Module 15 Presentations
Module 15: Clinical Evaluation of Medical Devices Date: 23 rd – 25 th April 2024 Module: 15 of the TOPRA MSc Data Management and Digitalisation in Regulatory Affairs
Module Leader: Adrian Keene
©The Organisation for Professionals in Regulatory Affairs 2023 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.
Module 15: Clinical Evaluation of Medical Devices
Location: Topra Office: 6th Floor, Harbour Exchange, South Quay, London, E14 9GE
& Online
Tuesday 23 rd April – Thursday 25 th April 2024
Module Leader(s) : Adrian Keene
Date: Tuesday 23 rd April 2024
Time
Activity
Speaker
12:55 – 13:00
Introduction
NAMSA Adrian Keene
13:00 - 14:00
Lecture 1: Current status of the EU Medical Device Regulation 2017/745
NAMSA Adrian Keene
Impact overview for Clinical Evaluation
14:00 - 15:00
Lecture 2: The Clinical Evaluation Process – definitions, key elements, and strategies
NAMSA Jane Arnold Round
15:00 – 15:30
Refreshment break
15:30 -16:30
Lecture 2 (cont’d): The Clinical Evaluation Process – definitions, key elements, and strategies
NAMSA Jane Arnold Round
16:30 – 17:00
Wrap up day
Adrian Keene
Module 15: Clinical Evaluation of Medical Devices
Date : Wednesday 24 th April 2024
Time
Activity
Speaker
08:55 - 09:00
Introduction
Adrian Keene
09:00 - 10:00
Lecture 3: The Place of Clinical Evaluation Within Device Live-Cycle and Technical Documentation
NAMSA – Adrian Keene
10:00 - 10:30
Refreshment Break
10:30 - 11:30
Lecture 4: The Notified Body Perspective on Clinical Evaluation – the Notified Body Clinical Evaluation Assessment Report
NAMSA – Rachel Gibbs
Lunch
11:30 - 12:30
Lecture 5: The Summary of Safety and Clinical Performance - how does the SSCP relate to the CER - challenges in drafting the SSCP to meet MDCG requirements
12.30 – 13.30
NAMSA – Rachel Gibbs
13.30 – 14.30
Case Study
NAMSA – Adrian Keene / Jane Arnold Round
14.30 - 15:00
Refreshment Break
15:00 - 16:00
Case Study discussion
NAMSA – Adrian Keene / Jane Arnold Round
Module 15: Clinical Evaluation of Medical Devices
Date: Thursday 25 th April 2024
09:00
Connection
Adrian Keene
09:00-10:00
Lecture 6: The relationship between clinical evaluation and post market surveillance/post market clinical follow-up
NAMSA Paul Risborough
10:00 - 10:30
Refreshment Break
10:30 – 11:30
Lecture 7: The Equivalence Assessment under MDR: When and how can this be leveraged?
NAMSA Paul Risborough
Lunch
11:30 – 12:30
12:30 - 13:30
Lecture 8: Clinical Investigations under MDR:
NAMSA Kiren Ajab
Types of clinical studies
•
ISO14155
• • •
Implication of MDR Clinical strategy notification requirements. The role of the clinical team and regulatory governance
13:30 - 14:30
Case study
NAMSA – Adrian Keene / TBC
14:30 – 15.00
Refreshment Break
15:00 – 15:30
Case Study Discussion
15:30 – 16:30
Lecture 9: Clinical Global Strategy Requirements – Focus on US FDA Specifics
Richard Vincins
16:30 – 17:00
Wrap up
NAMSA Adrian Keene
4/15/2024
Lecture 1: Current status of the EU Medical Device Regulation 2017/745 Impact overview for Clinical Evaluation
Presented by:
Adrian Keene, Associate Vice President, Global Biological Safety and Validation and EMEA Consulting Services
Date:
April 2024
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MDR history – how did we get here?
• 2008 – “recast” of existing AIMD and MDD • Consolidate 5 amending directives
• 2012 – proposals issued
• PIP • Ruptures reported as early as 2006-2007 • AFSSAPS (now ANSM) on site inspection March 2020 • Unapproved implant filler • 2013 – CEO sentenced to 4 years imprisonment • 300,000 women in 65 countries effected • EU Commission Action plan
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MDR history – how did we get here?
• Metal-on-metal hip implants (2012)
• Stemmed MOM hip implants for younger osteoarthritis patients • Larger head (ball) size (≥36 mm) higher failure rate compared to ceramic-on ceramic or metal-on-polyethylene • 35% US hip replacements in 2009 were MOM • Release of cobalt and chromium
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MDR history – how did we get here?
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MDR history – how did we get here?
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MDR history – how did we get here?
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International Consortium of Investigative Journalists Nov 2018
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MDR
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MDD
MDR Overview
MDD
MDR
• 60 Pages (MDD only) • 23 Articles • 12 Annexes • 13 Essential Requirements to be fulfilled D=Directive : Legislation that sets out rules and must be transposed into national law to be effective
• 175 Pages (MDD + AIMD) • 10 Chapters, 123 Articles • 17 Annexes • 23 GSPR to be fulfilled
Medical Device Directive vs. Medical Device Regulation
R=Regulation: Mandatory Jurisdiction that is directly applicable and enforceable in all EU Member States
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MDR Goals
“Regulations pave the way to a more patient-friendly environment, where transparency and patients' information and choice are a priority; where patients can benefit from innovative, highly performing devices and new therapies become possible.”
EU Commission Factsheet April 2017
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Headline Changes MDR/IVDR (EU Commission)
• stricter ex-ante (pre-market) control for high-risk devices • reinforcement of the criteria for designation and processes for oversight of Notified Bodies • inclusion of certain aesthetic devices which present the same characteristics and risk profile as analogous medical devices under the scope of these Regulations • new risk classification system for in vitro diagnostic medical devices in line with international guidance • improved transparency via EUDAMED and UDI • introduction of an “implant card” containing information about implanted medical devices for a patient • reinforcement of the rules on clinical evidence, including an EU-wide coordinated procedure for authorisation of multi-centre clinical investigations • strengthening of post-market surveillance requirements for manufacturers • improved coordination mechanisms between EU countries in the fields of vigilance and market surveillance
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Key MDR and IVDR timelines
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Transitional Timeline
31 December 2027 - Legacy class III and IIb Implantable devices (except WET) must be MDR certified
26 September 2024 - Manufacturer has formal signed agreement with NB
20 March 2023 - Amendment 2023/607 published in OJ
26 May 2024 -MDR compliant QMS - Formal NB application made
26 May 2026 - Class III custom made devices must be MDR certified
31 December 2028 - Legacy class IIb, IIa, Is, Im and Ir must be MDR certified
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MDR Structure
• Recitals – “whereas” statements (101 statements) • set out the reasons for the content of the articles – why this is happening – statement of purpose • Chapters I – X (Articles 1-123) • “enacting terms”, the normative part of the act – what you need to do – enumerate in detail specific legal requirements • Annexes I – XIII • generally contain rules or technical data which, for practical reasons do not appear in the enacting terms (Articles) – how you do it
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Certification process 93/42/EEC
Within scope of 93/42/EEC
Article 1
Classification
Article 9, Annex IX
Conformity assessment route
Article 11
Essential requirements
Article 3, Annex I
Technical documentation
Annex II, III, VII
Conformity assessment process
Annex II-VII
Declaration of conformity
Annex II-VII
CE mark
Annex XII
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Certification process MDR
Within scope of 2017/745
Article 2
Classification
Article 51, Annex VIII
Conformity assessment route
Article 52
General Safety and Performance Requirements
Article 5, Annex I
Technical documentation
Annex II, III
Conformity assessment process
Annex IX, X, XIA, XIB
Declaration of conformity
Article 19, Annex IV
CE mark
Article 20, Annex V
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Regulation Governance
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Medical Device Co-ordination Group (MDCG)
• Responsibilities (Article 105 and 106) • Contribute to assessment of notified bodies and input into other notified body-related activities; • Contribute to assessment of effectiveness of the GSPRs • Contribute to development of CS and other scientific guidance; • Assists CAs in their coordination activities in particular, in the fields of classification and the determination of the regulatory status of devices, clinical investigations, vigilance and market surveillance • Provision of scientific, technical and clinical opinions and advice • Expert panels • Expert laboratories • Advice or guidance on implementation of the MDR, and support harmonised processes in member states.
• https://ec.europa.eu/growth/sectors/medical-devices/guidance_en
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MDCG
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Medical Device Co-ordination Group (MDCG) Guidance
• Borderline and Classification • Class I Devices • Clinical investigation and evaluation • COVID-19 • Custom-Made Devices • EUDAMED • European Medical Device Nomenclature (EMDN) • Implant cards • Importers & Distributors • In Vitro Diagnostic medical devices (IVD) • New technologies • Notified bodies • Standards • Unique Device Identifier (UDI) • Other topics
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MDCG Guidance – Clinical Investigation and Evaluation
Reference
Title
Publication December 2023 March 2024 March 2024 December 2023 May 2023 December 2021 July 2021 May 2021 December 2023
Guidance on demonstration of equivalence for Annex XVI products - A guide for manufacturers and notified bodies Guidance on content of the Clinical Investigation Plan for clinical investigations of medical devices Clinical Investigation Plan Synopsis Template Guidance on exemptions from the requirement to perform clinical investigations pursuant to Article 61(4)-(6) MDR and on sufficient levels of access’ to data needed to justify claims of equivalence Commission Guidance on the content and structure of the summary of the clinical investigation report
MDCG 2023-6
MDCG 2024-3 MDCG 2024-3 Appendix A
MDCG 2023-7
2023/C 163/06
MDCG 2021-28
Substantial modification of clinical investigation under Medical Device Regulation
MDCG 2021-20 MDCG 2021-8
Instructions for generating CIV-ID for MDR Clinical Investigations Clinicalinvestigationapplication/notification documents
MDCG 2021-6 - Rev.1
Regulation (EU) 2017/745 –Questions & Answersregarding clinical investigation
MDCG 2020-13 - Word version MDCG 2020-10/1 Rev.1MDCG 2020-10/2 Rev. 1
Clinical evaluation assessment report template
July 2020
October 2022 October 2022
Guidance on safety reporting in clinical investigations Appendix: Clinical investigation summary safety report form
MDCG 2020-8 MDCG 2020-7
Guidance on PMCF evaluation report template
April 2020 April 2020
Guidance on PMCF plan template
Guidance on sufficient clinical evidence for legacy devices Background note on the relationship between MDCG 2020-6 and MEDDEV 2.7/1 rev.4 on clinical evaluation
MDCG 2020-6
April 2020
MDCG 2020-5
Guidance on clinical evaluation – Equivalence
April 2020
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Summary of safety and clinical performance
21 March 2022
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EUDAMED Database
EUDAMED
• IT system for implementation of theMDR and IVDR • 6 modules and a public website:
• Actors registration
December 2020
• UDI/Devices registration
October 2021
• Notified Bodies and Certificates
October 2021
• Clinical Investigations and performance studies
Under development
• Vigilance and post-market surveillance
Under development
• Market Surveillance
Under development
• EUDAMED public
Under development
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Classification
Classification
New Rules • Rule 11 software • Rule 19 nanomaterials
Based on risk and intended purpose
Class III
• Rule 20 administration by Inhalation • Rule 21 absorption/local dispersion • Rule 22 Active closed loop devices Changes • Devices containing active substances (Rule 14) • Up - classifications e.g. meshes, spinal implants, devices in direct contact with the heart
Class IIb
High
Class IIa
Class I
Risk
sterile measuring reusable
Low
Class I
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General Safety and Performance Requirements
GSPRs
Key Changes Multiple new requirements: MDD 13 ERs vs MDR 24 GSPRs
Key New requirements and nuances: • Label and Instructions for use • Devices to be used by laypersons • Electronic programmable systems and software • Devices containing CMRs • Devices absorbed/locally dispersed
More detail required: “justification, validation and verification”
Stronger links to the evidence: • “precise identity”
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Requirements for Lay Persons
Lay Persons
GSPR 22: Protection against the risks posed by medical devices intended by the manufacturer for use by lay persons Design and manufacture must : • Take account of : • skills and means available
Protection against risk
• Variations in the lay person’s technique and environment • Information/instructions easy to understand and apply • Ensure safe use (with training) • Reduce risks of injury (cuts) and risk of user error • Include a procedure to verify the device will perform as intended • Warning if the device fails to provide a valid result
GSPR 23.4 Instructions for use (w) for devices intended for use by lay persons, the circumstances in which the user should consult a healthcare professional
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Claims Article 7
Claims
In the labelling, instructions for use, making available, putting into service and advertising of devices, it shall be prohibited to use text, names, trademarks, pictures and figurative or other signs that may mislead the user or the patient with regard to the device's intended purpose, safety and performance by: (a) ascribing functions and properties to the device which the device does not have; (b) creating a false impression regarding treatment or diagnosis, functions or properties which the device does not have; (c) failing to inform the user or the patient of a likely risk associated with the use of the device in line with its intended purpose; (d) suggesting uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out. Article 2(12) ‘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
Labels IFU Brochures Trademarks Pictures Signs Website Social media CER
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Annex II
Technical Documentation
1. Device Description 2. Labels and IFU 3. Design and manufacturing 4. GSPRs
5. Risk management 6. Verification and Validation
• Preclinical data • Clinical data • Additional information for Specific cases
Annex III
1. PMS Plan 2. PSUR/PMS report
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The PMS Process
PMS
Key MDR requirements:
P ost M arket S urveillance
Requirement for all devices
Active, systematic continuous process
Proportionate and appropriate for the device and risk class
Feedback into multiple processes
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The PMS Process
PMS
Risk management
Updates to:
Benefit risk CEP/CER IFU Labelling SSCP
Central process
Clinical Evaluation
Design
PMS
Technical Documentation PMS Plan
Manufacture
PMCF
Report/PSUR PMCF Plan PMCF Report
CAPA/FSCA
Trend reporting
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MEDDEV 2.7.1 Rev 3 (2009) Rev 4 (2016)
“MEDDEV 2.7.1 rev 4 does not contain new criteria, but represent further explanations of the those introduced by Directive 2007/47/EC. These criteria were already explained in MEDDEV 2.7.1 rev 3 which has been published seven years ago.”
MEDDEV 2.7.1 Rev 3
MEDDEV 2.7.1 Rev 4
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MEDDEV 2.7.1 Rev 4 (2016) MDR
MDCG 2023-6 (Equivalence for Annex XVI products)
MDCG 2020-5 (equivalence) MDCG 2020-6 (legacy devices) MDCG 2020-1 (software) MDCG 2020-13 (CEAR Template)
MEDDEV 2.7.1 Rev 4 MDR (Annex XIV)
MDR (Article 61)
MEDDEV 2.7.1 Rev 4
April 2024
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Clinical Data requirements overview
MDR
Key sections of the MDR for Clinical data: • Chapter I Scope and definitions • Chapter VI
Clinical Evaluation and clinical investigations
• Annex XIV
Clinical Evaluation and PMCF
• Annex XV
Clinical Investigations
Guidance on Clinical Data: • MDCG 2020-1 (Guidance on CER for Medical Device Software) • MDCG 2020-5 (Equivalence) • MDCG 2020-6 (Legacy devices) • MDCG 2020-7 (PMCF template) • MDCG 2020-8 (PMCF report) • MDCG 2020-13 (Clinical Evaluation Assessment Report Template) • MDCG 2023-6 (Equivalence for Annex XVI products) • MDCG 2023-7 (Guidance on exemptions and “sufficient levels of access”)
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The UK
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Brexit and the Introduction of UKCA
UKCA
• The UK left the EU on 31January 2020 • Transition period, during which EU law (MDR/MDD/AIMD or IVDR/IVDD) continued to be recognized in the UK • This transition period ended 31 December 2020 • 1 January 2021: Medical devices and In Vitro Diagnostics (IVDs) subject to UK law • UK Conformity Assessment (UKCA ) mark was introduced • Devices on the UK market became legislated under the Medical Devices Regulations 2002 (SI 2002 No 618, as amended) ( UK MDR 2002) • UK MDR 2002 was based on the text of the EU Directives: • Directive 90/385/EECon active implantable medical devices (EU AIMDD) • Directive 93/42/EECon medical devices (EU MDD) • Directive 98/79/ECon in vitro diagnostic medical devices (EU IVDD)
UK C onformity A ssessed
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Great Britain Route to Market (excludes Northern Ireland)
UKCA • New route to market. Will ultimately replace the CE route • UKCA legislation currently based on UK MD law UKMDR2002 • Under revision to create new UKCA legislation more closely aligned to the EU Medical Device Regulation ((EU) 2017/745 or 746) • Expected July 2025 • [If third party conformity assessment is required, manufacturer applies to UKAB and UKCA Certificate Issued] • Manufacturer draws up DoC and applies UKCA mark to devices • Registers with MHRA • Places device on market
CE • Only valid until 30 June 2028/2030 • EU CE mark recognised during transition • EU legislation Medical Device Regulation (EU) 2017/745 or IVD Regulation (EU) 2017/746 • [If third party conformity assessment is required, manufacturer applies to EU NB and EC Certificate Issue] • Manufacturer draws up DoC and applies CE mark to devices • Registers with MHRA • Places device on market
• Note: MDD/AIMD Legacy devices require CE certificate + valid declaration
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The New UK Regulatory System
UKCA
The UK Responsible Person • Required for manufacturers located outside the UK • Appears on labelling of UKCA marked devices • A manufacturer can only appoint 1 UK Responsible Person • Responsibilities include:
• Registration of devices • Ensure DoC and technical file drawn up • Provide information/device samples to MHRA on request • Cooperate with MHRA on CAPAs • Inform manufacturer about complaints/suspected incidents • terminate the relationship if the manufacturer acts contrary to their obligations
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Lecture 2: Clinical Evaluation
Jane Arnold-Round
The Organisation for Professionals in Regulatory Affairs The Organisation for
Professionals in Regulatory Affairs
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Agenda
Clinical Evaluation Process
• Definitions
• Clinical Evaluation Team • The clinical evaluation Plan • Identify the data • Appraise the data • Generate data • Analysis the data • The Clinical Evaluation Report
• Equivalence
• Clinical Evaluation process
• Clinical Evaluation for high risk devices
• Clinical evaluation without clinical data
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Key Definitions for Clinical Evaluation
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MDR Key Definitions for Clinical Evaluation MDR Article 2 MEDDEV Section 4 MDD Article 1.2 Definition
Intended purpose
(g)
(12) Link to IFU/materials and CER
Clinical evaluation
Annex X
(44) Clinical Benefit, continuous
Clinical investigation
-
(45) similar
Clinical Data
(k)
(48) Includes PMS/PMCF
Clinical Evidence
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(51) Sufficient Quantity and quality
Sufficient Clinical Evidence
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Performance
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(22) New
Clinical Performance
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(52) Leads to clinical benefit
Clinical benefit
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(53) New
Benefit-risk determination
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(24) New
Equivalence
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Annex A1
Annex XIV
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Clinical Evaluation -definitions
MEDDEV 2.7.1 Rev.4
MDR 2017/745
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.
a methodologically sound ongoing procedure to collect, appraise and analyse clinical data pertaining to a medical device and to evaluate whether there is sufficient clinical evidence to confirm compliance with relevant essential requirements for safety and performance when using the device according to the manufacturer’s Instructions for Use.
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Clinical Data - definitions
MDR 2017/745
MDD/ MEDDEV 2.7.1 Rev.4
‘clinical data’ means information concerning safety or performance that is generated from the use of a device and is sourced from the following:
Clinical data: the safety and/or performance information that is generated from the clinical use of a device. Clinical data are sourced from:
- clinical investigation(s) of the device concerned
- 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 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 - 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.
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Article 2 Performance and Clinical Performance
Performance (22) The ability of a device to achieve its intended purpose as stated by the manufacturer Clinical Performance (52) The ability of a device resulting from any direct or indirect medical effects 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
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Article 2 (53) Clinical Benefit
Positive impact of a device on the health of an individual, expressed in terms of ● meaningful, measurable patient-relevant clinical outcome(s) ● including outcome(s) related to diagnosis, or a positive impact on patient management or public health;
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Clinical Performance versus Clinical Benefit
Examples
Clinical Performance
Clinical Benefit
Dressing
Reduction in wound size
Wound healed, pain reduction
Hip implant
Increased Range of Motion
QOL score e.g. Return to work
Stent
Increasein vessel patency
Survival, QOL score
Example
Clinical Performance
Indirect Clinical Benefit*
Enables an implant to achieve its intended purpose
Guidewire
Accurate placement
*MDCG 2020-5
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Equivalence
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Clinical Evaluation – Article 61 (3) A clinical evaluation shall follow a defined and methodologically sound procedure based on the following: (a) a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, where the following conditions are satisfied: — it is demonstrated that the device subject to clinical evaluation for the intended purpose is equivalent to the device to which the data relate, in accordance with Section 3 of Annex XIV, and — the data adequately demonstrate compliance with the relevant general safety and performance requirements; (b) a critical evaluation of the results of all available clinical investigations , taking duly into consideration whether the investigations were performed under Articles 62 to 80, any acts adopted pursuant to Article 81, and Annex XV; and (c) a consideration of currently available alternative treatment options for that purpose, if any.
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Equivalence Section 3 of Annex XIV A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. The following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence:
No clinically significant difference in the safety and clinical performance of the device as a result of any differences sufficient levels of access to the data relating to the equivalent device(s)
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The Clinical Evaluation Process
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Clinical Evaluation In the QMS
Clinical Evaluation is a required element of the quality system Article 10.9 (f): “The quality management system shall address at least the following aspects……. ..clinical evaluation in accordance with Article 61 and Annex XIV, including PMCF”
Clinical evaluation procedure: ● Define responsibilities ● Define the output: CEP, CER
● When to start the process, updates ● Interaction with other processes: risk management, design control, instructions for use, technical file, PMS, PMCF….
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Clinical Evaluation Process – Annex XIV
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Clinical Evaluation Team
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The Clinical Evaluation Team
Who should perform the clinical evaluation? MEDDEV 2.7.1 section 6.4
A suitably qualified individual or team with knowledge of: Research methodology, regulatory requirements, medical writing etc. The device technology: diagnosis and management of the relevant clinical condition (e.g., specialist clinical expert) and Relevant degree and 5 years professional experience, or 10 years professional experience (if degree not needed for task)
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The Clinical Evaluation Team
Who should perform the clinical evaluation? MEDDEV 2.7.1 section 6.4
● Manufacturer defines requirements and justifies choice ● Evaluators’ qualifications and experience documented ● Evaluator declarations of interest (App. A.11) • Relevant financial interests (e.g., employment, shares, study investigator) • Signed and dated by evaluator and manufacturer • Held by the manufacturer
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Clinical Evaluation Plan
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Clinical Evaluation Plan – Annex XIV Part A
Minimum requirements: ● Identification of relevant GSPRs ● Specification of the intended purpose of the device ● Clear specification of intended target groups (indications/contraindications) ● Detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters ● Specification of the methods to be used for examination of qualitative and quantitative aspects of clinical safety with a clear reference to the determination of residual risks and side-effects
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Clinical Evaluation Plan – Annex XIV Part A
Minimum requirements: ● An indicative list and specification of parameters to be used to determine based on the state of the art in medicine, the acceptability of the benefit/risk ratio for the various indications and for the intended purpose or purposes of the device ● An indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non viable animal or human tissues are to be addressed ● A clinical development plan (exploratory to pivotal)
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Clinical Evaluation – Identify the clinical data
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Identify the clinical data
MDR Annex XIV1(b): “identify available clinical data relevant to the device and its intended purpose and any gaps in clinical evidence through a systematic scientific literature review”
MEDDEV 2.7/1 section 8: ● Data generated and held by the manufacturer ● Data from the literature
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Identify the clinical data
Data generated and held by the manufacturer: ● All Pre-market clinical investigations ● All Clinical data from risk management and PMS activities ● Relevant Pre-clinical data Data from the literature Data from literature: ● Clinical data on the device ● Clinical data on equivalent device(s) ● Clinical data to establish the current knowledge/state of the art
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Identify the clinical data
State of the art: “Developed stage of current technical capability and/or accepted clinical practice in regard to products, processes and patient management, based on the relevant consolidated findings of science, technology and experience”. Note: The state-of-the-art embodies what is currently and generally accepted as good practice in technology and medicine. The state-of the-art does not necessarily imply the most technologically advanced solution.
Sources: Definition IMDRF/GRRP WG/N47, MDCG 2020-6
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Identify the clinical data
Data for the state of the art - objectives:
● Describe the clinical field ● Identify potential clinical hazards ● Support equivalence ● Support the validity of surrogate endpoints ● Identify parameters used for the risk benefit determination
Benchmarking based on data on similar devices
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Identify the clinical data
Literature searches:
● Identify all relevant favourable and unfavourable data ● Several searches /search approaches ● A documented search protocol and report required ● Sources of Literature Appendix A4 ● Literature search Appendix A5
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Identify the clinical data
Key elements of the search protocol:
● Background ● Objectives ● Methods
– Data sources with justification – Search terms and any limits – Inclusion/exclusion criteria – Plans to address: data integrity, duplicates, appraisal & Analysis of data
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Clinical Evaluation – Appraise the clinical data
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Appraise the clinical data
MDR Annex XIV1(c): “appraise all relevant clinical data by evaluating their suitability for establishing the safety and performance of the device”
MEDDEV 2.7/1 section 9: ● Pre-defined appraisal plan ● Use full text ● Document the appraisal
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Appraise the clinical data
Appraisal process for each document:
Identify relevant information Evaluate the methodological quality and the scientific validity Determine the relevance of the information to the clinical evaluation Systematically weight the contribution of that data set to the clinical evaluation
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Appraise the clinical data
Some negative examples - data lacking validity MEDDEV 2.7/1 A6: Lack of information Numbers too small for statistical significance Improper collection of mortality and serious adverse event data Misinterpretation by the authors
MDCG-6 (legacy devices) Appendix III Hierarchy of types of clinical data
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Appraise the clinical data
Required for class III/ implantables
Used for bench marking
Low quality clinical data supportive
Not clinical data
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Clinical Evaluation –generate clinical data
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Generate clinical data
MDR Annex XIV1(d):
“generate, through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issues”
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Clinical Evaluation – Analyse the clinical data
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Analyse the clinical data
MDR Annex XIV1(e): “analyse all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits.” MEDDEV 2.7/1 section 10: ● use sound methods ● make a comprehensive analysis ● determine if additional clinical investigations or other measures are necessary ● determine PMCF needs
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The Clinical Evaluation Report
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The clinical evaluation report - CER
MDR Annex XIV 4: “The results of the clinical evaluation and the clinical evidence on which it is based shall be documented in a clinical evaluation report which shall support the assessment of the conformity of the device”
● Contains the results of the clinical evaluation ● Contains the clinical evidence ● Must consider favourable and unfavourable data ● Forms part of the technical documentation
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The clinical evaluation report - CER
Typical Content of a CER: ● Scope ● Description of the devices ● Results of the searches and identification of any internal clinical data
● Results of selection and appraisal process ● Equivalence Assessment (if applicable) ● State of the art ● Analysis of the data ● Determination of the benefit /risk ratio ● Conclusions
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Additional Requirements for high risk devices
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Implantable and class III devices
ARTICLE 61 The MDR requires confirmation of conformity with GSPRs to be based on clinical data ARTICLE 61.4 The MDR requires clinical investigations to be performed on:
● implantable devices ● class III devices
Additional Guidance:
MDCG 2023-7
with some exceptions….
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Implantable and class III devices
Modification to the manufacturer’s own device: Article 61.4 ● the device has been designed by modifications of a device already marketed by the same manufacturer ● the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV ● demonstration of equivalence has been endorsed by the notified body ● the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements ● PMCF plan must include post market studies
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Implantable and class III devices Equivalent to another manufacturer’s marketed device : Article 61.5
● Requirements of 61.4 met: (equivalence, NB endorsed, CER sufficient) ● 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 ● the original clinical evaluation has been performed in compliance with the requirements of this Regulation ● the manufacturer of the second device provides clear evidence thereof to the notified body ● PMCF plan must include post market studies device.
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Implantable and class III devices Devices approved and on the market under MDD/AIMD: Article 61.6a ● which have been lawfully placed on the market or put into service in accordance with Directive 90/385/EEC or Directive 93/42/EEC ● Where the clinical evaluation: – is based on sufficient clinical data – is in compliance with the relevant product-specific CS for the clinical evaluation of that kind of device, where such a CS is available ● Justification for not conducting a clinical investigation is required in the CER and the Clinical Evaluation Assessment Report (CEAR)
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Implantable and class III devices
Certain Listed Devices : Article 61.6b
● sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors ● the clinical evaluation is based on sufficient clinical data ● in compliance with the relevant product-specific Common Specification (CS), where such a CS is available. ● Justification for not conducting a clinical investigation is required in the CER and the Clinical Evaluation Assessment Report (CEAR)
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Class III and implantable devices
Exceptions applicable for new/legacy devices
Article 61 section:
Legacy Device
New Device
61.4 Equivalent (modification) to manufacturer’s own device 61.5 Equivalent to another manufacturer’s MDR device
61.6a Already on the market under MDD/AIMD
x
61.6b Listed device: sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors
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MDR compliance without clinical data article 61.10
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Clinical Evaluation – Article 61 (10) Without prejudice to paragraph 4, where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate, adequate justification for any such exception shall be given based on the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer. In such a case, the manufacturer shall duly substantiate in the technical documentation referred to in Annex II why it considers a demonstration of conformity with general safety and performance requirements that is based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and preclinical evaluation, to be adequate.
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Clinical Evaluation – Article 61 (10)
Is article 61.10 appropriate for my device? Key considerations:
• interaction between the device and the human body • Intended clinical performance and claims • State of the art • What non clinical test methods are available • Risk management
Objective: Can I meet each GSPR with non clinical data Caution: Cannot be applied to class III devices & implantable devices
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Clinical Evaluation – Article 61 (10)
Example of a device suitable for article 61.10 Washer Disinfector for surgical instruments ● No contact or interaction with patients ● Not intended to treat or diagnose patients ● State of the art – clinical studies not carried out ● Product standards available ● Risks to patient can be addressed by bench testing/validation ● Risks to user can be evaluated through usability studies I can meet each GSPR with non clinical data
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Lecture 3: The Place of Clinical Evaluation Within Device Life-Cycle and Technical Documentation
Presented by:
Adrian Keene, Associate Vice President, Global Biological Safety and Validation and EMEA Consulting Services
Date:
April 2024
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MDR Article 2 (44) Clinical Evaluation
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.
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MEDDEV 2.7.1 Rev 4 Section 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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MEDDEV 2.7.1 Rev 4 Section 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.
If I need to generatedata, I’d better start my CER earlierthan the month before my submission…
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MDR Clinical Evaluation
MDCG 2023-6 (Equivalence for Annex XVI products)
MDCG 2020-5 (equivalence) MDCG 2020-6 (legacy devices) MDCG 2020-1 (software) MDCG 2020-13 (CEAR Template)
MEDDEV 2.7.1 Rev 4 MDR (Annex XIV)
MDR (Article 61)
April 2024
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Types of CER
Early stage CER
- Do I have equivalent devices with relevant data to leverage? - What is the current State Of The Art? -What are the clinical risks to mitigate? -What should be my claims? - What kind of pre-clinical data, hence clinical data will I need to produce?
Submission CER - Do I have all the data needed to support compliance with GSPRs ? - Are there any new published data confirming/revising my initial CER? - Have I generated all necessary data to support the device’s claims and addressed risks? - Is my Risk Management file aligned with the clinical evidence? - Is my labelling and IFU aligned with data?
Maintenance CER
- Is my device still “SOTA ”? - Are there any changes made to my device that would contradict initial conclusions? - How has PMS/PMCF impacted my clinical data? - What has changed in the therapeutic area, what are my competitors doing? - Is my device still safe and effective? - Is my Benefit/Risk ratio still favorable?
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