The Medical Devices Introductory Course 2020

The Medical Devices Introductory Course: Principles of Medical Devices Regulation in Europe

Module 13 of the TOPRA MSc Medical Devices

Monday 6 th July to Friday 10 th July 2020

Chairperson:

Jonathan Hughes, JHRA Ltd

All times are UK local (BST)

Monday 6 th July 2020

Sinead Whelan TOPRA

13:00

Introduction from TOPRA

Day 1 Welcome and Introduction

Jonathan Hughes JHRA Ltd

13:10

14:10

Medical Device Classification & Drug Device Borderline

Theresa Jeary SFL Regulatory Affairs

15:30

Break

15:45

Medical Device Classification & Drug Device Borderline (continued)

Theresa Jeary SFL Regulatory Affairs

Wrap up

16:55

Jonathan Hughes JHRA Ltd

17:15

Close of day

Tuesday 7 th July 2020

Jonathan Hughes JHRA

13:00

Case Study 1 Introduction

13:15

Case Study 1 (break to be taken within case study)

15:30

Case Study Feedback

16:00

Case Study 2 – Innovation Preparation

16:30

Close of Day

All times are UK local (BST)

Wednesday 8 th July 2020

Jonathan Hughes JHRA Ltd

12:00

Reconnect & Introduction

Howard Dobbs Howard Dobbs Consulting Ltd

12:10

Conformity Assessment, Technical Documentation & Standards

14:10

Break

Rachel Hattersley Dykes Devdone

14:25

Clinical Evaluation, Clinical Investigation & PMCF

15:40

Break

Simon Richards Abbott Jonathan Hughes JHRA Ltd

15:55

In-Vitro Diagnostics

Wrap up

17:25

17:40

Close of Day

Thursday 9 th July 2020

Jonathan Hughes JHRA Ltd

13:00

Reconnect & Introduction

Jonathan Hughes JHRA

13:05

Case Study 2 Introduction

13:15

Case Study 2 (break to be taken within case study)

15:15

Case Study Feedback

Peter Bowness BSI

15:45

Risk Management

Wrap up

Jonathan Hughes JHRA Ltd

17:30

17:40

Close of Day

All times are UK local (BST)

Friday 10 th July 2020

Jonathan Hughes JHRA Ltd

12:30

Reconnect & Introduction

Priya Tiwari Biogen Idec Limited

12:40

Post Market Surveillance, Device Vigilance & Field Safety Corrective Actions

Break

14:00

Jonathan Hughes JHRA

14:15

Case Study 3 Introduction

14:20

Case Study 3

15:05

Case Study Feedback

Break

15.35

Jonathan Hughes JHRA Ltd

15.50

Beyond CE Marking

Wrap up

Jonathan Hughes JHRA Ltd

17:20

17:30

Close of Meeting

Principles of Medical Device Regulation in Europe

6-10 July 2020

Jonathan Hughes PhD FTOPRA JHRA Ltd jhughesra@gmail.com +44 1494 727101

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Principles of Medical Device Regulation in Europe

Please …

• Take part • Be vocal • Ask questions • Answer questions • Contribute • Share experience • Work as a team • Have fun

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Medical Device Introductory Course Aims

To provide a good appreciation of the regulatory control of medical devices, particularly in the EU, in order to offer effective practical advice on the application of medical device legislation to enable products to be CE-marked.

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Principles of Medical Device Regulation in Europe - Learning Outcomes

Ability to classify devices, distinguish conformity assessment routes and identify key quality, safety and performance requirements to CE Mark a device in the EU

Understanding of the role of the competent authorities and the notified bodies

Confidence to define the requirements of post-market surveillance and vigilance, and the role that risk management plays throughout the device lifecycle

Understanding of the borderline between medical devices and medicinal products

Appreciation of how medical devices are regulated in other key markets.

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Principles of Medical Device Regulation in Europe – Topics Covered:

The changing legislative environment in the EU (MDR and MDD)

Classification, conformity assessment, quality management systems, standards, technical documentation, general safety & performance requirements [“The Route to the CE Mark”]

Clinical evaluation and investigation

Risk management, post-market requirements and vigilance

Drug-device borderline and combination products

In-vitro diagnostics.

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Course / Module Team:

Sarah Roberts – Conference & Accreditation Lead (TOPRA) Kay Platt – Education & Apprenticeship Lead (TOPRA) Laura Brown – Course Director (TOPRA) Samantha Cooper – Director of Professional Development (TOPRA) Jonathan Hughes – Module Advisor / Chair / Speaker (Consultant, JHRA Ltd) Theresa Jeary – Speaker (Consultant, Reg & Scientific Affairs Ltd) Howard Dobbs – Speaker (Consultant, Howard Dobbs Consulting Ltd) Rachel Hattersley Dykes – Speaker (Medical Writer, Dev Done)

Simon Richards – Speaker (VP RA , Abbott Rapid Dx) Priya Tiwari – Speaker (Assoc. Dir. RA (CMC), Biogen) Peter Bowness – Speaker (Technical Team Manager, BSI)

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Who are the Dream Team?

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7

Introductions ...

• Name • Affiliation • Industry / regulatory affairs experience • Experience with medical devices? • Medical Device regulatory experience? • Key objective for this course / what one thing would you like to come away with? PHARMA?

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Medical Devices?

SOURCE: The Museum of Questionable Medical Devices Online http://www.museumofquackery.com/welcome.htm

Medical Technology Test

Are you “using” a medical device right now?

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Medical Technology Test

How many different types of medical device are there on the EU market?

1,000 100,000 250,000 500,000

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Medical Technology Test

How many medical device companies are there in Europe?

10,000

15,000

20,000

25,000

Medical Technology Test

What is the EU medical device market worth?

€70 Billion annually €80 Billion annually €90 Billion annually €100 Billion annually

Medical Technology Test

What new / future medical device technologies are you aware of or are you interested in?

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AI digital systems / Microchip technology enabling real-time / invasive imaging / Smart drug delivery systems / Brain-Computer Interface (BCI) devices / Implantable microprocessor connected with wearable technologies enabling creation of visual imaging for the blind / Smart soft contact lens enabling continuous detection of blood glucose levels / Optogenetics – optical neuromodulation for new therapeutic approaches / Exoskeleton and robotics enabling paraplegic mobility / Imaging technology and e-health enabling alternate surgical procedures with computer graphic aided feedback and delivery / 3-D printing - additive manufacturing using advanced imaging and bioengineering for personalised surgery, organs, tissues, structures, scaffolds and spraying of cells and tissues

Medical Technology Overview

Are you using a medical device right now? How many different types of medical device are there on the EU market? How many medical device companies are there in Europe? What is the EU medical device market worth? What new / future medical technologies are you aware of?

… So what?

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Medical Technology Overview

The medical device industry is … ● diverse ● fragmented ● rapidly growing ● mainly SME ’ s, often with only limited resources (blended RA/QA roles?) ● expanding into novel, rapidly evolving technological areas

Typically medical devices have a short innovation cycle (average 12-24 months) and a short or continuous incremental life cycle development phase (seen as closer to I.T. rather than the pharmaceutical industry, with its extensive development cycle times and investment recovery period) These elements are reflected in the Regulatory legislation applied to devices in the EU ...

So, how are medical devices regulated? Because of the breadth of technologies involved (and likelihood of challenging new technologies, some not yet conceived) ...

Regulatory requirements and controls apply a general risk- based approach that needs to be adaptive to accommodate (and future proof for) this

High

High

Level of Regulatory Control

Product Risk Class

Medium

Medium

Low

Low

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The Pre-Existing EU Medical Device Regulatory Landscape

• Medical Devices have been regulated under “ New Approach ” Directives since the 1990’s

• These involve manufacturers declaring conformance to a diverse range of generic quality, safety, performance and risk-based principles and attaching the “ CE Mark ”

• Except for some higher risk devices, this may be done without a third-party pre-approval assessment of data

• Attaching the “CE Mark” allows the manufacturer to immediately market the device in all Member States of the EU and, in addition, the EFTA markets (and helps achieve registration in many markets e.g.: Turkey, Canada and Australia, with similar requirements)

The 3 Medical Devices Directives Active Implantable Medical Devices Directive

– Directive 90/385/EEC* – Implemented: July 1992 – Pacemakers, neuromodulators and cochlear ear implants

(General) Medical Devices Directive – Directive 93/42/EEC* – Implemented July 1994

In-Vitro Diagnostic Devices Directive – Directive 98/79/EC – Implemented June 2000 – Pregnancy tests, blood glucose monitors, tests for transmissible diseases

[* As amended by 98/79/EC, 2000/70/EC, 2001/104/EC, EC No 1882/2003 and 2007/47/EC]

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The Changing EU Medical Device Regulatory Landscape

• Media Impact - PIP Scandal, undercover NB scam and metal-on-metal hip, surgical mesh implants

• Joint Plan for Immediate Action (“PIP Action Plan”) ● Unannounced audits ... restoring confidence?

 New Medical Device / IVD Regulations

Swixit, Turkxit ..?

•

The EU Medical Device & IVD Regulations 2017/745 & 2017/746

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http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=OJ:L:2017:117:FULL&from=EN

Changing Regulatory Structure in the EU

Active Implantable Medical Devices Directive (90/385/EEC)

In-Vitro Diagnostic Medical Device Directive (98/79/EC)

Medical Device Directive (93/42/EC)

[60 pages]

[37 pages]

In-Vitro Diagnostic Medical Device Regulation

Medical Device Regulation

[177 pages]

[158 pages]

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23

The Changing EU Medical Device Regulatory Landscape

• “Regulation” versus current “Directive” • Key changes include new provisions for: • Classification changes (some devices ”up-classified”) • Person Responsible for Regulatory Compliance • Economic Operators • Unique Device Identification (UDI) / EUDAMED • Increased regulatory scrutiny and oversight (by EU Medical Device Co-ordination Group (MDCG)) • Post-market reporting • Products without a medical purpose • Coupled with extended or reinforced requirements for: • GSPR’s (previously Essential Requirements) • Clinical evaluation • Post-market surveillance • Retains the ‘New Approach’ CE Marking framework, with Notified Bodies as a contracted regulator

Medical Devices - Scope

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The MDD/ MDR – Key ‘ Players ’

EU Commission – develops the legislative framework and policy; interprets and arbitrates where disputes arise / MDR adds MDCG expert group Competent Authority – Member State government agency responsible for monitoring medical devices, reviewing clinical investigation notifications and accrediting ‘Notified Bodies’ in their market Notified Body – an independent, third-party conformity assessment body or test-house responsible for assessing medical devices and their ‘Manufacturers’ for compliance with the requirements of the MDD (70 54 different ones to chose from … for now!) and MDR (only 14 for now). Manufacturer – legal entity responsible for placing device on the EU (EEA) market under their own name EU Authorised Representative (EU-REP) - legal person established in the EU who, explicitly designated by a non-European manufacturer, acts on his behalf in carrying out certain tasks required in the applicable directives. Economic Operators – include manufacturers, EU-REP, importers and distributors

Structure of the Legislation and Key Content Define the requirements and the process of ‘ CE marking ’

Define the ‘ Essential Requirements ’ / ‘General Safety & Performance Requirements’ for quality, safety and performance that all devices must meet before being placed on the market

Provide risk-based classification for medical devices

Outline routes for manufacturers to demonstrate compliance for each classification of medical device: Conformity Assessment Procedures

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The CE Mark

"Conformité Européene"

Devices … must bear the CE Marking of Conformity when they are placed on the (European Union) Market

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The CE Mark

The CE Mark on a medical device indicates compliance with EU regulatory requirements for quality, safety and performance (not efficacy)

The CE Mark is affixed by the ‘ Manufacturer ’ and not by a Notified Body (NB) nor by the EU Commission nor any Member State Competent Authority

Where a NB has been involved in the device assessment then an Identifying Number for that NB is included next to the CE Mark on the product labelling

So, How Do You “Obtain” The CE Mark?

• Qualify your medical device - do you need a CE Mark? • Is it a medical device? Define intended purpose / primary mode of action • Classify your medical device

• Decide on the “conformity assessment” route

• Implement quality management system; contract with NB (if needed) • Conduct and document design development and testing; demonstrate compliance with the “Essential Requirements” / “General Safety & Performance Requirements” • Sign a Declaration of Conformity (obtain certification from NB and/or submit documentation to NB / regulatory body, if required)

• Attach the CE Mark , register and launch … But, don’t forget … post-market compliance ...

Key Post-Marketing Responsibilities

• Risk Management

• Medical Device Vigilance (incident reporting)

• Post-Market Surveillance (PMS), Post-Market Clinical Follow-up (PMCF) and ongoing Clinical Evaluation

• “Field Safety Corrective Action” (FSCA) and “Field Safety Notices”

• Quality Management System – NB Continuous Assessments and Unannounced Audits

• Technical File Maintenance – NB Technical Review sample audits

• National Registration (Notification Listings)

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Key Post-Marketing Responsibilities

• Risk Management

• Medical Device Vigilance (incident reporting)

• Post-Market Surveillance (PMS), Post-Market Clinical Follow- up (PMCF) and ongoing Clinical Evaluation MDR A ditional process / documentation requirements: • PMS Plan, • “Field Safety Corrective Action” (FSCA) and “Field Safety Notices” • Summary of Safety & Clinical Performance, • Periodic Safety Update Reports (PSURs), • Registration via and reporting to EUDAMED database • Quality Management System – NB Continuous Assessments and Unannounced Audits • Technical File Maintenance – NB Technical Review sample audits

• National Registration (Notification Listings)

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Course Programme 6 July 2020

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Please …

● Take part ● Be vocal ● Ask questions ● Answer questions ● Contribute ● Share experience ● Work as a team ● Have fun

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Medical Device Regulatory Affairs

Thank you Any Questions?

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JHRA Ltd +44 1494 727101 jhughesra@gmail.com Jonathan Hughes, Ph.D., FTOPRA

Medical Device Regulatory Affairs

Back–Up Information Slides

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BREXIT: Potential Implications

• For UK-based Manufacturers: • Set up contract with an EU-27 based Authorised Representative (and add them to the device label) • Transfer to an EU-27 based Notified Body (and change NB number on label) • Consider switching “Manufacturer” location to an EU-27 Member State • May need to identify / contract with an importer within EU-27 • For Manufacturers based outside the UK: • No impact, other than may need to meet new requirements to export to / import into UK, depending on regulatory approach adopted by UK for medical devices – contract with a UK-based Authorised Representative (label change), UK Notified Body? (label change) and may need to add “UK Mark” (TBD). Date of MDR application in UK (v. EU27 Delay)?

• For UK-based Notified Bodies EU REPs: • May need to set up a new NB / EU REP within an EU-27 Member State

Key Guidance Documents

• MEDDEV 2.1/3 rev.3 – Drug Device Borderline [and Borderline Manual 1.22, 05/2019]

• MEDDEV 2.1/4 rev. 2 – Borderline and Classification issues

• MEDDEV 2.1/6 rev.1 – Qualification and Classification of stand alone software

• MEDDEV 2.4/1 rev.9 – Classification of medical devices

• MEDDEV 2.7/1 rev.4 – Clinical Evaluation

• MEDDEV 2.12/1 rev.8 – Medical Device Vigilance

• MEDDEV 2.12/2 rev. 2 – Post-Market Clinical Follow-Up

• MEDDEV 2.14/1 rev. 2 – Borderline and Classification issues (IVD)

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Drugs & Devices - A Comparison of Principles & Terminology

DRUGS - Discovery

DEVICES - Design

Fundamental differences and drivers: • Precautionary principle • Chemistry / biology based • Long term / high investment development cycle • Large, multinationals Terminology – the same but different: • Stability testing • Analytical testing • Specifications • Package insert / Patient Information Leaflet Requirements and regulatory elements: • Prescriptive / specific requirements • Current good manufacturing practice (cGMP) • Pharmaceutical development • Insert readability / usability testing • Product characterization and clinical studies • Technology transfer • Toxicology / pharmacokinetics / systemic effects • Clinical phases: 1, 2 and 3 • Pharmacovigilance • Clinical Phase 4 / Post approval studies

Fundamental differences and drivers: • Principle of Proportionality (risk-based) • Engineering / physics based • Fast-paced, rapid innovation cycle • Mostly small midsize enterprises Terminology – the same but different: • Ageing and lifetime studies • Bench testing / physical test methods • Technical drawings / design outputs • Instructions for use / User manual Requirements and regulatory elements: • General, wide-ranging requirements • Quality management systems (QMS / QSRs) • Design controls • Human factors • Design verification and validation • Design transfer • Biocompatibility / contact / local effects • Clinical feasibility / pivotal studies • Medical device vigilance and reporting (MDRs) • Post-market clinical follow-up (PMCF)

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06 th July 2020

Medical Device Classification & Drug Device Borderline

Theresa Jeary, Regulatory & Scientific Affairs Ltd

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Learning Aims

What is and what is not a medical device MDD Vs MDR Definitions Classification rules and guidance – MDD Vs MDR How to determine product classification & its importance Borderline cases

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Medical Device Classification

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

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Medical Device Accessories

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

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Definition of a medical device Directive 93/42/EEC

An instrument, apparatus, appliance, software, material or other article, used on/in human body for the purpose of: – Diagnosis, prevention, monitoring, treatment, 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 principal action by pharmacological, immunological, or metabolic means , but which may be assisted in its function by such means

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Definition of a medical device Regulation 2017/745

Is defined as an 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, predication, 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 of state

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Definition of a medical device Regulation 2017/745 (continued)

And which does not achieve principal action by pharmacological, immunological, or metabolic means , 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 of those referred to in the first paragraph of this point.

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Medical Device Definition Key points

• Principle mode of action must be physical • As opposed to Medicinal products • Must be for use in/on human body • Must have a medical purpose or Annex XVI product under MDR • Can be software if it satisfies the above points • It must not be excluded from the scope of the MDD / MDR

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Active Implantable Medical device

Had its own Directive (90/385 EEC) • One Risk Classification – Class III Now included in the Regulation • Class III All AIMDs must be sold sterile

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IVDs

Medical devices are usually used directly on/in the patient In vitro diagnostic medical devices are used to perform a diagnosis based on a sample taken from the patient • Pregnancy tests • HIV tests • Glucose measuring device • IVDs do not usually touch the patient

IVD Directive 98/79/EEC – Classification is List based

IVDR – Risk Classification introduced

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Classification of Medical devices

Classification in the MDD and MDR MDD Art.9, MDR Art.51 • Class III - highest risk • Class IIb - medium to high risk • Class IIa - medium risk • Class I - lowest risk including measuring, sterile and reusable surgical instruments Im, Is & Ir

Risk classification is based on the manufacturer’s intended purpose

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Classification of medical devices Classification Criteria

MDD, Annex IX, MDR Annex VIII Duration of contact: ● Transient, Short term, Long term Degree of invasiveness: ● Implantable, Surgical, Body orifice

Anatomy affected Active / Non-active

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Classification of medical devices Classification Criteria

Duration of Contact Transient:

< 60 minutes

Short term: Long term:

60 minutes ≤ 30 days

> 30 days

Immediate replacement by similar device is a continuation of original use

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Degree of Invasiveness – MDD & MDR Surgically Invasive Device Classification of medical devices Classification Criteria

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

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Classification of medical devices Classification Criteria

Degree of Invasiveness – MDD & MDR Implantable Device Any device which is intended: — to be totally introduced into the human body or, — to replace an epithelial surface or the surface of the eye, by surgical / clinical intervention which is intended to remain in place after the procedure. Any device intended to be partially introduced into the human body through surgical / clinical intervention and intended to remain in place after the procedure for at least 30 days is also considered an implantable device.

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Classification of medical devices Classification Criteria

Degree of Invasiveness (2) Reusable surgical instrument

an instrument intended for surgical use by cutting, drilling, sawing, scratching, scraping, clamping, retracting, clipping or similar procedures, without connection to any active medical device and which are intended by the manufacturer to be reused after appropriate procedures such as cleaning, disinfection and sterilisation have been carried out

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Classification Rules - MDD

1 - 4

Non invasive devices

5 - 8

Invasive devices

9 - 12

Active devices

13 - 18 Special rules

13: medicinal substance / human blood derivative 14: contraception / prevention of sexual transmissible disease 15: disinfecting, cleaning and rinsing 16: recording X-ray images 17: animal tissue 18: blood bags

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Classification Rules - MDR

1 - 4 Non invasive devices Rule 4 also applies to invasive devices in contact with injured mucous membrane 5 - 8 Invasive devices 9 - 13 Active devices Rule 11 (New): Software (decision making for diagnosis or therapeutic purposes, monitoring of physiological parameters) from Class I to III 14 – 22 Special rules

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Classification Rules - MDR

14 – 22 Special rules 14

medicinal substance / blood derivative

15 16 17

contraception / prevention of sexual transmissible disease

disinfecting, cleaning and rinsing

recording X-ray images 18 animal & human tissue 19 Nanomaterials 20

Invasive devices with respect to body orifices to administer medicinal product via inhalation substance based intended to be introduced into human body

21

via body orifice or skin and are absorbed or locally dispersed 22 active therapeutic devices with a diagnostic function

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MDR Rules 1 - 4

Rule 1: No change Rule 2: Now includes “cells” & clarification that blood bags are class IIb (Blood bags moved to MDR Rule 2 from Rule 18 of MDD) Rule 3: also includes: All non-invasive devices consisting of a substance or a mixture of substances intended to be used in vitro in direct contact with human cells, tissues or organs taken from the human body or used in vitro with human embryos before their implantation or administration into the body are classified as class III. (Inclusion of organ storage solutions, IVF media into the rule which are class III) Rule 4: also includes “mucous membrane”, Replacement of ‘wounds’ with injuries to skin & applies also to invasive devices that come into contact with injured mucous membrane.

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Rule 8: (Up-classification of surgical meshes and spinal devices to Class III) Additional indents: • Active implantable devices or their accessories: Class III • Breast implants or surgical meshes: Class III • Total or partial joint replacements : Class III except for ancillary components such as screws, wedges, plates and instruments • Spinal disc replacement implants or implantable devices that come into contact with spinal column: Class III except for components such as screws, wedges, plates and instruments MDR – Surgical meshes and spinal devices Rule 8

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Classification of medical devices Significant MDR changes

Software - MDR Annex VIII (Rule 11) Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as class IIa, except if such decisions have an impact that may cause: — death or an irreversible deterioration of a person's state of health, in which case it is in class III; or — a serious deterioration of a person's state of health or a surgical intervention, in which case it is classified as class IIb. Software intended to monitor physiological processes is classified as class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as class IIb. All other software is classified as class I.

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Classification of medical devices Significant MDR changes

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

All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, as defined in Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, with action ancillary to that of the devices, are in class III. “liablity to act” wording has been removed from MDD Rule 13 definition

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Classification of medical devices Significant MDR changes

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

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

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Classification of medical devices Significant MDR changes

Nanomaterials MDR Annex VIII (Rule 19) All devices incorporating or consisting of nanomaterial are: ● in class III if they present a high or medium potential for internal exposure ● in class IIb if they present a low potential for internal exposure ● in class IIa if they present a negligible potential for internal exposure

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Classification of medical devices Significant MDR changes

Administration of Medicinal Product via Inhalation MDR Annex VIII (Rule 20)

All invasive devices with respect to body orifices, other than surgically invasive devices, which are intended to administer medicinal products by inhalation are in class IIa However, if their mode of action has an essential impact on the efficacy and safety of the administered medicinal product or if they are intended to treat life-threatening conditions, then they are in class IIb

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Classification of medical devices Significant MDR changes

Substance-based MDR Annex VIII (Rule 21) In class III if they, or their products of metabolism, are systemically absorbed by the human body in order to achieve the intended purpose In class III if they achieve their intended purpose in the stomach or lower gastrointestinal tract and they, or their products of metabolism, are systemically absorbed by the human body In class IIb in all other cases, except if they are applied on skin, in which case they are in class IIa, or If they are applied in the nasal or oral cavity as far as the pharynx, and achieve their intended purpose on those cavities, in which case they are in class IIa

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Classification of medical devices Significant MDR changes

Active Therapeutic Device with a diagnostic function MDR Annex VIII (Rule 22)

Active therapeutic devices with an integrated or incorporated diagnostic function, which significantly determines the patient management by the device are in class III, such as closed loop systems or automated external defibrillators

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MDR Scope Extension

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

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MDR Scope Extension (1/2)

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.

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MDR Scope Extension (2/2)

ANNEX XVI LIST OF GROUPS OF PRODUCTS WITHOUT AN INTENDED MEDICAL PURPOSE REFERRED TO IN ARTICLE 1(2) 4. Equipment intended to be used to reduce, remove or destroy adipose tissue, such as equipment for liposuction, lipolysis or lipoplasty. 5. High intensity electromagnetic radiation (e.g. infra-red, visible light and ultra-violet) emitting equipment intended for use on the human body, including coherent and non-coherent sources, monochromatic and broad spectrum, such as lasers and intense pulsed light equipment, for skin resurfacing, tattoo or hair removal or other skin treatment. 6. Equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain.

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• Sections 1 – 3: Understanding the rules • Section 4.1: Flowcharts: how to classify • Section 4.2 onwards: Rules and examples Guidance on Classification MEDEV 2.4/1

Note: Based on MDD, guidance to be written for MDR

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Rules 1 – 4

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Rule 5

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Rule 6

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Rule 7

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Rule 8

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Rules 9 - 12

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Special Rules 13 - 18

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How to apply the Rules

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

Decision criteria: time, invasiveness, powered or not (active/non-active), presence of medicinal product / animal tissue

All applicable rules must be considered and the highest classification applies

For multipurpose devices the highest class applies

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How to classify your medical device

1. Manufacturer must determine on the basis of the intended purpose 2. Confirm it is a medical device 3. Consider the definitions 4. Consider the implementing rules 5. Decide on the applicable rule(s) 6. All rules must be considered with highest possible classification applying 7. Classify

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Guidance and Disputes

• Guidance in MEDDEV 2.4/1 Rev 9 • Repeats Annex IX • Explains definitions • Gives examples • Disputes • NB and Manufacturer must agree the classification • If they can’t then refer to the CA • MDR details process (Article 51) • CA in Country of Manufacturer involved • CA notifies MDCG and Commission of its decision

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Borderlines cases

Be aware that many Borderlines exist – Cosmetics – Biocides – Medicinal products – PPE – Software

Scientific data to support the primary mode of action is required where more than one mode of action occurs Intended purpose is key

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Importance of Classification

• Determines the Conformity assessment route selection • Level playing field for Manufacturers • Consistent decision making

• Regulatory compliance • Data exclusivity and IP • Protection of Public Health

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Conclusion on Classification

• Based on manufacturers intended purpose • Look at the product • Read the label • What are the ingredients and what is their function ? • Medical device classification is risk based and determined by the manufacturer’s intended use. • Medical device manufacturer is responsible for compliance

to law as stated in the Declaration of Conformity • Many borderline areas so discuss with experts

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Any Questions?

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Drug Device Borderline Products in the EU

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What is a combination product ?

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What is a Combination product ?

• Medicinal Product containing a mixture of different APIs? • Product containing a combination of different technologies? • FDA have a definition as per CFR 21 3.2 (e) • Not defined in the EU and no such definition exists

The focus for todays session is the combination of a drug with a medical device

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Growth Area of Combination Products

Healthcare delivery is changing ● Care is moving from hospital to community and patients` homes Technological progress sees new ways of combining drugs with devices to improve product delivery, site of delivery and patient acceptability Drug delivery more patient friendly and patient focused Performance of the medical device can be enhanced by adding a medicinal substance Companion diagnostics identify patients most benefit from a drug Market expected to be $110 billion in 2020, increased from $22 billion in 2014

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Well established combinations

Pen injectors Metered dose inhalers Drug patch delivery systems Coated catheters Drug eluting stents Medicated bone cements Medicated dressings and plasters

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Newer Combinations

Laser activated drugs Bead technologies for cancer treatment Needle free delivery systems Nanotechnology drug delivery devices

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EU Legislation of Combinations

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Legislation

Medicines Medicinal Product Directive 2001/83/EC (MPD)

Medical Devices Directives 93/42/EEC (MDD), 98/79 (IVD) and 90/385 (AIMD) as ammended or MDR 2017/745

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Medicines

Medical Devices

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Comparison of Regulatory Systems

Medical Device CE mark allows access to all EU & EFTA Countries, without national measures Based on quality, safety, performance and risk/benefit Compliance with ERs / GSPRs underpinned by EU and International standards NBs verify that manufacturers meet requirements Level of scrutiny / Costs vary between NBs and Device Risk Classification Timescale for review varies between NBs Proportional approach

Medicinal Product Single market (for centrally authorized products) and individual MS participate in approval process (i.e. CHMP) Based on quality, safety, efficacy and risk/benefit Compliance with prescriptive data requirements underpinned by guidelines CA assesses and authorises each individual product High regulatory approval costs Same procedure applies to all products Timescale for review prescribed in legislation Precautionary approach

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Overlap of Legislation when combining a drug and medical device

Device Legislation

Medicines Legislation

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EU Legislation

• Combinations of devices and medicines are common but there is no “combination product” classification • A “combination” product is EITHER regulated as a medicinal product or a medical device • The Classification as either a drug or device depends on the principal mode of action & intended use of the product • Need to determine the appropriate regulatory route early in product development

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Types of combinations of a drug and device

No Type

Example

1. Device to administer a drug (not integral part of the device) but cross labeled or co-packaged with the device

2. Device and drug are integral (but not reusable) product.

3. Device and drug as integral product where the action of the drug is ancillary.

4. Device and human blood-derived substance (ancillary) as integral product.

5. Device combined with an Advanced Therapy Medicinal Product (ATMP). 6. Companion diagnostics (CDx): In vitro diagnostic which provides information about drug with which it used.

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Definitions

Medicinal Product Any substance or combination of substances having properties for treating or preventing disease in human beings; or used in or administered to human beings … by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis

Medical Device Any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination…, 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

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In Case of Doubt

Article 2(2) Medicines Directive “In cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a “medicinal product” and within the definition of a product covered by other Community legislation the provisions of this (medicines) Directive shall apply”

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How to classify a product with drug and device

What is the intended use of the product?

How does the product achieve these claims? “Primary Mode of Action”

What scientific data is available to support the primary mode of action?

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Legal Basis for Classification MDR Article 1 (8)

Any device which, when placed on the market or put into service, incorporates , as an integral part , a substance which, if used separately, would be considered to be a medicinal product as defined Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation (MDR). However, if the action of that substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 of the European Parliament and of the Council ( 1 ), as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation (MDR) shall apply as far as the safety and performance of the device part are concerned.

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Legal Basis for Classification MDR Article 1(9)

If the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 , as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation (MDR) shall apply as far as the safety and performance of the device part of the single integral product are concerned.

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Classification where a drug and device are combined in a single product

As a Medical Device The product must meet the definition as a medical device per MDR (EU) 2017/745 The drug must act in an ancillary way to the device The “device” cannot be merely a means of delivering a drug

As a Medicinal Product The product must meet the definition as a Medicinal Product as 2001/83/EEC Device acts in an ancillary way to the Drug

Drug and Device form a single integral product and intended exclusively for use in the given combination and which is not reusable

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What is meant by Integral

A medical device incorporates a medicinal substance as an integral part, if and only if the device and the substance are physically or chemically combined at the time of administration (i.e. use, implantation, application etc) to the patient.

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What is meant by ancillary

Action from the Medicinal Substance

Action from the Device Component

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Classification considerations and common arguments

What claims are made for the product ?

But, it only contains a small amount of drug”  No concept of “amount” of a medicinal substance in the medical device regulations  Inclusion must be justified and scientific data provided to support usefulness “ The drug is not intended to act” “The drug is only included to prevent bacterial contamination of the device” “We are including Human serum albumin rather than a bovine serum which is safer and how can that be a drug?”

Why would the product be used?

How does the product work?

What data is available (relative contribution of constituent parts to overall effects) ?

What are the precedents?

Presentation of product – how will it appear to the public ?

What does the literature say?

What does your website say?

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Guidance on Borderlines

Manual on Borderline Classification

There are differences in interpretations across the Community which can put public health at risk

To improve this situation and have a uniform approach there is a working party on borderline and classification that includes members from

 Commission Services

 Experts of Member States

 Other Stakeholders

Aim of group – provide a form to exchange opinions and reach consensus

Regular meetings held and publication of a Manual on borderline decision

https://ec.europa.eu/growth/sectors/medical-devices/current-directives/specific-areas- development_en

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