Essentials of European Medical Device Regulatory Affairs

Essentials of European Medical Device Regulatory Affairs Norgine Training 16 th January 2020 Theresa Jeary, Regulatory & Scientific Affairs Ltd

Time

Session

09:00 - 09:15

Introductions and overview of training,

09:15 - 10:00

Legislation MDD Vs MDR

10:00 – 10:30

Key Stakeholders

10:30 – 10:45

Break

10:45 – 11:30

Device Classification

11:30 – 12:30

Conformity Assessment and Technical Documentation

12:30 – 13:00

Lunch

13:00 – 14:30

Clinical Evaluation

14:30 – 14:45

Break

14:45 – 15:30

Post Marketing Requirements

Device labelling / IFU / Advertising and Promotional materials

15:30 - 16:45

16:45 – 17:00

Review of Day and Close

Essentials of European Medical Device Regulatory Affairs

Essentials of European Medical Device Regulatory Affairs Janis Bayley Eli Lilly and Company Jane Arnold-Round NAMSA

Norgine Training 16 th Ja uary 2020

Theresa Jeary, Regulatory & Scientific Affairs Ltd

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Agenda

• Housekeeping

• Legislation – MDD Vs MDR and key highlights • Who’s who – key stakeholders and useful guidance • Device classification and borderline products • Conformity assessment and technical documentation • Clinical evaluation requirements • Post Market Requirements - Vigilance / PSURs • Device labelling / IFU/advertising & promotion

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Learning Outcomes

• To provide a basic understanding of European medical device regulatory

requirements and how to ensure compliance • Aim today is to highlight some key changes and discuss the current and the future legislation

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Module 1

• Legislation in Europe • Directives Vs Regulation • Key changes in the Regulation • Transition to the New Regulations

• Guidelines (MEDDEVs) • Harmonised standards • MDCG Guidance

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Current - EU Medical Device Directives

• Medical device directive MDD Directive 93/42/EEC • Active implantable medical devices AIMD Directive 90/385/EEC • e.g pacemakers • In vitro diagnostic medical devices IVDMD Directive 98/79/EEC • E.g pregnancy testing kits

• Directives that also impact devices • Electromagnetic compatibility 2004/108/EC • Personal protection equipment

Directive

Directive

89/636/EEC

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Regulations published June 2017

3 year transition period

Medical Devices Directive (MDD)

Medical Devices Regulation (MDR)

Active Implantable Medical Devices

Directive (AIMDD)

5 year transition period

In Vitro Diagnostics Regulation (IVDR)

In Vitro Diagnostics Directive (IVDD)

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Drivers for change

• The legislation is over 20 years old • Substantial technical and healthcare developments • Device/Drug combinations • Companion diagnostics • Move from hospital to home setting • e-Health • Divergences in application and coordination • Globalisation

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Aim of the new Regulations

• Improvements to achieve more harmonisation, while leaving the current ‘new approach’ proportional principles intact • Restore confidence in the system • A level playing field across Europe in approach to CE Certification of Medical Devices

Patient welfare and safety

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Difference between a Directive and Regulation

• EU Directive:

• Applicable to all Member States • Sets certain aims, requirements and concrete results that must be achieved in every Member State • National authorities must create or adapt their legislation to meet these aims by the date specified in each given Directive • EU Regulation: • Immediately applicable and enforceable by law in all Member States • As good practice, Member States issue national legislation that defines the competent national authorities, inspection and sanctions on the subject matter.

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MD Directive

35 Whereas… = Why

Annex I: Essential Requirements Annex II to VII: Procedures to demonstrate conformity Annex VIII: Devices for special purposes Annex IX: Definitions, Classification Rules Annex X: Clinical Evaluations Annex XI: Notified Bodies Annex XII: CE mark

23 Articles = What

XII Annexes = How

Total of 60 Pages

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MDR (EU) 2017/745

Chapter I – Scope and Definitions Chapter II – CE Marking, Economic Operators, Reprocessing Chapter III – Identification and Traceability of Devices Chapter IV – Notified Bodies Chapter V – Classification and Conformity Assessment Chapter VI – Clinical Evaluation and Investigation Chapter VII – Vigilance and Market Surveillance Chapter VIII – Cooperation between Member States Chapter IX – Confidentiality, Data Protection, Funding, Penalties Chapter X – Final Provisions

101 Whereas = The Why

10 Chapters of 123 Articles (The What)

XVII Annexes = The How

Total: 177 Pages

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MDR (EU) 2017/745 Annexes

Annex I – General safety and performance requirements

Annex XI – Conformity Assessment – Product Conformity Verification Annex XII – Procedure for Custom-made Devices Annex XIII – Certificates issued by a Notified Body Annex XIV – Clinical Evaluation and Post- market clinical follow-up Annex XV – Clinical Investigations Annex XVI – Products without an intended medical purpose Annex XVII – Correlation Table 90/385, 93/42 and Regulation

Annex II – Technical Documentation Annex III – Technical Documentation on PMS Annex IV – EU Declaration of Conformity Annex V – CE Marking of Conformity Annex VI – European UDI System Annex VII – Requirements to be met by Notified Bodies Annex VIII – Classification Criteria Annex IX – Conformity Assessment – QMS and Technical Documentation Annex X – Conformity Assessment – Type Examination

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MDR KEY CHANGES

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Key Changes

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Main concepts introduced

Scope • Inclusion of products without a medical purpose (Annex XVI) • Supply chain regulation that obliges each entity in the supply chain to check compliance of the previous supplier (see Chapter II) CE marking and registration • Introduction of a special procedure for NBs for certain high- risk devices • Rules for designation of NBs have tightened • Introduction of strict rules for clinical investigations and alignment to the Clinical Trials Regulation • Mandatory Unique Device Identification (UDI) introduced with the intention to facilitate the traceability of devices Once the device is on the market • Introduction of manufacturers’ and Authorized representative’s liability specific to medical devices • Introduction of detailed rules for the execution and reporting of results of Post-Market Surveillance and Post-Market Clinical Follow-up

MDR Timelines

• 27 May 2017 :

Enters into force

• 26 May 2020: Fully applies • From 26 May 2024: All devices placed on the

market must be in conformity with the MDR

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Key Changes

Wider Scope

NotifiedBodies

Clinical Evidence

Pre-market

Post-market Surveillance& Vigilance

Transparency& Traceability

Governance& Oversight

Less equivalence, moredata for high risk devices

Strictdesignation & monitoring criteria

DevicesandEconomic Operators registered centrally

Deviceswithnon- medicalpurpose

Scrutiny for high riskdevices

Central database & Co-ordination

Central Committee:MDCG

PublishSafety & Performance data & outcomeof clinical evaluation (class III & implantable)

Medicaldevices utilisingderivatives of non-viable(or renderednon-viable) tissues or cellsof humanorigin

Joint audits: 3 MemberStates & Commission

Common Specifications

UniqueDevice Identification(UDI)

ExpertPanel,Expert Laboratories

Trend reporting

Responsible person for manufacturer& Authorised Representative

Strengthened positionof NBs & Unannounced audits

Implantcards, SSCP (summaryof safety & clinicalperformance)

Enforcement activities

PMCF

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EUDAMED – MDR Article 33

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Newly introduced provisions

New obligations across stakeholders • Economic operators: Manufacturer,

Requirements & QMS • General Safety and Performance Requirements • Technical documentation • Clinical requirements • Quality management system

Eudamed & Traceability • European Database on Medical Devices (Eudamed) • Unique Device Identifier: Commission Implementing Decision (EU ) 2019/939 of 6 June 2019 contains the designated tools for assignment of UDI’s Authorized Representative, Importer & Distributor required to have sufficient financial coverage • Person responsible for regulatory compliance (Art. 15 MDR)

Classification

Rule 11 software

•

• Rule 18 non-viable tissue of human or animal cells, • Rule 19 nanomaterials • Rule 20 inhalation of medicinal substances • Rule 21 substance-based devices • Rule 22 active therapeutic devices with an integrated diagnostic function

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The Transition Period and “The Grace Period”

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The Transition Period and “The Grace Period”

Article 120 MDR

Certificates issued under the directives: Certificates issued prior to 25 May 2017 remain valid for the period indicated on the certificate Certificates issued during the transition period remain valid for the period indicated (maximum 5 years), but become void on 27 May 2024 Example:

• Certificate issued May 2019 – expires May 2024 • Certificate issued Jan 2020 – void 27 May 2024

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Transitional provisions “The Grace Period”

Devices placed on the market under the Directives :

MDs and AIMDs legally placed on the market prior to 26 May 2020 or during the transition period via a valid certificate may be made available up to 27 May 2025 Other Key points: • MDR requirements for PMS, vigilance and registration apply from the end of the transition period – 26 May 2020 • Must remain in compliance with the MDD/AIMD • No significant changes in design and intended purpose • Originally No “grace period” for Class I devices which do not require a certificate i.e. they needed to comply with the MDR from 26 May 2020 • CORRIGENDUM Published 27 th November 2019 has allowed an increase in the transition period for Class I devices requiring NB involvement or Class I devices that are up-classified in the MDR

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MDR - Transition Strategy

• Is my QMS and technical documentation ready? • Is my supply chain ready? (distributors, importers) • When does my certificate expire? • Is my current Notified Body designated to the MDR? • Does my current Notified Body have the correct scope for my devices? • Do I want to make any significant design changes soon? • What is my plan for new devices?

Notified Body Designation: https://ec.europa.eu/growth/tools- databases/nando/index.cfm?fuseaction=directive.main

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Guidance MEDDEVs • The MEDDEVs promote a common approach to be followed by manufacturers and notified bodies that are involved in conformity assessment procedures. • The MEDDEVs are drafted by authorities in conjunction with all stakeholders (industry associations, health professionals' associations, notified bodies and European standardisation organisations). • MEDDEVs are carefully drafted through a consultation process with all interested parties and are subject to a regular updating process • The guidelines are not legally binding. However, it is expected that the guidelines be followed, ensuring the uniform application of relevant directive provisions. • Much of the MEDDEV Text has been incorporated into the MDR

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Guidelines MDD-MEDDEVs 2.1 Scope, field of application, definition (7) 2.2 Essential requirements (3) 2.4 Classification of Medical devices (1) 2.5 Conformity assessment procedures: - General rules (4) - 2.7 Clinical investigation, clinical evaluation (4) 2.10 Notified bodies (1 + 4 annexes) 2.11 Products using materials of biological origin 2.12 Post Market surveillance (2 + forms) 2.13 Transitional period (implementation of MDD) (2) 2.14 IVD (4) 2.15 Other guidance (1 on working groups)

Conformity assessment for particular groups of products (3)

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Guidance Documents

http://ec.europa.eu/growth/sectors/medical-devices/guidance_en MEDDEVS for medical device directive.

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Harmonized Standards

• A harmonised standard is: • a European standard developed by a recognized European Standards Organization: CEN, CENELEC, or ETSI. • Following a request from the European commission • Many are also ISO standards (EU deviations - Annex ZA) • Can be used to demonstrate that products, services, or processes comply with relevant EU legislation. • Use is voluntary • Presumption of compliance to relevant requirements of directive or the MDR • References of Harmonised Standards are published in the Official Journal of the European Union

https://ec.europa.eu/growth/single-market/europeanstandards/harmonised-standards_en

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Harmonized Standards Examples General Standards EN ISO 13485 Quality systems EN ISO 14971 Risk Management EN ISO 14155

Clinical Investigation of MDs for human subjects Good Clinical Practice

EN ISO 15223 -1

Symbols

EN 1041

Information supplied by the manufacturer

More Specific Standards EN ISO 10993 (series) Biological evaluation of medical devices EN 60601 (series) Medical Electrical safety EN ISO 11607 Product Specific Standards e.g. EN ISO 5840:2009 Cardiovascular implants - Cardiac valve prostheses Packaging Materials for devices to be sterilized

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MDCG Publications

• A range of guidance documents to assist stakeholders in implementing the medical devices regulations • Legally non-binding guidance documents, adopted by the medical device coordination group (MDCG) in accordance with Article 105 of Regulation 745/2017 • Objective of ensuring uniform application of the relevant provisions of the regulations within the EU • https://ec.europa.eu/growth/sectors/medical- devices/new-regulations/guidance_en

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Module 2

Key Stakeholders – Regulatory Agencies – Competent Authorities – Notified Bodies – European Commission and Committees

– Legal Manufacturer – Economic Operators

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European Regulatory Agencies

European Commission (EC) Legislation produced for both medicines and devices Medical devices http://ec.europa.eu/growth/sectors/medical-devices/

Medicinal products http://ec.europa.eu/health/human-use/

European Medicines Agency (EMA) manage medicinal product procedures (as yet limited device involvement) http://www.ema.europa.eu/ema/ Committee of Human Pharmaceutical Products (CHMP) provide scientific assessment with the support of specialised working groups

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National Regulatory Agencies

Some countries have one agency that implements both medical device and medicinal product legislation e.g. Ireland

Others have different agencies e.g. Netherlands

Netherlands: Devices: Health Care Inspectorate (IGZ)

Netherlands : Medicines: Medicines Evaluation Board (MEB)

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Competent Authority (CA) Role

Government agency per EU country responsible for Medical devices • Interpretation and Guidance on law (e.g. classification) • Inspect, Audit and can “deNotify” Notified Bodies in juristriction • Can inspect class I Manufacturers • Surveillance responsibilities – Oversees that manufacturer investigates serious incidents and implements corrective action (if necessary) – Informs other EU countries when a local manufacturer has a corrective action • Authorisation of clinical investigations • On going post-market communications – certificates withdrawn, suspended • Maintains national device register (class I database and EUDAMED)

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Notified Body (NB) Private Bodies who offer conformity assessment services • Evaluate manufacturer’s compliance to legislation • Under the jurisdiction of their National Competent Authority • Member States are not obliged to appoint a NB and may appoint any number of NBs • Company chooses its NB body: provided they are designated in that device area. – NBs designation and scope listed per directive/ regulation: http://ec.europa.eu/growth/tools- databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=1 3

• NB may sub contract but retains responsibility • Involvement increases with higher classification • NB number appears on labelling where involved in Conformity Assessment

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EU Commission - now

Committee on medical devices • Regulatory power to change classification rules

• Implementation of Eudamed • Measures are legally binding

– E.g. Hip replacement reclassification

• Only meets when necessary • Medical device expert group (MDEG) • Other working groups

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EU Commission - future • An expert committee, the Medical Device Coordination Group (MDCG), composed of persons designated by the Member States (MS) based on their role and expertise in the field of medical devices including in vitro diagnostic medical devices (meeting quarterly in 2019) • To provide advice to the Commission aiming for a harmonised implementation of the Regulation.

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MDCG Sub-groups

• Post Market Surveillance & Vigilance (PMSV) • International/IMDRF coordination (INT) • Notified body oversight (NBO) • Market Surveillance (MS) • New technologies (NET) and Software • Clinical investigation and evaluation (CIE)

• Annex XVI (no medical purpose products) • In Vitro Diagnostics (IVD) • Unique Device Identification (UDI) • Standards (STAND) • Borderline and Classification (B and C)

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MDCG publications

Topic

Content

Document

UDI

UDI rules for combination products

MDCG 2019-2, February 2019

Guidance in UDI for systems and procedure packs

MDCG 2018-3, October 2018

UDI assignment to medical device software

MDCG 2018-5, October 2018

EUDAMED

Timelines for registration of device data elements in EUDAMED

MDCG 2019-4, April 2019

Registration of legacy devices in EUDAMED

MDCG 2019-5, April 2019

Notified Bodies

Q&A: Requirements relating to Notified Bodies

MDCG 2019-6, June 2019

Application of transitional provisions concerning validity of certificates issued in accordance to the directives

MDCG 2-19 – 10, October 2020

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MDCG publications

Topic

Content

Document

Clinical

Summary of safety and clinical performance

MDGC 2019-9, August 2019

Other topics

Interpretation of article 54(2)b

MDCG 2019-3, March 2019

Guidance on article 15 of MDR and IVDR on a ‘person responsible for regulatory compliance’ (PRRC)

MDCG 2019-7, June 2019

Guidance document implant card on the application of Article 18 Regulation (EU) 2017/745 on medical devices

MDCG 2019-8, June 2019

SCHEER Guidelines

Guidelines on the benefit-risk assessment of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine-disrupting (ED) properties

June 2019

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Medical Device Manufacturer

Legal Manufacturer • The natural or legal person with responsibility for the design, manufacture, packaging and labelling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party • The Manufacturer signs a Declaration of Conformity when they are: • Satisfied that produce meets requirements • necessary conformity assessments are complete • The Manufacturer has product liability

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Person responsible for regulatory compliance

Key features • Manufacturers shall have available within their organization at least one person responsible for regulatory compliance • Micro and small enterprises are not required to have the person responsible for regulatory compliance within their organization but shall have such a person permanently and continuously at their disposal • The person shall suffer no disadvantage within the manufacturer's organization in relation to the proper fulfilment of his duties, regardless of whether or not he is an employee of the organization Qualifications • A diploma, certificate or other evidence of formal qualification awarded on completion of a university degree or of a course of study recognized as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices • Four years of professional experience in regulatory affairs or in quality management systems relating to medical devices

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Person responsible for regulatory compliance

Tasks •

Ensure the conformity of the devices is appropriately checked in accordance with the quality management system under which these devices are manufactured before a product is released • Ensure the technical documentation and the declaration of conformity are drawn up and kept up-to-date • Ensure compliance with post-market surveillance obligations • Ensure reporting obligations are fulfilled • In the case of investigational devices, to ensure that the statement referred to in point 4.1 of Chapter II of Annex XV is issued (MDR) • In the case of devices for performance studies intended to be used in the context of interventional clinical performance studies or other performance studies involving risks for the subjects, the statement referred to in Section 4.1 of Annex XIV is issued

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EU Authorised Representative

• Required if Legal Manufacturer is outside community • EU Rep must be established in the Community • Acts as a contact for CA and NB in the Community instead of the manufacturer • Brexit has Impacts for UK Based Manufacturers

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Economic Operators

Importer, distributor and economic operators MDR Art. 2

• Importer : any natural or legal person established within the Union who places a device from a third country on the Union market • Distributor : any natural or legal person in the supply chain, other than the manufacturer or the importer, who makes a device available on the market, up until the point of putting it into service • Economic operators : the manufacturer, the authorized representative, the importer, the distributor and the person responsible for regulatory requirements

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Stakeholders updates

Notified Body

Commission & MDCG

NB must be designated under MDR or IVDR prior to providing quote for conformity assessment services to Regulations Designation process takes approximately 18 months after Joint Assessment Several NBs have withdrawn from the business under the Directives

Commission Implementing Regulation (EU) 2017/2185 of 23 November 2017 on the list of codes and corresponding types of devices MDCG have met and are working on implementation items

•

•

•

•

•

Nando database (06 th January 2020):

•

• 55 NB’s under MDD and 21 NB’s under IVDD • 9 NB’s under MDR and 3 under IVDR

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Module 3

• Medical Device definitions and MDR Classification • Medicinal Products and Borderline Products • Combination/integral products

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Medical Devices Examples:- • Tongue depressors • Syringes • Dental fillings • Sutures • X-ray scanners • Blood bags • Prescription spectacles • Bandages • Wheelchairs • Artificial tears (unmedicated) • Hip replacements

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Medical Device Accessories ‘accessory’ means an article which whilst not being a device is intended specifically by its manufacturer to be used together with a device to enable it to be used in accordance with the use of the device intended by the manufacturer of the device; • Contact lens care products • Skin barrier powders and pastes for use with ostomy bags • Gases used to drive surgical tools

NOTE: Accessories treated as devices in their own right !

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Medical Devices for Drug Delivery

Examples:- • An empty syringe • Drug delivery pump • Nebulizers • Medicine Spoons • ‘Lock out’ tablet dispensers

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Medical Device Definition: ‘medical device’ means any instrument, apparatus, appliance, software, implant , reagent , material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes • diagnosis, prevention, monitoring, prediction , prognosis, treatment or alleviation of disease, • diagnosis, monitoring, treatment, alleviation of, or compensation for an injury or disability , • investigation, replacement or modification of the anatomy or of a physiological or pathological process or state , • providing information by means of in vitro examination of specimens derived from the human body, including organ blood and tissue donations And which does not achieve its principal intended action by pharmacological, immunological or metabolic means , in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices – Devices for the control or support of conception, – products specifically intended for the cleaning , disinfection or sterilisation of devices as referred to in article 1(4) and those referred to in the first paragraph of this point.

Ref: Regulation 2017/745

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Classification of medical devices

Classification in the MDD and MDR MDD Art.9, MDR Art.51 • Class III - highest risk • Class IIb - medium to high risk • Class IIa - medium risk • Class I - lowest risk (measuring, sterile, reusable)

• Risk classification is based on the manufacturer’s intended purpose

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Classification of medical devices Classification criteria

MDR Annex VIII • Duration of contact:

- Transient, Short term, Long term

• Degree of invasiveness:

- Implantable, Surgical, Body orifice

• Anatomy affected • Active / Non-active

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Classification of medical devices Classification criteria Duration of contact MDR Annex VIII • Transient: < 60 minutes • Short term: 60 minutes ≤ 30 days • Long term: > 30 days - Immediate replacement by similar device is a continuation of original use

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Classification of medical devices Classification criteria

Degree of invasiveness (1) • Surgically Invasive Device

- an invasive device which penetrates inside the body through the surface of the body, including through mucus membranes of body orifices with the aid or in the context of a surgical operation - a device which produces penetration other than through a body orifice • Body orifice - natural opening in the body, as well as the external surface of the eyeball, or any permanent artificial opening, such as a stoma

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Classification of medical devices Classification criteria Degree of invasiveness (2) MDR Annex VIII • Reusable surgical instrument - an instrument intended for surgical use by cutting, drilling, sawing, scratching, scraping, clamping, retracting, clipping or similar procedures, without connection to any active medical device and which are intended by the manufacturer to be reused after appropriate procedures such as cleaning, disinfection and sterilisation have been carried out

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Classification of medical devices Classification criteria

Classification rules in the MDR MDR Annex VIII 1 – 4 Non invasive devices

5 – 8 Invasive devices 9 – 13 Active devices 14 – 22 Special rules

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Classification of medical devices Classification rules in the MDR: special rules MDR Annex VIII 14 – 22 Special rules - 14 medicinal substance / blood derivative - 17 recording X-ray images - 18 animal & human tissue - 19 nanomaterials - 20 administer medicinal product via inhalation - 21 substance based - 22 active therapeutic devices with a diagnostic function - 15 contraception / prevention of sexual transmissible disease - 16 disinfecting, cleaning and rinsing

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Classification of medical devices Significant changes in the MDR

Software MDR Annex VIII (Rule 11)

• Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as class IIa, except if such decisions have an impact that may cause: — death or an irreversible deterioration of a person's state of health, in which case it is in class III; or — a serious deterioration of a person's state of health or a surgical intervention, in which case it is classified as class IIb. • Software intended to monitor physiological processes is classified as class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as class IIb. • All other software is classified as class I.

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Classification of medical devices Significant changes in the MDR

Devices with ancillary medicinal substances MDR Annex VIII (Rule 14)

• All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, as defined in Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, with action ancillary to that of the devices, are in class III.

• “liablity to act” wording has been removed from MDD Rule 13 definition

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Classification of medical devices Significant changes in the MDR

Non-Viable Human Tissues MDR Annex VIII (Rule 18)

• All devices manufactured utilising tissues or cells of human or animal origin, or their derivatives, which are non-viable or rendered non-viable are in class III , unless such devices are manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non- viable that are intended to come into contact with intact skin only

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Classification of medical devices Significant changes in the MDR

Nanomaterials MDR Annex VIII (Rule 19)

• All devices incorporating or consisting of nanomaterial are: - in class III if they present a high or medium potential for internal exposure - in class IIb if they present a low potential for internal exposure - in class IIa if they present a negligible potential for internal exposure

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Classification of medical devices Significant changes in the MDR Administration of Medicinal Product via Inhalation MDR Annex VIII (Rule 20) • All invasive devices with respect to body orifices, other than surgically invasive devices, which are intended to administer medicinal products by inhalation are in class IIa • However, if their mode of action has an essential impact on the efficacy and safety of the administered medicinal product or if they are intended to treat life-threatening conditions, then they are in class IIb

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Classification of medical devices Significant changes in the MDR

Substance-based MDR Annex VIII (Rule 21)

• In class III if they, or their products of metabolism, are systemically absorbed by the human body in order to achieve the intended purpose • In class III if they achieve their intended purpose in the stomach or lower gastrointestinal tract and they, or their products of metabolism, are systemically absorbed by the human body • In class IIb in all other cases, except if they are applied on skin, in which case they are in class IIa, or • If they are applied in the nasal or oral cavity as far as the pharynx, and achieve their intended purpose on those cavities, in which case they are in class IIa

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Classification of medical devices Significant changes in the MDR Active Therapeutic Device with a diagnostic function MDR Annex VIII (Rule 22) • Active therapeutic devices with an integrated or incorporated diagnostic function, which significantly determines the patient management by the device are in class III, such as closed loop systems or automated external defibrillators

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MDR – Scope Changes

Devices with no medical purpose – Annex XVI • Common specifications as a trigger • Covered for first time - General Safety & Performance Requirements • When used as intended should not pose any unacceptable risk to the user

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MDR Scope extension

ANNEX XVI LIST OF GROUPS OF PRODUCTS WITHOUT AN INTENDED MEDICAL PURPOSE REFERRED TO IN ARTICLE 1(2)

1. Contact lenses or other items intended to be introduced into or onto the eye. 2. Products intended to be totally or partially introduced into the human body through surgically invasive means for the purpose of modifying the anatomy or fixation of body parts with the exception of tattooing products and piercings. 3. Substances, combinations of substances, or items intended to be used for facial or other dermal or mucous membrane filling by subcutaneous, submucous or intradermal injection or other introduction, excluding those for tattooing. 4. Equipment intended to be used to reduce, remove or destroy adipose tissue, such as equipment for liposuction, lipolysis or lipoplasty. 5. High intensity electromagnetic radiation (e.g. infra-red, visible light and ultra-violet) emitting equipment intended for use on the human body, including coherent and non- coherent sources, monochromatic and broad spectrum, such as lasers and intense pulsed light equipment, for skin resurfacing, tattoo or hair removal or other skin treatment. 6. Equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain.

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Classification of medical devices How to classify?

Key points • Intended purpose • Confirm it is a medical device • Consider the definitions • Consider the implementing rules • Determine the applicable rule • Classify

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How to Apply the Rules

• Manufacturer decides on the basis of the decision rules in the Directive (Annex IX) and the intended purpose of the device

• Decision criteria: time, invasiveness, powered or not (active/non-active), presence of drugs

• All rules must be considered

• For multipurpose devices the highest class applies

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MDR Classification Case study

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Medicinal Product Definition*:

The definition of a medicine is: I. Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or II. Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis Article 2(2) of Directive 2001/83/EC also provides that, in cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a “medicinal product” and within the definition of a product covered by other Community legislation the provisions of the Directive shall apply.

*Article 1 and 2(2) of Directive 2001/83/EC

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Medicinal Products

Examples:- • Spermicidal preparations • Gases used in anaesthesia • Topical disinfectants • Toothache preparations (i.e. Eugenol) • Water for injections, IV fluids • Antacids • Artificial tears (medicated) • Root canal dressings

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Combination Products (which are medicines)

Definition:- •

Devices for administration of medicinal products such that the device and the medicinal product form a single integral product designed to be used exclusively in the given combination and which is not reusable.

Regulated as medicines: 2001/83/EEC .

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Integral Products (which are medicines)

Examples:- • Prefilled syringes/pens • Aerosols containing a medicinal substance • Pre-charged nebulizers • Implants that release a medicinal product • Patches for transdermal drug delivery

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Legislation of Combination Products

Combination products regulated as medicines (Article 117): – Action of the medicinal substance is principal (not ancillary) – Devices for administration - single integral product non reusable (prefilled syringe) • Marketing Authorisation (MA) is required • Device part must comply with the relevant GSPRS • MA application must include: – CE certificate and /or Declaration of conformity OR – Notified Body opinion if not CE marked and if a CE certificate would be required • Requirements apply from May 2020 • European Medicines Agency Guidance: - 1st EMA guidance issued February 2019 https://www.ema.europa.eu/en/news/first-guidance-new-rules-certain-medical-devices - Draft guideline -quality requirements for drug-device combinations 3 June 2019 https://www.ema.europa.eu/en/quality-requirements-drug-device-combinations

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Combination Products (which are devices)

Definition:- Device that incorporates, as an integral part, a substance .. if used separately, may be considered .. a medicinal product .. and which is liable to act on the body with action ancillary to that of the device

Regulated as device

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Combination Products (regulated as devices)

Examples:- • Catheters coated with Heparin or an antibiotic agent • Bone cements containing antibiotic • Root canal sealers which may incorporate medicinal substances with secondary action • Blood bags containing anti-coagulant • Soft tissue fillers incorporating local anaesthetics • Condoms coated with spermicides • Wound dressings with antimicrobial agent

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Legislation of Combination Products

Combination devices regulated as a device • Meets the definition of a medical device and

• Incorporates a substance which meets the definition of a drug and • The action of the substance is ancillary to that of the primary action of the device

Examples: Included : Drug eluting stent

Combination devices under the MDR are class III under rule 14

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Legislation of Combination Products The Notified Body must: • Review the technical file (information on the device) • Verify the usefulness of substance as part of the device • Seek an opinion of: • Medicines authority/EMA issues an opinion (within 210 days) • NB “due consideration” to opinion when making certification decision - No CE certificate if opinion is unfavourable - NB must inform Medicines Authority of final decision - a medicines authority (EU member state) - or the European Medicines Agency (EMA)

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Combination product examples

Prefilled insulin pen • The insulin cartridge is fixed in the pen • Several injections, the entire pen is discarded once empty (medicine) the empty pen (medical device). • Several injections and once the cartridge is empty, the cartridge is discarded • A new cartridge is put into the pen Reusable insulin pen • Insulin cartridge (medicine) is put into

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Products packaged together in a Carton/Procedure Packs Medicinal products with a device • e.g. a medicine(antibiotic) with a device (dosing spoon) • Present the submission as per the common technical document i.e. MAA. • Provide a copy of the CE certificate for the device. • Introducing a new device or device supplier is a Type 1B variation Procedure packs (more than one device) • Procedure packs per Article 12 of Directive 93/42/EEC each device keeps its own classification. • If pack includes devices without a CE mark, or combination is not compatible with original intended use, the pack is a device in its own right.

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Medicinal Product or a Medical Device? Depends on mode of action of the Product to achieve its indication

Primary Intended Purpose achieved by one of the following means:

Primary intended purpose achieved by other means:

Pharmacological Metabolic Immunological All ATMPs All In-Vivo Diagnostics

Physical Simple Chemical Mechanical Digital

Medical device

Medicinal Product

Ancillary Drug

Deliver/ Localise

Device-Drug Combination

Drug-Device Combination

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Device or Medicine ?

Consider the manufacturer’s claim

• Device – NOT by pharmacological, immunological or metabolic means • Medicine – correcting or modifying physiological functions

Device action tends to be physical e.g. a support or barrier.

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• Borderline products are those for which it’s not clear whether they fall under the medical device's legislation or another piece of legislation • Due to the diverse interpretations that exist in determining the appropriate regulatory pathway for some medical products a working party on borderline and classification was established to facilitate a dialogue among regulators and industry to provide a forum to exchange opinions and reach consensus to ensure a consistent approach in product • The working party on borderline and classification publish the outcome of discussions in a manual which represents the views agreed by the regulators in the group, the views expressed in the manual are not legally binding, since the interpretation of Community law can only be provided by the European Court of Justice • It is also important to note that defining a given product as a medical device and interpretation of the application of the classification rules fall within the competence of the competent authorities of the Member States where the product is on the market The Working Party on Borderline and Classification

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Guidance https://ec.europa.eu/growth/sectors/medical-devices/current- directives/guidance_en

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Other Guidance

• Notified body

• National Competent Authorities (CA) obliged to render decisions for any individual product (if asked) - Note: European opinion may differ

• European Court of Justice (“the Court”) the authoritative interpretation of Community law.

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Classification of medical devices Classification dispute

Dispute on classification in the MDR MDR Art.51

• Any dispute between the manufacturer and the notified body concerned, arising from the application of the classification criteria, shall be referred for a decision to the competent authority of the Member State where the manufacturer has his registered place of business • The Competent Authority of the manufacturer shall notify the MDCG and the Commission of its decision • The decision shall be made available upon request

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Classification of medical devices Conclusions Key points • Based on manufacturers’ intended purpose - Look at the product - Read the label - What are the ingredients and what is their function? • Medical device classification is risk-based and determined by the manufacturer’s intended use • Medical device manufacturer is responsible for compliance with the law as stated in the Declaration of Conformity • Many borderline areas to discuss with experts

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Module 4

• Conformity Assessment Process - Conformity assessment procedures - Risk Assessment - Technical Documentation - General Safety and Performance Requirements (GSPR) - Notified Body selection

- CE marking - Registration

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Process (Conformity Assessment)

Definition: MDR article 2 (40) ‘conformity assessment’ means the process demonstrating whether the requirements of this Regulation relating to a device have been fulfilled;

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Process (Conformity Assessment)

1. Define intended purpose of the device 2. Classify device 

3. Establish Quality Management System (QMS) 4. Choose a conformity assessment procedure 5. Establish post market surveillance system 6. Conduct Risk Assessment 7. Prepare technical documentation (incl general safety and performance requirements ( GSPR ) checklist 8. Submit to NB if required and get CE certificate(s)

9. Register the device Electronic system 10. Sign the declaration of conformity 11. Place on the EC market

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