Essentials of European Medical Device Regulatory Affairs - June 2020

Essentials of European Medical Device Regulatory Affairs

23 June 2020

Programme

Presenters: Janis Bayley, Eli Lilly & Company and Theresa Jeary, Regulatory & Scientific Affairs Ltd

All times are UK local (BST)

Time

Presentation

10am

Introduction from TOPRA

Cristina Dragan, TOPRA

10.05am Introduction

Theresa Jeary

10.15am Scope and definitions

Janis Bayley

11am

Making available on the market and putting into service of device, obligations of economic operators, reprocessing, CE marking and free movement

Theresa Jeary

11.30am Break

12pm

Identification and traceability of devices, registration of devices and of economic operators, summary of safety and clinical performance, European data base on medical devices.

Theresa Jeary

12.15pm Notified bodies

Theresa Jeary

12.35pm Classification and conformity assessment

Janis Bayley

1pm

Break

1.30pm Clinical evaluation and clinical investigation

Janis Bayley

2.10pm Postmarket surveillance vigilance and market surveillance

Theresa Jeary

2.45pm Cooperation between member states, medical device coordination group, expert laboratories, expert panels and device registers

Theresa Jeary

2.50pm Break

3.10pm Confidentiality, data protection, funding and penalties

Janis Bayley

3.15pm Final provisions

Janis Bayley

3.20pm Annex 1 and labelling

Janis Bayley

4pm

Conformity assessment

Theresa Jeary

5pm

Close

23 June 2020

Essentials of European Medical Device in Regulatory Affairs

Janis Bayley Eli Lilly and Company Theresa Jeary Regulatory and Scientific Affairs Limited

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Agenda to follow the MDR chapters

Chapter

Articles

Introduction

Theresa 10 am to 11.45

I

Scope and definitions

1-4

Janis

II

Making available on themarket and putting into service of device, obligationsof economic operators, reprocessing, CEmarking and free movement Identification and traceability of devices, registration of devices and of economic operators, summary of safety and clinical performance, European database onmedical devices.

5-24

Theresa

coffee

III

25-34

Theresa 12 to 1pm

IV

Notified bodies

35-50

Theresa

V

Classification and conformity assessment

51-60

Janis

lunch

VI

Clinical evaluation and clinical investigation

61-82

Janis

1.45 to 3.15

VII

Postmarket surveillance vigilance andmarket surveillance

83-100

Theresa

VIII

Cooperation betweenmember states,medical device coordination group, expert laboratories, expert panels and device registers

101-108

Theresa

coffee

IX

Confidentiality, dataprotection, funding and penalties

109-113

Janis

3.30 to 5pm

X

Final provisions

114-123

Janis

A

Annexes 1

Janis

A

Conformity assessment

Theresa

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Objective: To provide a basic understanding of the European medical device regulatory requirements

3 year transition period Ends May 2020delayed May 2021

Medical Devices Directive (MDD)

Medical Devices Regulation 2017/745 (MDR)

Active Implantable Medical Devices

Directive (AIMDD)

In Vitro Diagnostics Regulation 2017/746 (IVDR) 5 year transition period Ends May 2022

In Vitro Diagnostics Directive (IVDD)

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1

MDR Transition Strategy

• Delay by one year, so more time available, less resources for AIMD? • Switzerland and Turkey extra year applicable. • UK _ Brexit is 31 st December 2020 • 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 about my new devices?

Notified Body Designation: https://ec.europa.eu/growth/tools- databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=34

4

Medical Devices Regulation 2017/745 (MDR)

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02017R0745-20170505&from=EN

Since publication there have been two corrigendums (corrections) published

• May 2017 https://eur-lex.europa.eu/legal- content/EN/TXT/PDF/?uri=CELEX:32017R0745R(02)&qid=1585043243768&from=en

• November 2019 https://data.consilium.europa.eu/doc/document/ST-13081-2019-INIT/en/pdf

• Delay https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32020R0561&from=EN

•Examplesofdirectives that couldalso impactdevices •Electromagneticcompatibility

Directive2004/108/EC

•Personalprotectionequipment

Directive89/636/EEC Directive2014/53/EU

•Radioequipment (RED)

There is the regulation, but then MEDDEVs and MDCG guidance to help

5

Transitional provisions “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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2

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 2021 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 2021 • 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 2021 • 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 Period

1 year delay on date of application but grace period remains unchanged

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Scope and definitions

Chapter I

Articles 1-4

• What is and what is not a medical device

• Medical Device definition

• Medicinal Products

• Combination/integral products

• Borderline Products

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Is the Product a Medical Device?

A medical device is different to •

Cosmetic Products -Regulation 1223/2009 • Invitro diagnostics -Regulation 2017/746 • Medicinal Products -Regulation 2001/83 • Advanced therapy medicinal products - Regulation 1394/2007 • Human blood products • Biocide products • Toys • Foods - Regulation 178/2002

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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 followingspecific medical purposes • diagnosis,prevention, monitoring, prediction , prognosis, treatment or alleviationof disease, • diagnosis,monitoring, treatment, alleviationof, or compensation for an injury or disability , • investigation, replacement or modificationof the anatomy or of a physiological or pathological process or state , • providing informationby means of in vitro examinationof specimens derived from the human body, includingorgan bloodand tissue donations And which does not achieve its principal intended action by pharmacological, immunologicalor metabolic means , in or on the human body, but which may be assisted in its function by such means. The followingproducts shall also be deemed to be medical devices – Devices for the control or support of conception, – products specifically intended for the cleaning , disinfectionor sterilisationof devices as referred to in article1(4) and those referred to in the first paragraph of this point.

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Onecomb is for humanbeings

for the specific medical purposeof prevention,ortreatmentdisease

andother is for humanbeings tokeep theirhair tidy butdoesnothaveamedical purpose.

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4

As a medical device, compliance to the regulation is needed and then a CE mark can be attached.

Having a CE mark, does not mean this toy penguin is a device

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• 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 humanbody through surgically invasive means for the purposeofmodifying the anatomyor fixation of bodypartswith the exceptionof tattooingproductsandpiercings. • 3.Substances,combinations of substances,or items intended to beused for facial or otherdermal or mucousmembrane filling by subcutaneous,submucousor intradermal injection or other introduction, excluding those for tattooing. • 4. Equipment intended to beused to reduce, remove or destroyadipose tissue, such as equipment for liposuction, lipolysis or lipoplasty. • 5.High intensity electromagnetic radiation (e.g. infra-red,visible light andultra-violet) emitting equipment intended for use on the humanbody, including coherentandnon-coherent sources, monochromatic andbroad spectrum,such as lasers and intense pulsed light equipment, for skin resurfacing, tattooor hair removalor other skin treatment. • 6. Equipment intended for brain stimulation thatapply electrical currentsor magnetic or electromagnetic fields thatpenetrate the cranium tomodify neuronalactivity in the brain.

This Regulation shallalso apply, as from the date of application of common specifications The necessarycommon specifications shall be adopted by 26 May 2021. They shall apply as from six months after the date of their entry into forceor from 26 May 2021, whichever is the latest.

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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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5

Guidance Documents

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

medical device coordination group (MDCG)guidance is under development for the regulation.

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Other sources

Notified body (if you have one)

•

• National Competent Authorities (CA) obliged to render decisions for any

individual product (if asked) - Note: opinions may differ

• MDCG Group: Borderline and Classification - CA and industry represented . - Provides a potential common position for Member States

- Note: US /Japan opinions on classification sometimes differ from EU - Manual on borderline and classification in the community regulatory framework for medical devices. https://ec.europa.eu/docsroom/documents/35582

• commission can introduce implementing acts to say if a specific product is a medical device, accessory, or not.

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

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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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6

Medical Device Accessories ‘accessory’ whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical devices to specifically enable the medical device to be used in accordance with its intended purpose ….. For example:- • Contact lens care products • Skin barrier powders and pastes for use with ostomy bags • Gases used to drive surgical tools

NOTE: Accessories are 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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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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Integral 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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Integral Products (which are devices)

Definition:- Any device which, when placed on the market or put into service, incorporates , as an integral part, a substance which , if used separately , would be considered to be a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device , shall be assessed and authorised in accordance with this Regulation.

article 1(8)

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Integral Products (which are 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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An example…………

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 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) Article2(10) • Procedure packs 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. • Article22

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9

Borderline with other Directives

• Skin peeling products (device or cosmetic) – Depends if a medical claim (appearance vs scar removal) – Depth (top layer of skin or deeper action) – Frequency of application • Insect repellent (device or biocide) • Manufacturer wanted a medical claim of prevention of injuries from insects • No - primary action is to repel insects (and not humans) and so not a medicinal claim. It is a biocide.

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1. Medical device or not a medical device?

2. A potential question for the regulatory department

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Three toothpastes:

Sensodyne rapid relief •Clinically proven to relieve the pain of sensitive teeth •Mineral like seal over the dentine and within microscopic channels

Sensodyne total care •Clinically proven relief from the pain of sensitive teeth •Potassium nitrate relieves the pain of sensitive teeth by directly calming the nerve endings inside teeth

Macleans •Deep down protection against plaque and decay •Clinically proven for healthy gums •Antibacterial action for protection against bad breath

30

Macleans,Sensodyne and ringsare trademarksofGSK

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Chapter II

Articles 5-24

Making available on the market and putting into service of device, obligations of economic operators, reprocessing, CE marking and free movement

• To put a producton the market you need to conform to

Annex I

General safety and performance requirements

(GSPR)

• You must not make misleading claims

• Devices in conformity with commonspecifications shall be presumed to be compliant with the regulation

• Devices in conformity with standards shall be presumed to be compliant with the regulation

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Harmonized Standards

• A harmonised standard is: • a Europeanstandarddevelopedbya recognisedEuropeanStandardsOrganisation:CEN, CENELEC,or ETSI. • Following a request from theEuropeancommission • 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/european-standards/harmonised-standards/

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Harmonized Standards Examples

General Standards EN ISO 13485

Quality systems Risk Management

EN ISO 14971 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

Packaging Materials for devices to be sterilized

Product Specific Standards e.g. EN ISO 5840:2009 Cardiovascular implants - Cardiac valve prostheses

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11

Establish Quality Management System (QMS) Key elements required by the MDR Article 10: a) Regulatory strategy for compliance b) GSPRs c) Management responsibility d) Resource management

Can I use ISO 13485?

e) Risk management f) Clinical evaluation g) Product realization h) Verification of UDI i) PMS system j) Communications with CAs NBs EOs… k) Vigilance l) CAPAs m)Product improvement

 Harmonised standard  Covers many required elements ! Need to add EU specific elements

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Economic operators 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 Obligations • Manufacturers need to draw up the appropriate documentation and amend it as standards change, and the product changes

• Manufacturers need a quality management system to manage processes (e.g. reporting obligations)

European Authorised Representative (AR) • If manufacturer is outside community they need a natural or legal person to act on their behalf. • Article 11 describes obligations. Record in the mandate between AR and manufacturer tasks. • A UK AR is no longer possible post BREXIT. Person responsible for regulatory compliance (PRRC) • Manufacturer needs someone responsible for compliance of MDR(PRRC-m) and the AR needs access to someone in the community (PRRC-AR).

MDCG 2019-7Guidance onArticle 15 of theMedicalDevice Regulation (MDR)and in vitroDiagnostic Device Regulation (IVDR) regarding a ‘person responsible for regulatory compliance’ (PRRC)

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12

Importer Obligations

• Check compliance to MDR • Check product is registered in electronic system • Forward complaints and AEs to manufacturer and AR • Provide samples to competent authorities if necessary • Repacking is possible – article 16

Distributor Obligations • Check product is CE marked and has a declaration of conformity • Has the correct labelling • That the importer has done necessary tasks • And that a UDI is assigned • Forward complaints and AEs to manufacturer and AR • Provide documents to competent authorities if necessary

37

Single –use devices

•The re-processor becomes the manufacturer

Implant cards • Needs to be provided to the patient • Identify the device • Warnings and precautions • Expected lifetime of the device • Some implants exempt e.g. tooth crowns Parts

• Replacement parts : documentation of performance required • If significantly change the device they are considered devices

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Declaration of conformity (DoC)

By drawing up the EU declaration of conformity, the manufacturer shall assume responsibility for compliance with the requirements of this Regulation and all other Union legislation applicable to the device • Declared by the manufacturer- sole responsibility • Clearly identified device(s) sizes /variants • Approve once the technical documentation is complete • Retain for at least 10 years after the last device • Copy to importers, distributors and AR • Continuously update (article 19) • Translated into at least one EU language

• If you comply to other legislation it can be included in the one certificate

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13

Annex IV lists what to include in DOC Content of the DoC (Annex IV): 1 • CompanyName • Registeredtradename /trademark • SRN ifavailable

Content of the DoC continued 6 A statementdeclaring conformityof the devicewithMDR andany other relevant Union legislation 7 Common Specifications 8 • NotifiedBodyNameandnumber • ConformityAssessmentProcedure • Certificate(s) 9 Any additional informationwhere applicable 10 • Placeanddateof issue • Signature • Nameand functionofperson signing • Signed for/onbehalfoff

• EUARnameandaddress (ifapplicable) 2 A statement that theEUdeclarationof conformity is issuedunder the sole responsibilityof themanufacturer 3 BasicUDI-DI 4 • Productand tradename • Unambiguous reference allowing identificationand traceability: EgProduct code, catalogue number Or Ref toBasicUDI-DI 5 Risk classificationof thedevice (AnnexVIII)

40

Affix the CE mark

• All devices must bear the CE mark except: • Custom made devices • Investigational devices • Demonstrations at trade fair or similar (disclaimers required) • Affixed to the device or the sterile packaging or the packaging (if not applicable/possible) • Must appear in any instructions for use and any sales packaging • shall be accompanied by the NB number (where applicable) (check NB rules on their logo) • Form of the CE mark per Annex V

0000

Free movement of goods if comply

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Chapter III

Articles 25-34

Identification and traceability of devices, registration of devices and of economic operators, summary of safety and clinical performance, European data base on medical devices.

AnnexVI

Registration requirements and UDI

• Traceability • Eudamed • UDI • Registering devices

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14

Traceability

Traceability of devices to be kept for 10 years (15 years (implantable)) after last device placed on market

Economi c Operator

Economi c Operator

Health institute

Economic operator will need to record devices received and passed on

To record devices Eudamed database is being created with access to a free database so that a commondictionary is used for device types. https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en

43

Eudamed Will house • Device registrations • UDI data base • Registration of economic operators • Notified bodies and certificates • Clinical investigations • Vigilance and post market surveillance reports and summaries

• Commission and member states will have access • Others will have access to some • Meant to be fully functional by March 2021 .

44

Guidance

 UDI number will need to be on the device, label or packaging

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15

Registration- Devices

UDI Database (Article 27/29)

 Assign Basic UDI  Register Basic UDI with core data elements (annex VI)

Who

Device*

Assign UDI

Register

Manufacturer

Class I Class IIa Class IIb non implantable Class III Class IIb implantable

Before placing on the market

Before placing on the market

Manufacturer

Before conformity assessment

After certificate Before placing on the market Before placing on the market Before placing on the market

System/Procedure packer System/Procedure pack steriliser

Systems and Procedure packs Systems and Procedure packs

Before placing on the market Before placing on the market

*No registration for Custom made devices

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Registration EOs

EO database (Article 31) For manufacturers, authorized representatives and importers:  EOs Submit information per Section 1 of Annex VI Part A  Competent Authority verifies data and issues Single Registration Number (SRN)  Registration timing depends on device class (see previous slide)

 Changes - EO must update within 1 week  Competent Authority can charge a fee

 Routine check will be required to confirm certain data (EO) remains accurate.

47

Summary of safety and clinical performance

• For implantable devices and class III. Will be made public via Eudamed • Key information is prescribed in MDR • NB will review • Label or IFU needs to reference the published documents

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Chapter IV

Articles 35-50

Notified bodies

Who’s who? Key Stakeholders

RegulatoryAgencies – CompetentAuthorities

Notified Bodies

European committees and organizations

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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/ MDR responsibility moved from DG Health to DG Sante Jan 2020

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 MD directives

• Notifies Bodies to the EC based on assessed ability (NB) • Interpretation and Guidanceon law (e.g. classification) • Can ask the EU Commission for a classificationdecision • Inspect, Audit and “deNotify” NB , includingduringNB activities • Can inspect class I Manufacturers • Surveillance responsibilities

• Oversees that manufacturer investigates serious incidentsand implements corrective action (if necessary) • Informs other EU countrieswhen a local manufacturer has a corrective action

• Authorisationof clinical investigations • On going post-market communications– certificates withdrawn,suspended • Maintains nationaldevice register (class I databaseand EUDAMED)

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Notified Body (NB)

• Evaluatemanufacturer’s compliance to legislation • Issue certification (EC) topermit CE marking of a device • NB’s tend to be private sector companies • Companychooses its NB body:provided they are designated in thatdevice area. • IMPACT OF BREXIT in choice of NB • NB fees should be publicly available • NBs listed per directive • http://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=13 • NationalStandardsAuthorityof Ireland (NSAI)

1SwiftSquare,Northwood,Santry, Dublin9, Ireland Phone :+353.1.807.38.00 Email : info@nsai.ie Website : www.nsai.ie NotifiedBody number :0050

Lists the Notified Body requirements/obligation

•

AnnexVII

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Considerations for choosing a NB:

Are they designated under the MDR?

– –

Do they have the right scope?

– Is my NB sustainable? Multisite? Resource? Brexit? – Can I work with these people? – Do these people understand my technology? – Do we share: testing, validation & clinical approach? – Will their reputation enhance mine? – Will there be language issues? – What is the time and cost – will quotes hold? – Consider who your contractors and competitors use • Factor into your product launch plans!

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Notified Body (NB)

• NB may sub contract but retains responsibility • Involvement increases with higher classification of a product • NB numberappears on labelling • Competentauthorities regularly audit NBs andmonitor their assessments of manufacturers

• A NB can cease working (through choice/take over/ CA suspends them) • Certificates are valid for 9 monthsduring any switch

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Notified body oversight (NBO)

• MDR formalises the need for a NB coordination group to meet at least annually • To improve the overall performance of NBs • Provide examples of best practice • Training function • Aim for consistency • Used by NBs and CA • Review TEAM-NB’s NB-MED documents

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19

Chapter V Classification and conformity assessment

Articles 51-60

• Classification of devices

• Annex VIII - Classification rules

• Reclassification of devices

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Classification of Devices More risky the product the higher the classification

• Class I

eg. tongue depressor

• Sterile • Measuring eg. dosing spoon

• Class IIA • Class IIB • Class III

eg. blood pressure measuring

eg. ventilators eg. heart valve

• Any dispute on classification between NB and company needs to be referred to competent authority

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Classification – Key Concepts

Rules apply according to intended purpose - :

Duration (continuous use):

transient (<60 mins)

short term (<30 days) long term (>30 days)

Invasiveness:

Non-invasive invasive in a body orifice (eyes/stoma) surgically invasive implantable (hip replacement)

Non-Active/Active:

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20

Concept of Time

• Application quick, but in situ for longer e.g. cream

• Continuous use: uninterrupted actual use of the device for the intended purpose.

• However where usage of a device is discontinued in order for the device to be replaced immediately by the same or an identical device this shall be considered an extension of the continuous use of the device

Ref: MDR Annex VIII Chapter II 3.6

61

Active Medical Device

• Any medical device operation of which depends on a source of energy other than that generated by the human body for that purpose, or by gravity, and which acts by changing the density of or converting that energy. • Devices intended to transmit energy, substances or other elements between an active device and the patient, without any significant change, shall not be deemed to be active devices.

• Hearing aids, TENs machines, light boxes to treat SAD

• Stand alone software is considered to be an active medical device. Ref: MDR Article 2 An active non implantable regulated by this MDD now MDR. Active implantable was regulated by Directive 90/385/EEC but now MDR . MEDDEV 2.1/6 Guidance on software (what is and what is not a medical device)

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How to Apply the Rules

• Manufacturer decides on the basis of the decision rules in the MDD(Annex IX) MDR Annex VIII 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 • For devices used together consider classification separately • Accessories need to be classified in their own right

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Impact of classification • The choice of conformity route depends on classification • Article 11 MDD indicates choice of annexes to be followed e.g. Class IIb Annex II (full quality system) or Annex III plus Annex IV or V or VI.

• MDR refer to Chapter V Article 52. e.g. Class IIb

Chapter I and II of Annex IX and section 4 or Annex X plus XI.

NB involvement differs per route

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MDD - 18 rules

Rules 1 - 4

Non-invasive devices

Rules 5 - 8

Invasive devices

Rules 9 – 12

Active devices

Rule 13- 18

Special rules

http://ec.europa.eu/DocsRoom/documents/10337/attachments/1/translations

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Example: Rule 6

Surgically invasive devices - transient use - Class IIa unless: • Intended to control, diagnose, monitor or correct defect of the heart or of the central circulatory system through direct contact -Class III (angioplasty balloon catheters) • Reusable surgical instruments - Class I (scalpels) • Intended for direct contact with the central nervous system - Class III (brain spatulas) • To supply energy in the form of ionising radiation - Class IIb • Intended to have a biological effect or to be absorbed - Class IIb • Intended to administer medicines by means of a delivery system, if in a potentially hazardous manner - Class IIb

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MDR-Classification Annex VIII

• 22 rules (4 extra versus MDD)

• Rule 11 software

• Rule 19 nanomaterials

• Rule 20 All invasive devices with respect to body orifices, other than surgically invasive devices, which are intended to administer medicinal products by inhalation • Rule 21 Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body

• Review your product under MDD (if marketing before May 2021) and MDR. Plan for any change.

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Reclassification Process MDD Art. 9.3.

Where a Member State considers that the classification rules set out in Annex IX require adaptation in the light of technical progress and any information which becomes available under the information system provided for in Article 10, it may submit a duly substantiated request to the Commission and ask it to take the necessary measures for adaptation of classification rules.

MDR Article 51 3.

Commission can also decide by an implementing act to reclassify

Process can be used to avoid divergence of opinion

TheOrganisation for Professionals in Regulatory Affairs

EU Directives for Reclassification • Reclassification of breast implants: http://eur- lex.europa.eu/LexUriServ.do?uri=OJ:L:2003:028:0043:0044:e n:PDF • Reclassification of hip, knee and shoulder joint replacements: http://eur- lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:210:0 041:0043:en:PDF

TheOrganisation for Professionals in Regulatory Affairs

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Standalone Software - current

• Rules 9, 10,11 and 12 on active devices need to be reviewed • Current no specific rule for software in MDD

TheOrganisation for Professionals in Regulatory Affairs

MDR- Software rule 11

Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes

If suchdecisionshavean impact thatmaydirectlyor indirectly cause: –thedeathoran irreversible deteriorationof the stateofhealth - a seriousdeteriorationof the stateofhealthor a surgical intervention -If it is intended formonitoringof vitalphysiologicalparameters, where thenatureof variations is such that is could result in immediatedanger to thepatient.

Class III

Class IIa

Except

Class IIb

Software intended to monitorphysiological processes.

Class IIa

Except

Class IIb

All other software

Class I

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Classification Exercise

Product

Non Invasive (1,2,3,4) Invasive (5,6,7,8) Specialrules (13- 18)

Duration <60mins transient <30daysshort term >30days long term

Rule

Classification

A Hydrocolloid (creates a moist environment) plasters B Corrective daily contact lenses

Non-invasive Short term

Invasive (in a body orifice) Invasive (in a body orifice) Surgically invasive

Short term

C Corrective contact

Long term

lenses continuous wear for a year

D Device for self

Transient

administration of a medicine (not infusion, but short)

E Dentist hand held mirror

Invasive

Transient

TheOrganisation for Professionals in Regulatory Affairs

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TheOrganisation for Professionals in Regulatory Affairs

TheOrganisation for Professionals in Regulatory Affairs

TheOrganisation for Professionals in Regulatory Affairs

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Classification Exercise

Product

Non Invasive (1,2,3,4)

Duration <60mins transient <30daysshort term >30days long term

Rule

Classification

Invasive(5,6,7,8) Specialrules (13- 18)

A Hydrocolloid (creates a

Non-invasive

Short term

4

IIA

moist environment) plasters

B Corrective daily contact lenses

Invasive (in a body orifice)

Short term

5

IIA

C Corrective contact lenses continuous wear for a year

Invasive (in a body orifice)

Long term

5

IIB

D Device for self

Surgically invasive Transient

6

IIB

administration of a medicine (not infusion,but short)

E Dentist hand held mirror

Invasive

Transient

5

I

TheOrganisation for Professionals in Regulatory Affairs

Chapter VI

Clinical evaluation and clinical investigation

Articles 61-82

Witha few MDD notes as still applicable

TheOrganisation for Professionals in Regulatory Affairs

Life Cycle Clinical Evaluation

PostLaunch Activities

Concept

Feasibility

Development

Launch

Prototype development Benchandpre-clinical

Initialclinical evaluation ‒ Literature review ‒ Initialclinical investigations

Clinical investigations to supportCEmark

ObtainCE Mark

Postmarketing surveillance

User testing

Real life studiesto support ‒ Reimbursement ‒ Marketing

Human factors

PMCF studies

Studies onnon CEmarkedproducts

Studies onCEmarkedproducts

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Clinical Evaluation : Article 61

Conformity to the general safety and performance requirements (AnnexI) is based on clinical data to show

AnnexI. (1). device performance, acceptable benefit/risk

AnnexI. (8). any foreseeable risks and minimisingundesirable side effects

Provide necessary labelling information required in AnnexIII.

The level of clinicalevidence required should be appropriate to the device and its intended performance.

a clinical evaluation is required for all devices (Follow Annex IV Part A and MEDDEV).

The requirement for a clinical evaluation report is not new.

(MDD Essential requirement 6a.)

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Clinical Evaluation

The clinicalevaluation report will contain • Scientific literature of equivalent devices • Results of clinical investigations– critical assessment • Device shouldbe discussed in the context of alternative treatments.(not just devices)

-----------------------------------------------------------------------------------

For Class IIIand Class IIbactive devices for administering/removingmedicines

the company can ask the clinical expertpanel for advice on the development strategy and about the planned clinical investigation.

The panel’s advice needs to be recorded in the CER.

There is no provision for gaining scientificadvice other classifications

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Clinical Evaluation Clinical investigations(CI) areexpected for implantable and class III devices unless it is duly justified to rely on existing clinical dataMDD AnnexX directive 93/42/EEC MDR exceptions arenow…… -------------------------------------------------------------------------------------- if it is a modification of a device by the samemanufacturer. TheNBwill check thepostmarketing clinical follow up (PMCF) plan contains appropriatepost marketing studies to demonstratesafetyandperformanceof the device. --------------------------------------------------------------------------------------- Wheredatewas generatedunder theMDD and meetsa common specification ---------------------------------------------------------------------------------------- is on the list ofwell understoodproductse.g. dentalbraces. ---------------------------------------------------------------------------------------- If equivalent to anothermanufacturer’sMDR compliant device and contractallows access to the technical file. ----------------------------------------------------------------------------------------- Article61 (10) if clinicaldata isnotappropriate ----------------------------------------------------------------------------------------- And thatmodification createsan equivalent device to the first device and theNBagrees it is equivalentand the clinical evaluation of the original devicewould cover themodification.

Any justifications for not conductingaCI are included in theCER.

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Clinical Evaluation

CER needs to be updated based on • Information from PMCF • Post market surveillance plan

The PMCF evaluation report and summary of safety and clinical safety and clinical performance (article 32) for Class III and implantable devices needs to be updated annually.

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Clinical Investigations Article 62

• Need a legal representative in the EU if sponsor is from outside the EU • if trial in a single EU country the member state may allow a local contact

• Ethics review is required (per national requirements) • A trial can start once the CA and ethics approval is obtained

• Vulnerable populations are protected • The benefits of the CI justify the risks • Consent is obtained (special pops see articles 63-68) • Personal data is protected • Study as pain free and comfortable as possible • Conducted by a medical doctor/dentist, qualified staff and in suitable facilities • No undue pressure (including financial) to take part • The device conforms to Annex I except the end points in the CI • Annex XV needs to be followed (protocols etc) • If a patient withdraws the information can still be used • Compensation /insurance per national law (article 69)

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Applications for CIs

Non CE marked devices (article 70)

and

CE marked devices outside of scope of intended purpose (article 74)

TheOrganisation for Professionals in Regulatory Affairs

28

Process of CI Review-

no cooperation between MS

Sponsor respon ds toQs

respond to validationQs 10 days or MSmay extend by amax20 days Article 70 (3)

Validation 10days +5days Validation 10days +5days

Confirm valid 5days +5days Confirm valid 5days +5days Confirm valid 5days +5days

Assessment 5days +5days Assessment 5days +5days Assessment 5days +5days

Approv al Within45 days of validation +20days if expert review required (Minus the sponsor response time.)

MS 1 MS 2 MS n

Sponso r files Docum

Electronic system PerArticle73

Validation 10days +5days

ents Article70

• Trial in scope • Documents complete • Article 70(1)

Study numb er

Or reject

Sponsor can appeal

ACI can start for • Class I, non invasive IIAand non invasive IIB devices After validation and with no negative ethic opinion. • Other devices (invasive IIA , invasive IIB and class III) Notification of approval and with no negative ethic opinion. Article 70 (7)

Process of Clinical Investigation Review- cooperation (voluntary process for MS until 2027)

respond to validationQs 10 days or MSmay extend by amax20 days Article 70 (3)

Approval Or approvalwith conditions Within45daysofvalidation And5days ofFinalAR +50days ifexpertreview requiredforclass IIband III

Validation 7days Validation 7days Validation 7days

MS 1 MS 2 MS n

MS c Valida tion Withi n 10 days of submit

Sponso r files docum

Electronic system PerArticle73

Confirm valid 5days + 5 days

Draft AR 26 days post valid

Final AR 45 days post valid

MS n comme nts by day 38

ents Article70

(Minus thesponsor response time.)

Study numb er

Coordinating MS assigned within6days

MS n can disagree With an approval of MS c BasedonArticle78 (8) Rejection byMS c is

Propose a coordinatingMS. fordevicesthat require assessment Article78

Sponsor respon ds toQs from MS n or MS c <12days

Or reject

• Trial in scope • Documents complete • Article 70(1)

ACI canstart for • Class I, non invasive IIA andnoninvasive IIB devices Aftervalidationandwithnonegative ethicopinion. • Otherdevices (invasive IIA , invasive IIB and class III) Notificationof approval andwithnonegative ethic opinion. Article70 (7)

applicable to allMS n

Sponsor can appeal

Changes to documents/ trial

If documents submitted change, provide to electronic system within 7 days (tracked). Article 70 (2)

Substantial modifications (Article 75)

Implement modification 38 days from notification unless • MS requires +7 days to consult experts

Sponsor files Documents (Tracked) with explanation Within 7days

MS 1 MS 2 MS n

Electronic system PerArticle73

• MS indicates a refusal • Or • Ethics negative opinion

If a coordinated assessment: MS n but can only reject as per article 78(8)

will comment on the documents in their scope ,

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CE marked devices – used per label but additional procedures (article 74)

E.g. Post market clinical follow up (PMCF) studies

In the case of implantable devices and class III devices, where clinical investigations have not been performed, the notified body shall check that the PMCF plan is appropriate and includes post market studies to demonstrate the safety and performance of the device. Article 61(4) Sponsor notifies MSs via at least 30 days prior to study start. Electronic system PerArticle73

End of clinical investigation (Article 77)

Temporary halt or early termination • Sponsor informs specificMS within 15 days with justification • If halted for safety reasons inform all concerned MS within 24 hours Scheduled end of the CI • End of CI = LPV unless defined otherwise in the clinicalplan. • inform MS of their LPV within 15 days • Multi country study inform all MS of the LPV of all MS with 15 of the last LPV.

Submit Clinical investigation report (signed by PI) and summary (suitable for the intended user) 3 months from early termination, one year from scheduledend of trial. If one year is not feasible this should be stated in the clinicalplan with justification.

The reports will become publicallyavailable immediately in the case of an early termination, otherwise when the device is registered or after 1 year which ever is earliest.

Adverse event reporting Record • AEs critical to the evaluation • SAEs • Device deficiencies that might have led to an SAE • Relevant new findings Report to all concerned MS (via portal) • SAE causally related to the device, comparator or procedure • Device deficiency that might have led to SAE • Events in non EU countries involved in the CI Timeline • Without delay: an initial to allow that and follow up report

If a PMCF investigation then follow marketed product reporting rules

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