the ‘Film Team’ Sandra Meinschad and Michael Ring for adding audiovisual sparkle to my chapter through their professional conversion of text passages and graphics into comprehensible words and appealing images. Additionally, I would like to thank everyone who provided me with encouragement, food and patience during the writing process.

Brigitte Raffeiner

My first thanks go to Mag. Andreas Raffeiner GmbH who made it possible for me to dedicate parts of my working time and my knowledge to this book. Furthermore, I would like to thank my family and friends, who have been very patient with me while writing the text passages of this book.

Michael Ring

I want to thank Sandra E. Mae for her awesome work regarding the creation, voice-over and cutting of the tutorial videos.

Bernhard Schwartz

I want to thank Michael Ring and the other authors for giving me the opportunity to provide a brief insight into biostatics and statistical planning of clinical trials.

Hon (FH) Prof. Dr. Wolfgang Ecker MD, graduated at the Medical Faculty of the University of Vienna, has accomplished his medical training as GP in various Viennese hospitals. He has served the Austrian Health Ministry and the EU Medical Device Sector for 30 years. He has been member of various expert groups at EU level, i.a. as Chair of the EU Working Group on Clinical Investigation and Evaluation (CIE) and as an EU representative in GHTF Study Group 5 on Clinical Evidence. As a member of the EU Council Working Group on Medical Devices, he has helped shaping the new EU Regulations on Medical Devices and IVDs. He is giving lectures and training seminars on these new Regulations at various Universities of Applied Sciences in Austria and at Health Technology Clusters.

Ass. Prof. Dr Gerold Labek MD, graduated at the medical faculty of Vienna University. He has accomplished training for General Practitioner and senior consultant for orthopedic surgery at AKH Linz (now Kepler University Clinic Linz). He conducted research focused on the topics of registries/real world evidence and quality of published research for almost 20 years and received habilitation at Innsbruck Medical University on research methodology.

He was been working for the Notified Body TÜV SÜD as Director for Clinical Market Surveillance and is active now as clinical expert for several Notified Bodies.

Tarquin Mittermayr BA(Hons) MA, is an Information Specialist at the Austrian Institute for Health Technology Assessment (AIHTA), where he is responsible for the institute’s information management including the systematic searching for scientific literature. He studied History, Archive and Museum Studies as well as German, European Studies and Bookbinding. He worked as an assistant librarian at the monastery of St. Florian, as an Information Assistant at Roehampton University and St. George’s Hospital Medical School (University of London), and more recently as an archivist at the Konrad Lorenz Institute for Evolution & Cognition Research.

Brigitte Raffeiner PMSc, is CEO of the Competence Center for Medical Devices GmbH (CCMD). Her personal focal points in the company are corporate management, project management, monitoring and data management. She can look back on many years of experience in the handling of clinical studies. Together with her partners, she supports companies in successfully bringing their products to market.

DI (FH) Dr. Michael Ring, is co-founder and one of the managing directors of R'n'B Consulting GmbH and co-founder and consultant at the Competence Center for Medical Devices GmbH (CCMD). Together with his business partners and cooperation partners, he supports companies in the medical technology industry in the compliant implementation of the process of the clinical evaluation, including the conduct of clinical investigations and systematic literature searches.

In addition, Michael worked from 2014 to 2019 as a study coordinator at the newly established Kepler University Hospital in Linz. His responsibilities included the coordination of sponsored studies and academic research.

Dr. Bernhard Schwartz BSc MSc, is a researcher at the University of Vienna and at the University for Applied Sciences for Health Professions Upper Austria as well as a co-founder of Competence Center for Medical Devices GmbH (CCMD). As scientific member and biometrician at an institutional ethics board and laureate of an Austrian State Price for science (Award of Excellence), he - in partnership with the other CCMD members – supports customers in the pharmacological and medical technology industry in planning, execution and statistical analysis of clinical trials. In addition, Bernhard regularly conducts systematic reviews, clinical evaluations and mini health technology assessments (mini HTAs). Based on his former experience in the field of toxicology (Seibersdorf Laboratories) and medical devices (University for Applied Sciences Upper Austria), he has a perfect background for solving clinical and technical problems.

Foreword

‘I first met Wolfgang in 2015, having moved from working as a busy junior doctor in an Irish hospital to working as a medical officer for medical devices for my national Authority.

In my second week on the job, I was asked to attend a meeting in Brussels to discuss what became Annex VII of the Medical Device Regulation. I still remember being introduced to Wolfgang and I was immediately struck by his kind and enthusiastic manner. Wolfgang was a key figure in representing the importance of clinical evidence as part of the European Council Working Party negotiations for the Medical Device Regulation. At the Clinical Investigation and Evaluation Working Group, Wolfgang also worked very hard to ensure progress the last revision of the guidance for clinical evaluation (MEDDEV 2.7/1 revision 4), in addition to a range of other technical achievements.

In Europe, you learn very quickly that achieving progress requires teamwork, consultation and effective communication. This textbook represents a thorough and detailed guidance, with many practical and useful elements to help medical device developers to meet the requirements of the new Regulation.

When I speak about medical device regulations, I often find myself explaining the differences between medical devices and medicinal products, in terms of the numbers of products, the decision makers for market access, the legal standard for clinical evidence, but also the differences of profiles of drug and device developers. Medical devices are often developed in smaller institutions, whether ‘spin-out’ companies or small and medium sized enterprises. As such, a thorough and practical textbook explaining the requirements and providing practical solutions is an important addition to the available knowledge and I congratulate Wolfgang and the fellow authors for their achievement.’

Dr. Tom Melvin

Co-Chair, Clinical Investigation and Evaluation Working Group

Table of Contents

CLINICAL EVALUATION

1.1. Introduction

1.2. Clinical Evaluation - Definitions

1.3. History of Clinical Evaluation within the EU Regulatory System for Medical Devices

1.4. The Legal Basis for Clinical Evaluation within the MDR

1.4.1 Compliance with the General Safety and Performance Requirements

1.4.2. The Core Legal Elements for Clinical Evaluation

1.4.2.1. Summary of Tasks for the Clinical Evaluation out of the Core Legal Requirements

1.4.3. Other Legal Requirements for Clinical Evaluation within the MDR

1.4.3.1. Clinical Evaluation as a Manufacturer’s Obligation under the QMS (Art. 10)

1.4.3.2. Technical Documentation (Annexes II and III)

1.4.3.3. Conformity Assessment

1.4.3.4. Requirements for NBs

1.4.3.5. Market Surveillance

1.4.3.6. Post-Market Surveillance (PMS)

1.4.3.7. Exemptions to the Need of Clinical Data

1.4.3.8. Use of Clinical Data of an Equivalent Medical Device

1.4.3.9. Scientific Advice, according to MDR

1.4.3.10. Summary of Safety and Clinical Performance (SSCP)

1.4.3.11. Clinical Evaluation of Annex XVI Products

1.4.3.12. Qualifications and Selection of Clinical Evaluators

1.5. Clinical Benefit/Risk Determination and the Clinical Evaluation Process - Overview

1.5.1. Clinical Benefit/Risk Determination

1.5.2. Clinical Evaluation Process – Short Survey on Steps

1.6. Steps of the Clinical Evaluation Process

1.6.1. Stage 0: Scoping and Clinical Evaluation Plan

1.6.1.1. Essential Elements of Clinical Evaluation Planning

1.6.1.1.1. Parts of the Clinical Evaluation Plan

1.6.1.1.2. A Clear Description of the MD

1.6.1.1.3. General Safety and Performance Requirements (GSPR) to be Demonstrated by Clinical Evaluation

1.6.1.1.4. The Clearly Specified Intended Purpose

1.6.1.1.5. Determining the Specific Need for Clinical Data

1.6.1.1.6. Intended Target Groups, Indications, Contraindications

1.6.1.1.7. Intended Clinical Benefits

1.6.1.1.8. Aspects of Clinical Safety

1.6.1.1.9. Parameters to Address Acceptability of B/R-R Against the State of the Art

1.6.1.1.10. Device Specific Guidances, Common Specifications

1.6.1.1.11. Clinical Aspects of Specific Components

1.6.1.1.12. Clinical Development Plan

1.6.1.2. Specific Aspects of Clinical Evaluation Planning

1.6.1.2.1. Demonstration of Equivalence

1.6.1.2.2. Well Established Technologies

1.6.1.2.3. Unmet Clinical Needs

1.6.1.2.4. Breakthrough Devices

1.6.1.3 Diagnostic Algorithms Implemented in Software; Clinical Evaluation of SaMD and MDSW

1.6.2. Stage 1: Identification and Generation of Pertinent Data

1.6.2.1 Introduction

1.6.3. Stage 2: Appraisal of Pertinent Data

1.6.3.1 Tasks of Appraisal

1.6.4 Stage 3: Analysis of the Clinical Data

1.6.4.1 The Main Tasks and Conclusions to be Achieved by the Analysis Step 3

1.6.4.2 Four Methodological Topics of Analysis

1.6.4.3. Analysis of Benefit-Risk Determination of the MD/Equivalent MD and of the State of the Art in the Medical Field Concerned

1.6.4.4 Definitions to be Recalled here for Analysis

1.6.4.5. Evaluation of the Description of the Intended Purpose of the Device

1.6.4.6. Evaluation and Quantification of the Device`s Benefit to the Patient

1.6.4.7. Evaluation of the Clinical Risks of Devices

1.6.4.8. Evaluation of Acceptability of the Benefit/Risk Profile

1.6.5 Stage 4: The Clinical Evaluation Report (CER)

1.6.5.1 Some Practically Important Topics

1.6.5.2 Structure of the Clinical Evaluation Report

1.6.5.3. Proposal for Possible Structure and Content of a CER

1.6.6 Stage 5: Post Market Clinical Follow Up (PMCF)

1.6.6.1. Scope and Role of PMCF in MDR

1.6.6.2. Main Sources for PMCF in MDR

1.6.6.2.1. PMCF as seen under the Clinical Evaluation Process

1.6.6.2.2 PMCF as seen in Relation to the Post Market Surveillance System (PMS)

1.6.6.3. The PMCF Plan

1.6.6.4. PMCF Evaluation Reports (MDR: Annex XIV.B.7 and 8)

1.6.6.5. Main Documents PMCF-Information has to be included in addition to the CER are

1.6.6.5.1. Periodic Safety Update Report (PSUR) for Risk Class and III Devices.

1.6.6.5.2. Summary of Safety and Clinical Performance (SSCP)

1.6.6.5.3. Post Market Surveillance Report (PMS Report) for Risk Class I Devices

1.6.6.5.4. PMS Plan

1.6.6.5.5. The Clinical Evaluation Plan and its Updates

1.6.6.5.6. IFU, Promotional Material and other Relevant Statements and Claims of the Manufacturer

SYSTEMATIC SEARCHING FOR LITERATURE ON CLINICAL (STATE OF THE ART) EVIDENCE OF MEDICAL DEVICES

2.1. Checklist to Support Efficient Information Retrieval on Medical Devices Evidence

2.2.1. Description and Technical Characteristics of the Technology

2.1.1.1. Characteristics of the Technology

2.1.1.2. Regulatory status of the technology

2.1.1.3. Health Problem and Current Clinical Practice

2.1.1.3.1. Summary of Issues Relating to the Health Problem and Current Clinical Practice

2.1.1.3.2. Overview of the Disease or Health Condition

2.1.1.3.3. Target Population

2.1.1.3.4. Clinical Management of the Disease or Health Condition

2.1.1.3.5. Comparators in the Assessment

2.1.1.4. Current Use of the Technology

2.1.1.4.1. Summary of Issues Relating to Current Use of the Technology

2.1.1.4.2. Current Use of the Technology (experience and scale)

2.1.1.4.3. Reimbursement and Assessment Status of the Technology (if known)

2.1.1.5. Investments and Tools Required

2.1.1.5.1. Requirements to Use the Technology

2.1.1.5.2. Procedures Required to Use the Technology

2.1.1.5.3. Investments, Disinvestments and Changes in Service Organisation

2.1.1.6. Clinical Effectiveness and Safety

2.2. Planning a Search Using the PICO framework

2.3. Developing a Literature Search Protocol (according to MEDDEV 2.7/1 rev 4, A5.3.)

2.4. Scientific (medical) Databases for Retrieving Clinical Evidence: An Overview

2.4.1. Introduction to Medline and PubMed

2.4.1.1. Medline

2.4.1.2. PubMed

2.4.1.2.1. How to Access PubMed

2.4.1.3. Planning a Search in PubMed

2.4.1.3.1. Consider the Topic and Appropriate Search Terms (according to PICO)

2.4.1.3.2. Write a Search Plan

2.4.1.4. Additional Features

2.4.1.4.1. Automatic Mapping and the MeSH Database

2.4.1.5. The MeSH Database

2.4.1.6 Clinical Queries

2.4.2. Introduction to Embase (via Elsevier)

2.4.2.1. Using the Dedicated Embase Medical Devices Search Form

2.4.2.2. Planning a Search Using the PICO Framework

2.4.2.3. Browsing Emtree

2.4.2.4. Using the Dedicated Embase PICO Search Form to Retrieve Clinical Device Evidence

2.4.2.5. Results Management (Emailing and Exporting References)

2.4.3. Searching the Cochrane Library

2.4.3.1. What is the Cochrane Library?

2.4.3.2. The Databases

2.4.3.3. When to Use the Cochrane Library

2.4.3.4. Accessing the Cochrane Library

2.5. Efficient Search Strategies for Identifying Clinical Trials on Medical Devices

2.5.1. Trial databases

2.5.1.1. ClinicalTrials.gov

2.5.1.2. WHO ICTRP (International Clinical Trials Registry Platform)

2.5.1.3. EU Clinical Trials Register

2.5.2. Searching Clinical Trials Databases

2.6. The Literature Search Report

2.6.1. A Possible Format for the Literature Search Report

CLINICAL INVESTIGATIONS WITHIN THE CONTEXT OF THE MDR

3.1. Sources

3.2. Definitions

3.3. OVERALL ASPECTS OF CLINICAL INVESTIGATIONS UNDER THE MDR

3.4. Clinical Development Stage

3.4.1. Pre-Market Clinical Investigations

3.4.2. Confirmatory/Pivotal Clinical Investigations,

3.4.3. Post-Market Clinical Investigations

3.4.4. Clinical Development Strategy

3.5 Clinical Investigation Plan (CIP)

3.5.1. Formal Aspects of the Clinical Investigation Plan (CIP)

3.5.2. Objective(s) of Clinical Investigation

3.5.3. Endpoint(s) of Clinical Investigations

3.6 Statistical Considerations

3.6.1. RANDOMISATION

3.6.2. S

TATISTICAL

M

ETHODS

3.6.3. M

ULTIPLE

T

ESTING

3.6.4. S

AMPLE

S

IZE

C

ALCULATION

3.7. Investigators’ Brochure (IB)

3.8. Clinical Investigation Report (CIR) and its Summary Report

3.9. Informed Consent and Special Protection of Vulnerable Subjects/ Populations

3.9.1. General considerations on Basic Ethical Principles

3.9.2. Informed Consent

3.9.2.1. The Legal Basis for Informed Consent

3.9.2.1.1 Definition

3.9.2.1.2. The General Requirement to Obtain Informed Consent

3.9.2.1.3. Specific Conditions for Informed Consent for Clinical Investigations on Minors

3.9.2.2. Process of Obtaining Informed Consent

3.9.2.3. Special Circumstances for Informed Consent

3.9.2.4. Information to be Provided to the Subject

3.9.2.5. Informed Consent Signature Form

3.9.3. Clinical investigations in Specific Vulnerable Subjects/Populations and Situations

3.9.3.1. Clinical investigations on incapacitated subjects

3.9.3.2. Clinical Investigations on Minors

3.9.3.3. Clinical investigations Involving Pregnant and Breast-Feeding Women

3.9.3.4. Additional Vulnerable Groups in Clinical Investigations Considered by National Measures

3.9.3.5 Clinical investigations in Emergency Situations

3.9.3.6 Damage Compensation

MONITORING OF CLINICAL INVESTIGATIONS OF MEDICAL DEVICES FOR HUMAN SUBJECTS

4.1. Sources

4.2. General Requirements for Monitoring

4.3. The Monitor

4.4. Assessment of the Investigation Site

4.5. Initiation of the Investigation Site

4.6. Routine Monitoring Visits

4.7. Close-Out Visits

4.8. Monitoring Reports

4.9. Supporting Documents

4.9.1. Monitoring Plan

4.9.2. Documents Related to Informed Consent (see chapter 3.9.2)

4.9.3. Site Evaluation Visit Report

4.9.4. Site Initiation Visit Report

4.9.5. Monitoring Visit Report

4.9.6. Site Closure Report

4.9.7. Document for Centre Release

4.9.8. Site Level: Medical Device Accountability Log

4.9.9. Subject Level: Medical Device Accountability Log

4.9.10. Temperature Log

4.9.11. Storage Temperature Excursion Form

4.9.12. Site Training Documentation Form

4.9.13. Site Visit Log

4.9.14. Delegation of Investigation Site Team Responsibility Log

4.9.15. Biological Sample Log

LIST OF FIGURES

LIST OF TABLES

LIST OF BOXES

LIST OF FORMS

INDEX

List of Abbreviations

Abbreviation

Definition, Explanation, Remarks

acc.

According to

AIMDD

Active Implantable Medical Device Directive 90/385/EEC

App.

Appendix (used in MEDDEV 2.7.1. rev. 4)

Art.

Article (of MDR)

Basic UDI DI

Basic UDI Device Identifier

B/R

Benefit/Risk

B/R-R

Benefit/Risk-Ratio

CA

Competend Authority

CDRH

Center for Devices and Radiological Health (of FDA)

CEAR

Clinical Evaluation Assessment Report

CEN

Comitee Europeene de Normalisation (European Standardisation Committee)

CENELEC

European Committee for Electrotechnical Standardization

CER

Clinical Evaluation Report

CIE

Working Group for Clinical Investigation and Evaluation of the EU MDEG

CIP

Clinical Investigation Plan

COM

Commission of the European Community

COMET

Core Outcome Measures in Effectiveness Trials (

comet-initiative.org

)

CRA

Clinical Research Associate / Monitor

CRF

Case Report Form

CRO

Clinical Research Organisation

CS

Common Specification (Art. 9 of MDR)

CV

Curriculum Vitae

DD

Device Deficiency

DoI

Declaration of Interest

DSG

Device Specific Guidance

EbM

Evidence based Medicine

EC

Ethics Committee

eCRF

Electronic Case Report Form

EMA

European Medicines Agency

EUDAMED

European Database for Medical Devices

EudraCT

European Union Drug Regulating Authorities Clinical Trials

EUnetHTA

European network for health technology assessment

FDA

Food and Drug Administration (US)

GCP

Good Clinical Practice

GHTF

Global Harmonisation Task Force, now superseded by IMDRF

GMDN

Global Medical Device Nomenclatura

GSPR

General Safety and Performance Requirements, see Annex I of MDR

HN

Harmonised Norm – EU Harmonised Standard with presumptions of conformity in their Annexes Z for specific Directives/Regulations of EU

HTA

Health Technology Assessment

IB

Investigators Brochure

ICH

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

IEC

International Electrotechnical Commission

IMDRF

International Medical Device Regulatory Forum, Successor of GHTF

IP

Investigational Product

IQWiG

Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen

ISF

Investigator Site File

ISO

International Standardization Organization

IVD

In Vitro Diagnostic (Medical Device)

IVDR

IVD Regulation (EU) 2017/746

MDCG

Medical Device Coordination Committee

MDEG

Medical Device Expert Group of EU, now superseded by MDCG

MEDDEV

Medical Device Guideline of the EU COM, now superseded by MDCG-Guidance

MD

Medical Device

MDD

Medical Device Directive 93/42/EEC

MDR

Medical Device Regulation (EU) 2017/745

NB

Notified Body

NCBI

National Center for Biotechnology Information

PI

Principal Investigator

PICO

HTA structured search strategy with Population; Intervention; Control/Comparator; Outcome(s)

PLEG

Post Launch Evidence Generation; Concept in HTA for post market evidence generation

PMCF

Post-Market Clinical Follow-Up

PMS

Post Market Surveillance, see Chapter VII.1 and Annex III of MDR

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta Analyses

PSUR

Periodic Safety Update Report, see Art. 86 of MDR

rev.

Revision (MEDDEV 2.7.1. rev. 4)

RMS

Risk Management System

RWD

Real World Data – Concept of IMDRF for post market evidence generation

RWE

Real World Evidence

SAE

Serious Adverse Event

SaMD

Software as a Medical Device (IMDRF concept)

SMF

Study Master File

SOP

Standard Operation Procedures

SRN

Single Registration Number (of manufacturer, authorized representative or importer) in EUDAMED

SSCP

Summary of Safety and Clinical Performance, see Art. 32 of MDR

TD

Technical Documentation

TPLC

Total Product Life Cycle – Concept of IDEAL D Initiative

UDI

Unique Device Identifier

WHO

World Health Organization

WHO ICTRP

World Health Organization International Clinical Trials Registry Platform

Symbol meanings

Symbol for relevant hints:

Hint

Symbol for MDR citation:

Citation

Symbol for Guidance (MEDDEV, MDCG, GHTF/IMDRF etc) citation:

Citation

The QR Codes shown in this book can be captured by a QR Code Scanner, which allows a forwarding to the website where the videos and supporting documents are provided.

Further reference material and updates (e.g. references to new MDCG Guidelines ...) can be found under the following link:

https://www.rnb-consulting.at/doku/doku.php/en/referenzen/start

1. Clinical Evaluation

1.1. Introduction

Both in the old and new EU regulatory system for medical devices (MD), the manufacturer has to demonstrate safety and performance of MDs not only by technical and preclinical evaluation but also by clinical evaluation on the basis of sufficient and relevant clinical data.

One of the main challenges for clinical evaluators is to adequately reflect the complex character of the clinical evaluation, ranging from regulatory, organizational, technological to clinical aspects. Subsequently, the expectations on the documentation of the clinical evaluation are manifold and in large parts related to the perspective of evaluators serving manufacturers or third parties (National Competent Authorities, Notified Bodies, Public…). This complexity is additionally increased since MDR is explicitly placing clinical evaluation as an active systematic life cycle process under the manufacturer's mandatory QMS.

From a regulatory perspective: In order to assure that the expectations, claims and requirements concerning clinical safety and effectiveness are fulfilled in the intended target population(s) and indications, the manufacturer must generate, identify, appraise, analyse, evaluate, document and update sufficient and methodologically valid clinical data over the life-cycle of the MD (including PMCF1) and demonstrate this as the clinical evidence in conjunction with the clinical evaluation report (CER), following a proper process of clinical evaluation.

From an organizational perspective: The improvement of the clinical evaluation (CEV) of MDs has been one of the main target areas of the new medical device regulation (MDR). MDR is explicitly placing clinical evaluation as an active systematic life cycle process under the manufacturer's mandatory QMS. Clinical evaluation is now more closely integrated into the systemic context of the new regulation, especially with regard to its connections to QMS, PMS, risk management, manufacturer’s obligations (Art. 10), demonstration of conformity with the general requirements for safety and performance (Annex I), technical documentation (Annexes II and III), tasks and competencies of notified bodies (Annex VII) and to conformity assessment (Annexes IX-XI2).

This also implies that the interconnections to other processes have to be established and be continuously evaluated. This integration into the quality management system requires that the responsible persons involved are adequately qualified3 - a respective rationale also needs to be provided if (parts of) the process is outsourced. These aspects can be seen as the organizational framework for the activities related to the clinical evaluation.

From a technological perspective it is expected that the device description within the clinical evaluation report 4 correctly identifies the current configuration of the medical device, including (but not limited to) the name, model, sizes, variants, components of the device (including software, accessories or intended product combinations). Clinical evaluators have to critically rely on previous technical and preclinical evaluation, based on concise physical, chemical, technical specifications and mechanical and functional characteristics and a clear understanding of the mode of action. Further on, the technological and biological differences between predecessor devices and potential equivalent devices must be precisely described and further discussed from a clinical perspective.

From this clinical perspective it is additionally expected that the clinical data supports the initial and continuous evaluation of the acceptability of the clinical benefit-risk ratio with respect to the current state of the art in medicine, including applicable clinical standards and guidance documents, scientific information regarding the medical condition managed, its natural course and the medical alternatives to the target population 5. This requires – relating to the device, its technology and its clinical application - deep, usually scientifically based knowledge and critical expertise.

It cannot be emphasized enough, that – due to the necessity of different perspectives - the clinical evaluation process typically cannot be conducted by one single person and in isolation from other processes. An effective implementation of the clinical evaluation requires deep and fundamental changes within the organizational structure of medical device manufacturers and a close interaction with the life-cycle processes of the device.

For clinicians and related scientists, the new EU medical device system offers excellent opportunities, based on their professional know-how and on their knowledge of regulatory, normative and scientific principles and processes. This applies both if you want to cooperate with the stakeholders (above all manufacturers, notified bodies or competent authorities) and even more if you want to make your own involvement stand out in start-ups, spin-offs or other development projects or in counselling services.

The increased emphasis on clinical aspects in the MDR is also reflected in the creation of an improved clinical infrastructure of the EU regulatory system with (clinical) expert panels6 and the provisions for product group-specific clinical guidelines as ‘Device Specific Guidance’ (DSG7) or in the form of implementing acts of the COM as Common Specifications (CS8) for clinical investigations and/or clinical evaluation and/or PMCF of certain types or groups of (usually high-risk) MDs. The clinical aspects are now more clearly highlighted in the terminology (Art.2 of MDR).

Clinical Evaluation and its assessment are now clearly at the centre of the manufacturer’s and notified bodies obligations; Clinical Evaluation and its assessment has to be properly set up, documented and updated. Its results will be more transparent to the public9.

The new EU medical device regulatory system now needs significantly more competence for Clinical Evaluation and its assessment!

1.2. Clinical Evaluation - Definitions

The following terms play an important role in clinical evaluation in the MDR10. More definitions and detailed explanations will be provided at respective chapters within this document.

‘clinical evaluation’ means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer;

‘clinical data’ means information concerning safety or performance that is generated from the use of a device and is sourced from the following:

clinical investigation(s) of the device concerned,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,clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up;

‘clinical evidence’ means clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer;

‘clinical performance’ means the ability of a device, resulting from any direct or indirect medical ef-fects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer;

‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) re-lated to diagnosis, or a positive impact on patient management or public health;

‘benefit-risk determination’ means the analysis of all assessments of benefit and risk of possible rel-evance for the use of the device for the intended purpose, when used in accordance with the in-tended purpose given by the manufacturer;

‘intended purpose’ means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation;

Medical Device Registry: ‘an organized system that uses observational study methods to collect uniform data (clinical or other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and that serves a predetermined scientific, clinical, or policy purpose(s)’11

1.3. History of Clinical Evaluation within the EU Regulatory System for Medical Devices

The initial EU Directives 93/42/EEC on medical devices (MDD) and 90/385/EEC on active implantable medical devices (AIMDD) had been rather general and unsophisticated on clinical evaluation. Clinical evaluation as a more sophisticated, defined process within the EU regulatory system for MD has first been inspired primarily by GHTF12 Study Group 5: Clinical Safety/Performance (initially SG 5: Clinical Evidence) and its Guidance SG5-N2R8:2007 on ‘Clinical Evaluation’. This Guidance had been rapidly ‘transposed’ by EU Working Group CIE13 into earlier versions of the European MEDDEV Guideline 2.7.1. on Clinical Evaluation.

Amendment Directive 2007/47/EC has brought a first major ‘clinical turn’ of EU Directives 93/42/EEC (MDD) and 90/385/EEC (AIMDD). The EU MDEG Working Group on Clinical Investigation and Evaluation (CIE), composed of all major stakeholders, transposed the changes by Directive 2007/47/EC on the ‘clinicals’ into a new and very mature interpretative document as MEDDEV 2.7.1. rev. 4 to assist stakeholders in proper compliance with the amended Directives.

Major achievements of rev. 4 of the MEDDEV have been:

Clear definitions of the steps of the clinical evaluation process over the life-cycle,The clinical specification of the clinical benefit/risk determination of MDs,Improved documentation requirements (specifically for the clinical evaluation report, CER)First considerations on Post Market Clinical Follow-up (PMCF);Requirements for clinical evaluators and their Declarations of Interest (DoI) andConsiderations on the role of NBs in their assessment of the clinical evaluation of the manufacturer.

The MDR has strongly built on the partly overlapping development of MEDDEV 2.7.1 rev. 4, has refined parts of it and has significantly beefed-up its role and importance in the EU MD regulatory system:

Clinical evaluation is now:

a major life cycle process based on a plan to be carried out under the manufacturer’s QMS,

an explicit obligation of any manufacturer of MD (see Art. 10 of MDR),

an intrinsic part of the General Safety and Performance Requirements (Annex I),

a major issue of conformity documentation (see e.g. Technical documentation acc. to Annexes II + III),

a major issue of NB competence and procedural principles to assess it (Annex VII),

a major issue of conformity assessment (‘European Premarket Approval’; Annexes IX-XI)

closely connected to other life-cycle processes, like RMS, PMS (specifically PMCF) and

an issue of enhanced transparency to stakeholders and the public

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Considering the heritage from the MEDDEV 2.7.1. rev. 4, two elements of MDR deserve specific attention for clinical evaluation (see details under chapter 1.5.):

specification of the clinical benefit/risk determination(Table 1)

Sequence of working steps of clinical evaluation(Figure 1)

Table 1 Specification of Clinical Benefit/Risk Determination

Figure 1 Sequence of working steps of clinical evaluation

The additional elements of the legal text within MDR for clinical evaluation will have to be integrated and specified again in forthcoming rev. 5 of MEDDEV 2.7.1.

1.4. The Legal Basis for Clinical Evaluation within the MDR

1.4.1. Compliance with the General Safety and Performance Requirements

Clinical Evaluation, including PMCF, is an essential part of the applicable General Safety and Performance Requirements (GSPR)15 of Annex I of MDR (see below), any MD must meet in order to be placed on the market or to be put into service:

‘Article 5: Placing on the market and putting into service

…

2. A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose.

3. Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation in accordance with Article 61. …’

Clinically relevant GSPR are primarily mentioned in Chapter I of Annex I.I.1. and I.I.8 of MDR. The following aspects of Annex I.I. address in particular aspects to be demonstrated by clinical evaluation:

Clinically relevant GSPR in MDR: Annex I.I. these are to be highly specified for the MD and its intended purpose and indications in question!

MDs provide the intended performance and are suitable forachieving the intended purpose;Safety and effectiveness;no compromising of clinical condition, safety and health;positive benefit/risk ratio;compatible with a high degree of health protection and safety;State of the art (in medicine);Acceptability of minimized residual risks and side effects related to achieved clinical performance and clinical benefits of MD;