Essentials of European Medical Device Regulatory Affairs

Essentials of European Medical Device Regulatory

Affairs 9 July 2019 Programme

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

Presentation

Presenter

Time

10.00 Registration and Coffee

Samantha Cooper

10.30 Welcome from TOPRA

Janis Bayley

10.35 Introductions

Janis Bayley

10.45 Module 1: What is a Device?

Janis Bayley

11.20 Module 2: Who is who

11.45 Coffee break

Theresa Jeary

12.00 Module 3: Legislation

Janis Bayley

12.30 Module 4: Classification of devices

13.00 Lunch

Theresa Jeary

13.45 Module 5: Conformity Assessment

Janis Bayley

14.45 Module 6: Device Labelling

15.15 Coffee break

Janis Bayley

15.30 Module 7: Clinical considerations

Theresa Jeary

16.00 Module 8: Post Marketing

17.00 Close of Meeting

July 2019

Essentials of European Medical Device Regulatory Affairs

Janis Bayley Eli Lilly and Company Theresa Jeary SFL Regulatory Affairs

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 Directives • Legislation of combination products • Revision of the directives

• Guidelines (MEDDEVs) • Harmonised standards

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

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)

40

• Regulation rather than a directive - to improve consistency in interpretation • Introduction of a risk based classification system for IVD’s. • Inclusion of some new classes of MDs - e.g. like products utilizing non-viable cells of human origin • Clarify: • Regulatory status of some borderline products • Basic concepts related to clinical investigation and evaluation • Requirement for Increased testing of marketed devices • Strengthening oversight of NBs - improve consistency • Improvements in monitoring performance in the market of MDs e.g. like central reporting of incidents by manufacturers • Improved coordination of CAs in the areas of vigilance and market surveillance • more audits of manufacturing sites with unannounced inspections • Improved traceability - throughout the supply chain • EC will chair and provide logistical and technical support for the new MD Coordination group (MDCG). • Rolling introduction of implanting acts. NB requirements, Eudamed, UDI. Main changes (not all)

41

Current products need to comply to MDR

2014 Device No.1 Certified under  current MD  Directive

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

2023 Device No.1 Certified under  new MD  Regulation

2016  Device No.2 Certified under  current MD  Directive

2021  Device No.2 Certified under  new MD  Regulation

2014

2015

2017

2019

2021

2023

2025

Early 2017 Regulations formally adopted and enter into force

Q1 2019 NBs 1 st wave re-

Late 2023 Devices placed on EU market must be certified under new MDR

Q1 2017 NB to start assessing

Late 2019 MDR fully applied

designation, can only issue MDR certs – NB here

against MDR requirements but no new cert to be issued

Q1 2017 to Q1 2019 2 years of pre-assessment to manage

42

IVDR Timeline

2022 Device No.1 Certified under new IVD Regulation

2017 Device No.1 Certified under  current  IVD  Directive

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

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

2022 Device No.2 Certified under new IVD Regulation

2016

2017

2018

2019

2021

2023

2025

Early 2017 Regulations formally adopted and enter into force

2019 NBs 1 st wave re-designation, can only issue IVDR certs - NB here

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

Early 2022 IVDR fully applied

Q2 2017 NB to start assessing

against IVDR requirements but no new cert to be issued

Q1 2017 & Q1 2021 4 years of pre-assessment to manage

43

Implementation – priorities & challenges

European Commission • Eudamed & UDI system • NBOG codes – enabling act published • Expert panels • Implementing / delegated acts (43 in MDR), common specifications and guidance. National agencies • Defining national policy (where there are Member State derogations) • Re-processing • In-house manufacturing • Re-designating NBs – plan needs to be published and consistent across EU for manufacturers and Notified Bodies.

44

Transitional provisions for certificates issued under the old Directives Certificates issued prior to the entry into force of MDR remain valid for the period indicated on the certificate: • Except certificates under Annex 4, Directive 90/385/EEC or Annex IV, Directive 93/42/EEC, which expire at the latest 2 years after the Date of Application (DoA) – EC Type verification Certificates issued during the transition period remain valid for the period indicated (maximum 5 years), but expire at the latest 4 years after the DoA: • Certificate MDD Jan 2020 – expiry May 2024 • Certificate MDD May 2019 – expiry May 2024 Devices legally placed on the market under the Directives prior to the DoA may be made available up to 4 years after that date. • Certificate MDD Jan 2020 - if on market can be sold to May 2024 • Certificate MDD May 2019 - if on market can be sold to May 2024

45

MDD – 93/42/EEC

• 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 

• Total pages: 60.

46

MDR 177 pages

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

47

MDR Annexes

48

Legislation of Integral Products

• Products should be regulated either by the device or medicines review  process.   Not both . • Assess under the primary legislation, general principles of the other legislation  should apply • Medicine with a device  Device portion must meet the relevant essential requirements to annex 1 to directive  93/42/EEC and shall apply as far as safety and performance related features are concerned :  Article 1 (3)  Present the dossier as required by the common technical dossier (CTD). Include device  information in the quality section (Module 3) usually in regional information. • Device with a medicine  Medicine must meet medicinal scientific requirements : Directive 2001/83/EC  Technical file will cross refer to the EU‐wide approved medicinal product or if new medicine  to the CTD medicinal product section submitted

49

Consultation Between Agencies

Agency can gain advice for the portion of the product outside of their expertise.  Device agency can  ask their medicinal product agency and vice versa. http://ec.europa.eu/consumers/sectors/medical‐devices/files/meddev/2_1_3_rev_3‐ 12_2009_en.pdf

For a medicinal product approved via  the centralised procedure consultation with the EMA/CHMP is possible.

http://www.ema.europa.eu/docs/en_GB/docum ent_library/Regulatory_and_procedural_guideli ne/2009/10/WC500004337.pdf

more formal input required with article 117 MDR. manufacturers of administrative devices must seek the opinion of a Notified Body regarding  the conformity of the device component of the product.

1 st EMA guidance issued February 2019 https://www.ema.europa.eu/en/news/first‐guidance‐new‐rules‐certain‐medical‐devices Draft guideline on the quality requirements for drug‐device combinations published 3 June 2019 https://www.ema.europa.eu/en/quality-requirements-drug-device-combinations

50

Guidelines -MEDDEVs

2.1 Scope, field of application, definition (6) 2.2 Essential requirements (2) 2.4 Classification of Medical devices 2.5 Conformity assessment procedure - General rules (5) - 2.7 Clinical investigation, clinical evaluation (5) 2.10 Notified bodies (1 + 4 annexes) 2.11 Products using materials of biological origin 2.12 Market surveillance (2) 2.13 Transitional period (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

51

Harmonized Standards

• A harmonised standard is a European standard developed by a recognised European Standards Organisation: CEN, CENELEC, or ETSI. • Medical device arena is very broad - thousands of products, need to be grouped • Developed by consensus: • Created following a request from the European Commission to one of these organisations. • Manufacturers, other economic operators, or conformity assessment bodies can use harmonised standards to demonstrate that products, services, or processes comply with relevant EU legislation. • The references of harmonised standards must be published in the Official Journal of the European Union. • Use of standards to demonstrate compliance to essential requirements is voluntary • Where used, notified bodies presume compliance to directive • Standards are listed in the Official Journal of the European Union https://ec.europa.eu/growth/single-market/european- standards/harmonised-standards_en

52

More Information Sources

More Specific Standards • Sterilization • Biological evaluation of medical devices • Medical Electrical safety • Packaging Materials for devices to be sterilized General Standards

• Quality systems • Risk Management • Clinical Investigation of MDs for human subjects Good Clinical Practice • Graphic Symbols • Information supplied by the manufacturer Product Specific Standards • e.g. For Respiratory equipment, Joint replacement implants, Clinical thermometers, Oxygen monitors

53

Module 4

• Classification of devices

• Classification rules

• Reclassification of devices

54

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

55

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:

56

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

57

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)

58

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

59

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

60

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

61

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

62

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.

63

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

64

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.

65

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

68

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:

69

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

70

Module 5

• Conformity Assessment Process

• Specific Requirements

71

Process (Conformity Assessment) 1. Define intended use of the device 2. Classify device 

3. Establish Quality Management System 4. Establish post market surveillance system 5. Choose a conformity assessment procedure  6. Conduct Risk Assessment 7. Prepare technical documentation (incl essential requirement (ER) checklist) 8. Submit to NB if required and get issued certificates 9. Sign the declaration of conformity 10. “Affix” the CE mark and place on the EC market 11. Register the Product (if necessary)

72

Define intended use of the device

‘intended purpose’ means the use for which the device is intended according to the data supplied by the manufacturer on the labelling , in the instructions and/or in promotional materials;

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 – Needs upfront agreement and documentation in the tech file – Needs approval process with regulatory review to prevent ‘drift’

Establish Quality Management System to support device

Usually 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

Establish post market surveillance system

May include:- –

Vigilance process

FSCA process

– – – – –

User / Patient group feedback User / Patient Questionnaires

Input from Scientific Advisory Boards

Post Market Clinical Follow Up

– Remember you may be restricted from direct patient contact – Remember GDPR may affect what you hold as data

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.

Conduct Risk Assessment • Principles

What can go wrong?

How often?

How bad?

Do I need to do something?

What do I need to do?

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

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

Prepare technical documentation

 “ Technical File” demonstrate compliance to the directive  Evidence to show one conforms to the assessment procedure  Evidence of conformity with the Essential Requirements  Prepared and retained by manufacturer – under document control  Auditable  “Design Dossier” if a product falls into Class 3  Content type is the same but extent of detail is usually greater.  Major difference from all other classifications of product submitted to the NB for examination before product can be CE marked  All changes must be submitted prior to implementation

Prepare technical documentation • Technical “File” NB-MED 2.5.1Rec5Rev4 or GHTF STeD – Product description – General Information include accessories, classification with rule, conformity assessment route chosen – List of Standards used to demonstrate compliance – Essential Requirements Checklist – Risk Analysis – Clinical Data – Labelling including Instructions for Use – List of manufacturing sites – what is made where including subcontractors – Manufacturer name and address + Authorised Rep (if applicable) – Declaration of Conformity

Prepare technical documentation • - Technical File Contents

Test and verification reports

–

– Design history from the QMS especially validation reports – Product specifications / drawings from raw materials to finished product – Description of, or reference, to manufacturing processes and procedures – Subcontractor details – Product inspection / release procedures

MDR Defined by Annexes 2, 3, 4, 14 and 15

Essential Requirements

General (as per Annex I) 1. Device to be designed and made to reduce risk when used as intended taking into account the intended users experience.* 2. effective risk management to include protective measures and information for the user 3. Must demonstrate performance 4. Must continue to meet performance throughout the product’s lifetime 5. Must be packed to survive shipment 6. Any undesirable side effects must constitute an acceptable risk when weighed against the performance intended. 6a. Must include a clinical evaluation*

•

Essential Requirements

Requirements regarding Design and Construction

•

7. Consider chemical, physical and biological properties 8. Infection and Microbial Contamination 9. Construction and Environmental Properties 10. Device with a Measuring Function 11.Protection against Radiation 12.Devices connected with an energy source 13. Information supplied by the manufacturer (see later)

MDR: GSPR

MDD: ER AIMDD:ER Other

1 2 3 4 5 6 7 8 9

1, 2, 3 1, 2,6

-

2

8-

-

-

EN ISO 14971

2

6-

1-

-

4 5 6

3-

4EN ISO 11607-2

5-

-

-

MDR Annex XVI

10.1 10.2 10.3

7.1

9ISO 10993 series

7.2- 7.3-

- -

10.4 7.5

-

Regulation 1272/2008, Regulation 1907/2006, Regulation 528/2012

10.5

7.6

9-

10.6 -

-

MDR Annex VIIIRule 19

11.1

8.1

7-

11.2 - 11.3 -

- -

- -

MDR: GSPR • Red: Major changes • Grey: Important Changes • White: Significant Modifications

11.4 11.8 12.1

8.3

7-

8.7-

-

7.4

10Directive 2001/83/EC Directive 2001/83/EC 10Directive 2001/83/EC

12.2 -

-

13.1

7.4

13.2 8.2

-

EN ISO 22442-2 EU Reg 722/2012

13.3 -

-

-

14.1

9.1 9.2

9- 8-

14.2a

14.2b 9.2

8EN 60601-1+A1 EN 60601-1-2

14.2c

7.3-

-

14.2d -

-

EN 60601-1+A1 ISO 800001

14.2e 14.2f 14.2g

7.6- 9.2-

- -

9.2

8-

14.3

9.3-

- -

14.4 -

-

14.5 14.6

14.1

9.1-

10.2-

- -

14.7 -

-

15 10.1, 10.3-

Directive 80/181/EEC

16.1a 16.1b

11.1- 11.4-

- - - - - - - - -

16.2a 11.2.1 - 16.2b 11.2.2 -

16.3

11.3-

8 2013/59/Euratom

16.4a 11.5.1

16.4b -

-

16.4c 11.5.2 - 16.4d 11.5.3 -

17.1 17.2 17.3 18.1 18.2 18.3 18.4 18.5

12.1

12.29, part 7

- -

-

17.4 -

EN 60601-1+A1

12.1- 12.2- 12.3- 12.4- 12.5-

-

EN 60601-1+A1

- - -

What do I do? 1. GSPRs Need New Justification 2. Cross-Referencing across topics to other sections

18.6 -

-

EN 60601-1+A1 EN 60601-1-2

18.7

12.6-

- -

18.8 - 19.1 - 19.2 - 19.3 - 19.4 -

-

8- 9-

11-

12MDR, Article 31

20 12.7

-

EN ISO 14708

EN 45502

20.5 -

-

-

21.1 12.8.1

9-

21.2 12.8.2 -

- -

21.3

12.9-

22 -

-

EN 62366 EN 60601-1-11 EN 62366-1 EN TR 62366-2 EN 60601-1-6

23.1a -

-

23.1b

13.111, 12

- - - -

23.1c -

-

23.1d

13.1-

23.1e - 23.1f - 23.1g -

- - -

EU Reg 207/2012

- EN 980:2008

23.1h

13.2-

IEC 60417 IEC 60878

23.2a 13.3c 14.2, part 2- 23.2b 13.3b, 13.414.2, part 2 - 23.2c 13.3a 14.2, part 1- 23.2d 13.3a - - 23.2e 13.3n 14.2, part 11- 23.2f 7.5- - 23.2g 13.3d 11- 23.2h - - - 23.2i 13.3e 14.2, part 9- 23.2j 13,3 (l) - - 23.2k 13.3i - - 23.2l 13.3c, 13.3- - 23.2m13.3k - - 23.2n 13.3f - - 23.2o - - - 23.2p 13.3g 14.2, part 6- 23.2q 13.3h 14.2, part 5- 23.2r - - - 23.2s 13.3d - - 23.3a 13.3c 14.1, part 2- 23.3b - 14.1, part 7- 23.3c 13.3m 14.1, part 1- 23.3d 13.3a 14.1, part 3- 23.3e 13.3b 14.1, part 4- 23.3f 13.3h 14.1, part 5- 23.3g 13.3g 14.1, part 6- 23.3h 13.3l 14.1, part 8- 23.3i 13.3e 14.1, part 9- 23.3j 13.3i - - 23.4a 13.6a 15 part 2 - 23.4b 13.415 part 2 - 23.4c - - 23.4e 13.6b 15, part 3 - 23.4f - 15, part 2 - 23.4g 13.6e 15, part 2 - 23.4h 13.6d, p - - 23.4i 13.6i - - 23.4j 13.3j, 13.615, part 5 - 23.4k 13.6d, - - 23.4l 13.6g 15, part 8 - 23.4m13.6h - - 23.4n 13.6h - - 23.4o - 15, part 9 - 23.4p 13.6h - - 23.4q 13,6c - - 23.4r 13.6j - - 23.4s 13.6k-m 15 part 2 - 23.4t - - - 23.4u - - - 23.4v 13.6n - - 23.4w- - - 23.4x - - - 23.4y 13.6q 15, part 1-4- 23.4z - - - 23.4aa- - - 23.4ab- - - Absent6a 5a 23.4d - -

MDR Art 32 MDR Art 32

85

MDR Annex XIV Absent7.4 - consu10 - consultaMDR Annex IX, Chapter II, Section 5.2

MDR: GSPR

ANNEX IGENERAL SAFETYANDPERFORMANCEREQUIREMENTS CHAPTER IGENERALREQUIREMENTS

1

Thedevicesmustbedesignedandmanufactured in suchaway that,whenusedunder the conditionsand for  thepurposes intended, theywillnot compromise the clinical conditionor the safetyofpatients,or the  safetyandhealthofusersor,whereapplicable,otherpersons,provided thatany riskswhichmaybe  associatedwith their intendeduse constituteacceptable riskswhenweighedagainst thebenefits to the  patientandare compatiblewithahigh levelofprotectionofhealthand safety . This shall include: *reducing,as faraspossible, the riskofuseerrordue to theergonomic featuresof thedeviceand the  environment inwhich thedevice is intended tobeused (design forpatientsafety),and *considerationof the technical knowledge,experience,educationand trainingandwhereapplicable the  medical andphysical conditionsof intendedusers (design for lay,professional,disabledorotherusers). The solutionsadoptedby themanufacturer for thedesignandconstructionof thedevicesmustconform to  safetyprinciples,  takingaccountof thegenerallyacknowledged stateof theart *eliminateor reduce risksas faraspossible (inherently safedesignandconstruction), *whereappropriate takeadequateprotectionmeasures includingalarms ifnecessary, in relation to risks  thatcannotbeeliminated, * informusersof the residual risksdue toany shortcomingsof theprotectionmeasuresadopted. Thedevicesmustachieve theperformances intendedby themanufacturerandbedesigned,manufactured  andpackaged in suchaway that theyare suitable foroneormoreof the functions  referred to inArticle1 (2)  (a),as specifiedby themanufacturer. The solutionsadoptedby themanufacturer for thedesignandconstructionof thedevicesmustconform to  safetyprinciples, takingaccountof thegenerallyacknowledged stateof theart * eliminateor reduce risksas faraspossible  (inherently safedesignandconstruction), *whereappropriate takeadequateprotectionmeasures includingalarms ifnecessary, in relation to risks  thatcannotbeeliminated, * informusersof the residual risksdue toany shortcomingsof theprotectionmeasuresadopted.

 1.             Devices shallachieve theperformance intendedby theirmanufacturerand shallbedesignedand  manufactured in suchaway that,duringnormal conditionsofuse, theyare suitable for their intendedpurpose .  They shallbe safe  and  effective  and  shall  not  compromise  the  clinical  condition  or  the  safetyof  patients,  or   the  safety  andhealthofusersor,whereapplicable,otherpersons,provided thatany riskswhichmaybe  associatedwith theiruse constituteacceptable riskswhenweighedagainst thebenefits to thepatientandare  compatiblewithahigh levelofprotectionofhealthand safety,  taking intoaccount the generallyacknowledged  stateof theart.

2

1.             Devices shallachieve theperformance intendedby theirmanufacturerandshallbedesigned  andmanufactured  in suchaway that…

3

 2.            The requirement in thisAnnex  to reduce risksas faraspossible means the reductionof risksas faras  possiblewithoutadverselyaffecting thebenefit‐risk ratio.

2

(f)   based  on  the  evaluation  of  the  impact  of  the  information  referred  to  in  point  (e),  if  necessary   amendcontrolmeasures in linewith the requirementsofSection4. 4.            Risk controlmeasuresa doptedbymanufacturers for  thedesignandmanufactureof  thedevices shall  conform to  safety  principles,  taking  account  of  the  generally  acknowledged  state  of  the  art.   To  reduce  risks,   Manufac‐ turers shallmanage risks so that the residual riskassociatedwitheachhazardaswellas theoverall  residual risk is judgedacceptable. In selecting themostappropriate solutions,manufacturers shall, in the  followingorderofpriority: (a)  eliminateor reduce risksas faraspossible  through safedesignandmanufacture; (b)  where  appropriate,  take  adequate  protection  measures,  including  alarms  if  necessary,  in  relation   to  risks thatcannotbeeliminated;and (c)  provide information forsafety (warnings/precautions/contra‐indications)and,whereappropriate,  Manufacturers shall informusersofany residual risks.  (c)  estimate  and  evaluate  the  risks  associated  with,  and  occurring  during,  the  intended  use  and   (d)  eliminateorcontrol the risks referred to inpoint (c) inaccordancewith the requirementsofSection4; (e)  evaluate  the  impact  of  information  from  the  production  phase  and,  in  particular,  from  the  post‐ marketsurveillance  system,  on  hazards  and  the  frequency  of  occurrence  thereof,  on  estimates  of   their  associated risks,aswellason theoverall risk,benefit‐risk ratioand riskacceptability;and  3.            Manufacturers shallestablish, implement,documentandmaintaina riskmanagementsystem.  Risk management  shall  be  understood  as  a  continuous  iterative  process  throughout  the  entire  lifecycle  ofa  device, requiring regularsystematicupdating. Incarryingout riskmanagementmanufacturers shall:  (a)  establishanddocumenta riskmanagementplan foreachdevice;  (b)  identifyandanalyse theknownand foreseeablehazardsassociatedwitheachdevice;

2

The solutions adoptedby themanufacturer for thedesignandconstructionof thedevicesmustconform to  safetyprinciples, takingaccountof thegenerallyacknowledged stateof theart

eliminateor reduce risksas faraspossible  (inherently safedesignandconstruction), whereappropriate takeadequateprotectionmeasures includingalarms ifnecessary, in relation to risks that  cannotbeeliminated,

informusersof the residual risks due toany shortcomingsof theprotectionmeasuresadopted.

86