Essentials of European Medical Device Regulatory Affairs - October 2019

Essentials of European Medical Device Regulatory Affairs 16 October 2019 Programme

Presenters: Janis Bayley, Eli Lilly & Company and Jane Arnold-Round, NAMSA

Presentation

Time

10.00

Registration and Coffee

10.30

Welcome from TOPRA

10.35

Introductions

10.45

Module 1: What is a Device?

11.20

Module 2: Who is who

11.45

Coffee break

12.00

Module 3: Legislation

12.30

Module 4: Classification of devices

13.00

Lunch

13.45

Module 5: Conformity Assessment

14.45

Module 6: Device Labelling

15.15

Coffee break

15.30

Module 7: Clinical considerations

16.00

Module 8: Post Marketing

17.00

Close of Meeting

October 2019

Essentials of European Medical Device Regulatory Affairs

Janis Bayley

Eli Lilly and Company

Jane Arnold-Round NAMSA

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Agenda • Housekeeping

• What is a Device? • Who’s who – Key Stakeholders • Legislation • Classification of Devices • Conformity Assessment • Device Labelling • Clinical Evaluations • Post Market Requirements

2

Learning Outcomes

• To provide a basic understanding of European medical device  regulatory requirements and how to ensure compliance

New regulations were published June 2017 Aim today is to highlight some key changes as we discuss the current and the future legislation

Future learning opportunities: • TOPRA Introductory course (two days with case studies) • TOPRA MSC Medical Technology

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)

4

Module 1

• What is and what is not a medical device 

• Medical Device definitions

• Medicinal Products

• Combination/integral products

• Borderline Products

5

Is the Product a Medical Device?

It could be a :

• Cosmetic Product

• Medicinal Product

• Biocide Product

• Toy

• New regulations acknowledge deciding where a product is regulated can be difficult !

6

Medical Device Definition:

‘medical device’ means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of: - diagnosis, prevention, monitoring, treatment or alleviation of disease, - diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap, - investigation, replacement or modification of the anatomy or of a physiological process, - control of conception, And which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means , but which may be assisted in its function by such means.

Ref: Council Directive 93/42/EEC 

7

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 8

Scope change

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. This Regulation shall also apply, as from the date of application of common specifications The necessary common specifications shall be adopted by 26 May 2020. They shall apply as from six months after the date of their entry into force or from 26 May 2020, whichever is the latest.

•

Ref: Regulation 2017/745

9

IVD MD Definition: “‘in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information: — concerning a physiological or pathological state, or — concerning a congenital abnormality, or — to determine the safety and compatibility with potential recipients, Or — to monitor therapeutic measures.”

10

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.

11

Guidance Documents

http://ec.europa.eu/growth/sectors/medical-devices/guidance_en MEDDEVS for medical device directive. Guidances under development for the regulation.

12

Other Guidance

• Notified body (if you have one) • National Competent Authorities (CA) obliged to render decisions for any individual product (if asked) - Note: European opinion may differ • Borderline and Classification Medical Devices Expert Group - CA and industry represented . - MDEG can help with an opinion - Guidelines, not legally binding - Provides a potential common position for Member States - Note: US /Japan opinions on classification sometimes differ • European Court of Justice (“the Court”) the authoritative interpretation of Community law.

13

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

14

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; For example:- • 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 ! Ref: Council Directive 93/42/EEC

15

Medical Devices for Drug Delivery

Examples:-

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

16

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

17

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 .

18

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

19

Integral 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: 93/42/EEC article 1(4)

20

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

21

An example…………

Reusable insulin pen • Insulin cartridge (medicine) is put into 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

Prefilled insulin pen • The insulin cartridge is fixed in the pen • Several injections, the entire pen is discarded once empty (medicine)

22

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 ie 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.

23

IVD examples

IVD • Pregnancy testing kits • Specimen collection tubes • Blood analysis (ABO, rhesus) • Companion diagnostics ----------------------------------------- Not IVD • Research use only – biomarkers • Breathalyzers • Laboratory reagents (unless diagnostic)

24

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.

25

Exercise 1

• Medical device or not a medical device?

• A potential question for the regulatory department

26

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

Macleans, Sensodyne and rings are trademarks of GSK

27

Module 2

• Who’s who? Key Stakeholders

– Regulatory Agencies – Competent Authorities

– Notified Bodies

– European committees and organizations

– Companies

28

European Regulatory Agencies European  Commission (EC) 

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 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/

29

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)

30

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 Guidance on law (e.g. classification) • Can ask the EU Commission for a classification decision – (MDEG) • Inspect, Audit and “deNotify” NB , including during NB activities • 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)

31

Notified Body (NB) • Evaluate manufacturer’s compliance to legislation • Issue certification (EC) to permit CE marking of a device • NB’s tend to be private sector companies • Company chooses its NB body: provided they are designated in that device  area. • NBs listed per directive • http://ec.europa.eu/growth/tools‐databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=13 • National Standards Authority of Ireland (NSAI)

1 Swift Square, Northwood, Santry, Dublin 9, Ireland Phone : +353.1.807.38.00 Email : info@nsai.ie Website : www.nsai.ie Notified Body number : 0050

• NB may sub contract but retains responsibility • Involvement increases with higher classification • NB number appears on labelling  • IMPACT OF BREXIT in choice of NB

32

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

33

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. • MDCG will have subgroups

• 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)

34

Notified Body Operations Group (NBOG) • Membership – European Commission – Member States’ CA – NB representatives by invite only • 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

35

TEAM-NB

36

In the Company 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 European Authorised Representative If LM is outside community • established in the Community • Contact for CA and NB in the Community instead of the manufacturer • IMPACT OF BREXIT where your AR lives.

Additional in the regulation • Person responsible for regulatory compliance

• importer obligations • distributor definitions

Module 3

• Legislation in Europe • Medical Device Regulation • Transition to the New Regulations • Guidelines (MEDDEVs) • Harmonised standards • Legislation of combination products

38

Current _ EU Medical Device Directives

• Medical device directive   MDD

Directive 93/42/EEC Directive 90/385/EEC

• Active implantable medical devices AIMD • 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

Directive 2004/108/EC Directive 89/636/EEC

• Personal protection equipment

39

Regulation 2017/745 MDR Regulation 2017/746 IVDR

3 year transition period Ends May 2020

Medical Devices  Directive  (MDD)

Medical Devices  Regulation  (MDR)

Active Implantable  Medical Devices 

Directive  (AIMDD)

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

In Vitro Diagnostics  Directive  (IVDD)

40

Key changes (not all)

New: • Inclusion of some new products in scope • Products utilizing non-viable cells of human origin • Products without a medical purpose • Economic operators – requirements for distributors and importers • UDI system – Unique device identifiers • EU registration system • Electronic databases • Additional centralised review processes for high risk devices • Responsible Person • Risk based classification system and certification for IVD’s Greater emphasis: • oversight of NBs • Clinical data • PMS/PMCF

41

MDD vs MDR

• 35 Recitals (background, justification, scope) • 23 Articles (describes general principles, definitions) • 12 Annexes (specific requirements) • I: essential requirements • II to VII: procedures to demonstrate conformity 

• VIII: devices for special purposes • IX: definitions , classification rules • X: clinical evaluations • XI: notified bodies • XII: CE mark 

MDR  • 10 Chapters • 123 Articles • 17 Annexes Total Pages: 175

• Total pages: 60

42

MDR

Articles

Chapter

101 Recitals

I

1‐4

Scope and definitions

II

5‐24

Making available on the market and putting into service of device,  obligations of economic operators, reprocessing, CE marking and free  movement Identification and traceability of devices, registration of devices and of  economic operators, summary of safety and clinical performance,  European data base on medical devices.

25‐34

III

35‐50 51‐60 61‐82

IV

Notified bodies

V

Classification and conformity assessment

VI

Clinical evaluation and clinical investigation

83‐100 101‐108 109‐113 114‐123

VII

Postmarket surveillance vigilance and market surveillance

VIII

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

IX

Confidentiality, data protection, funding and penalties

X

Final provisions

43

MDR Annexes

Annex I

General safety and performance requirements  (GSPR) Technical documentation requirements Technical documentation on post market  surveillance (PMS)

Annex II  Annex III 

Annex IV  Annex V Annex VI  Annex VII  Annex VIII 

Declaration of conformity (DOC)

The CE Mark

Registration requirements and UDI

Notified Body requirements

Classification rules

44

MDR Annexes

Annex IX  Annex X Annex XI  Annex XII 

Conformity Assessment  – Quality Management System

Conformity Assessment  – Type Examination

Conformity Assessment  – Product Conformity Verification

Certificates issued by a Notified Body

Annex XIII  Custom‐made devices  Annex XIV  Clinical evaluation and 

Post market clinical follow up (PMCF)

Annex XV  Clinical investigations Annex XVI  List products without a medical purpose  Annex XVII  Correlation table with the MDD

45

The Transition Period and “The Grace Period”

46

The Transition Period and “The Grace Period”

Article 120 MDR and Article 110 IVDR Certificates issued under the directives: Certificates issued prior to 25 May 2017 remain valid for the period indicated on the certificate except: • MDD Annex IV certificates void 27 May 2022 • AIMD Annex 4 certificates void 27 May 2022 • IVD Annex VI certificates void 27 May 2024 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

47

Transitional provisions “The Grace Period”

Devices placed on the market under the Directives :

MDs, AIMDs and IVDs 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/IVDR requirements for PMS, vigilance and registration apply from the end of the transition period

• Must remain in compliance with the MDD/AIMD or IVD • No significant changes in design and intended purpose

• There is no “grace period” for Class I devices which do not require a certificate i.e. they need to comply with the MDR from 26 May 2020

48

MDR Transition timing

2014 Device No.1 Certified under  current MD  Directive

2019  Device No.1 Re‐certified under  current MD  Directive or MDR

2024 Device No.1 Re‐certified under  MDR

2016  Device No.2 Certified under  current MD  Directive

2021  Device No.2 Re‐Certified  under MDR

2015

2017

2019

2020

2021

2024

2025

May 2017 Transition period starts

Q1-Q3 2019 NBs re-designation under MDR so far 5 only NBs can issue MDR certs

May 2024 All MDs must be certified under new MDR

May 2020 Transition period ends

49

IVDR Transition timing

2017 Device No.1 Certified under  current  IVD  Directive

2022 Device No.1 Re-certified

2020 Device No.1 Re-certified under current IVD Directive or IVDR

2022  Device No.2 Re‐certified under  IVDR

2019 Device No.2 Certified under  current IVD  Directive or IVDR

under IVDR

2016

2017

2018

2019

2021

2023

2025

May 2017 Transition period starts

Early 2025 Devices placed on EU market must be certified under new IVDR

2019 NBs re-designation so far No NBs can issue IVDR certs

May 2022 Transition period ends

50

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 about my new devices?

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

51

Implementation – priorities & challenges

• Notified Body Resource

• Eudamed & UDI system

• Expert panels

• Implementing / delegated acts (43 in MDR), common specifications and guidance.

52

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)

http://ec.europa.eu/growth/sectors/medical‐devices/guidance_en

53

Guidelines MDR-MDCG Documents UDI

Issuing entities, application (9)

EUDAMED

Timelines, legacy devices (2)

Notified Bodies Designation, certificates (2 + 10 NBOG) Clinical Investigation SSCP: Summary of safety and Clinical and Evaluation Performance (1) Other Topics: - Responsible Person - Implant Cards - Article 54(b) expert panel exemptions

https://ec.europa.eu/growth/sectors/medical‐devices/new‐regulations/guidance_en

54

Harmonized Standards • A harmonised standard is: • a European standard developed by a recognised European Standards Organisation: 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

55

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

56

Legislation of Combination Products

?

Devices MDD/MDR

Drugs: 2001/83/EC

Physical

Stent

Drug eluting stent

Sirolimus

57

Legislation of Combination Products Products should be regulated either by the device or medicines review process.   Not both . Combination devices under the MDR: • 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 Excluded: Antimicrobial wound contact layer –primary purpose is the medicinal action Borderline: haemostats

Combination devices under the MDR are class III under rule 14

58

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) 

59

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

60

Module 4

• Classification of devices

• Classification rules

• Reclassification of devices

61

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

62

Classification – Key Concepts

Rules apply according to intended purpose - :

Duration:

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:

63

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: Directive 93/42/EEC Annex IX Sect 2.6 Chapter II

64

Active Medical Device • Any medical device operation of which depends on a source of electrical energy or any source of power other than that directly generated by the human body or gravity and which acts by converting this energy. • Hearing aids, TENs machines, light boxes to treat SAD • Stand alone software is considered to be an active medical device. Ref: Directive 93/42/EEC Annex IX Sect 1.4 An active non implantable regulated by this directive. Active implantable regulated by Directive 90/385/EEC

MEDDEV 2.1/6 Guidance on software (what is and what is not a medical device)

65

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

66

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

67

Currently - 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

68

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

69

Reclassification Process

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.

70

EU Directives for Reclassification • Reclassification of breast implants: http://eur- lex.europa.eu/LexUriServ.do?uri=OJ:L:2003:028:0043:004 4:en:PDF • Reclassification of hip, knee and shoulder joint replacements: http://eur- lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:21 0:0041:0043:en:PDF

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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 and MDR. Plan for any change.

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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

MDR- Software rule 11

If such decisions have an impact  that may directly or indirectly  cause: – the death or an irreversible  deterioration of the state of health ‐ a serious deterioration of the state  of health or a surgical intervention

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

Class III

Class  IIa

Except

Class  IIb

Software intended to  monitor physiological  processes.

‐ If it is intended for monitoring of  vital physiological parameters, where  the nature of variations is such that  is could result in immediate danger  to the patient.

Class  IIa

Except

Class  IIb

All other software

Class I

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IVD classification

Is a Notified Body Required? Yes:  design dossier review (includes compliance to common technical  standards) Audit of Quality Management System  Batch released by the NB Yes: Audit of technical documentation & quality management system

Annex II List A

HIV Hepatitis ABO blood grouping

Annex II List B

Rubella  PSA*  self test for blood glucose

Self Test

Pregnancy self test

Yes: review of design & labelling for lay user  suitability

General

Test for hormones cardiac markers hematology and clinical chemistry tests

NO: Manufacturer self declares

* only cancer test listed

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IVDR classification

Is a Notified  Body  Required?

Class D

Blood screening for life threatening entities e.g. suitability  for transfusion

Yes

Class C

Detection of infectious agents Selection of patients e.g. companion diagnostics Genetic testing Diagnosis of cancer

Yes

Self testing (critical outcome) Blood glucose determination Self testing ( noncritical outcome) Anything not in A, C and D Reagents Instruments for IVD procedures Specimen receptacles

Class B

Yes

Class A

NO:

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Classification Exercise

Product

Non Invasive (1,2,3,4) Invasive (5,6,7,8) Special rules (13‐18)

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

Rule

Classification

A Hydrocolloid (creates a moist  environment) plasters B Corrective daily contact  lenses C Corrective contact lenses  continuous wear for a year

Non‐invasive

Short term

Invasive (in a body orifice) Invasive (in a body orifice)

Short term

Long term

D Device for self 

Surgically invasive Transient

administration of a medicine  (not infusion, but short)

E Dentist hand held mirror

Invasive

Transient

F Contact lens solution

Special rule

G Breast implants

Surgically invasive Long term

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Module 5

• Conformity Assessment Process • Key Requirements: - 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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Define intended purpose of the device

‘intended purpose’ means the use for which a device is intended according to the data supplied by the manufacturer on the labelling , in the instructions or in promotional or sales materials or statements and as specified… in the CER”

intended use indications contraindications warnings and precautions claims and benefits

who user whom patient

expertise

population where environment environment when concomitant compatibility

Align marketing materials with technical information and CER – Needs upfront agreement and documentation in the tech file – Needs approval process with regulatory review to prevent ‘drift’

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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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Establish Quality Management System (QMS)

EN ISO 13485 – the harmonised standard – Framework for the policies, procedures, work

instructions, records etc., that are needed to bring your device to market. – Includes regulatory requirements (vigilance, Field safety corrective actions (FSCA), risk management etc.) – Needs to be assessed and certificated – Watch out: • Ensure scope of QMS certification covers the devices you wish to CE mark • Ensure all activities are covered between yours, your suppliers and distributors certificates

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Conformity Assessment Procedures: Annex IX to XI

Annex IX • Based on QMS & Assessment of Technical Documentation – Chapter I (1-3): QMS – Chapter II (4-6): Technical documentation – Chapter III (7-8): Administrative provisions • QMS audit every 12 month (minimum) • QMS certificate • Significant changes to QMS /device range require approval • Additional requirements some devices: – Technical document certificate - class III and some IIb – Additional assessment processes for some devices (section 5)

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Conformity Assessment Procedures: Annex IX to XI

Annex X • Based on Type Examination • Assessment of the technical documentation • Assessment and testing of device – representative sample – Notified Body tests the device (or manufacturer) – Type examination certificate • Any changes to the device design require approval • Additional assessment processes for some devices (annex IX section 5)

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Conformity Assessment Procedures: Annex IX to XI

Annex XI • Product Conformity Verification • Linked to type examination • Follow Part A or Part B: • Part A: Production Quality Assurance – QMS (excluding design processes) – Technical documentation • Part B: Product Verification – NB Examines and tests every manufactured device – documented manufacture process – PMS – EU product verification certificate

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Conformity Assessment Procedures - Options

87

Conformity Assessment Procedures - Options

88

Conformity Assessment Procedures - Options

Custom made devices: • Annex XIII • Class III: + QMS (via Annex IX or Annex XI Part A)

89

Conduct Risk Assessment

ISO 14971 Harmonised standard

•

• Risks need to be eliminated or reduced risk as far as practicable • Any remaining residual risk must be outweighed by the benefits associated with the device – risk benefit analysis. • Risk Assessment required throughout the product life cycle -Pre market AND post market. • EU specific requirements/deviations

90

Conduct Risk Assessment • Principles

What can go wrong?

How often?

How bad?

Do I need to do something?

What do I need to do?

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Conduct Risk Assessment • 3 phases

PREPARATION AND PLANNING IdentifyTeam PrepareRisk AssessmentPlan

PHASE 1

RISK ASSESSMENT Identifyhazards Identify causes Identifyharm Listexisting controls Assess risk

PHASE 2

Determine risk acceptability Develop recommendations

REVIEW AND FOLLOW- UP Review recommendations Implement additional measures Re-assess risk

PHASE 3

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Conduct Risk Assessment

Product not Corporate Requirements • Irreversible injury or fatality never ok • Frequent minor problems require commercial review • Clear acceptability threshold

Example Risk Matrix

•

High

3 Medium High

9 8 7 6 5 4 3 2 1

2

Low Medium High

(L)

1

Low

Low Medium

Likelihood of Harm

1

2

3

3x3 Risk  Matrix

Severity of Harm (S)

1 2 3 4 5 6 7 8 9

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Prepare technical documentation The Technical File Annex II : 1. Device description and specification, including variants and accessories 2. Information to be supplied by the manufacturer 3. Design and manufacturing information 4. General safety and performance requirements 5. Benefit-risk analysis and risk management 6. Product verification and validation 6.1 Pre-clinical and clinical data 6.2 Additional information required in specific cases PMS documentation Annex III : – PMS Plan – PMCF Plan – PSUR or PMS report

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GSPRs General Safety and Performance Requirements

Article 5 “A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose.” • Similar to the current Essential Requirements • Increase in number from 13 to 23 • Stronger emphasis on risk management and life-cycle • Active devices and software • Labelling requirements significantly expanded

95

GSPRs General Safety and Performance Requirements

96

GSPRs General Safety and Performance Requirements

97

GSPRs General Safety and Performance Requirements

98

GSPRs General Safety and Performance Requirements

99

Submit to NB if required

• 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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• Sign the 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 • Sign only once the technical documentation is complete and necessary CE certificates received • 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

101

Sign the DoC Content of the DoC (Annex IV): 1 • Company Name • Registered trade name /trade mark • SRN if available • EUAR name and address (if applicable) 2 A statement that the EU declaration of  conformity is issued under the sole  responsibility of the manufacturer 3 Basic UDI‐DI 4 • Product and trade name • Unambiguous  reference  allowing   identification and  traceability: Eg Product  code, catalogue  number  Or  Ref to Basic UDI‐DI 5 Risk classification of the device (Annex VIII)

Content of the DoC continued 6 A statement declaring  conformity of the  device with MDR and any  other  relevant   Union  legislation  7 Common Specifications  8 • Notified Body Name and number • Conformity Assessment Procedure • Certificate(s) 9 Any additional information where  applicable 10 • Place and date of issue • Signature • Name and function of person signing • Signed for/on behalf off

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Affix the CE mark and place on the EC market

• All devices must bear the CE mark except: • Custom made devices • Investigational devices • 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

103

Registration- Devices

UDI Database (Article 29)  Assign Basic UDI  Register Basic UDI with core data elements (annex VI)

Who

Device* Class I Class IIa

Assign UDI

Register

Manufacturer

Before placing on the  market

Before placing on  the market

Class IIb non  implantable

Manufacturer

Class III Class IIb implantable

Before conformity  assessment

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

System/Procedure packer Systems and  Procedure packs

Before placing on the  market Before placing on the  market

System/Procedure pack  steriliser

Systems and  Procedure packs

*No registration for Custom made devices

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Registration EOs

EO database (Article 30): 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 before placing the device on the market  For Class III and Class IIb implantable devices SRN

must be obtained prior to NB assessment  Changes - EO must update within 1 week  Competent Authority can charge a fee

105

Module 6

• Device labelling

106

ER 13.1 and 2: Information Supplied by the Manufacturer • Each device must have information suitable for the user to safely use the product • Label (ER 13.3) and instructions for use (IFU) (ER 13.6) • Information to be on the device unless this is not practicable in which case in the IFU • Instructions for use must be included in the packaging for every device. – Exception, Class I or IIa devices if they can be used safely without any instructions. • Must use symbols if claim compliance to EN 980 ISO 15223 • EN 1041 Information to be supplied with a medical device

107

Symbol exercise

Symbol

Meaning

Symbol

Meaning

108