Module 19 2021

©TOPRA ( The Organisation for Professionals in Regulatory Affairs) 2021

Please note that all printed material contained in the course handouts is, unless copyright is assigned elsewhere, the copyright of The Organisation for Professionals in Regulatory Affairs. Such materials are intended for the personal use of the registered students/delegates. Agreement must be reached with the Institute before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form or by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

First Name

Last Name

Company

Country

Novartis Pharma AG - Basel Orchid Orthopedic Solutions

Angelika

Hoenlinger

Switzerland

United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom

Steven

Hollingworth

Saeed

Raoufmoghaddam AstraZeneca - Cambridge

George

Moore-Arthur

MHRA

Lisa

Agyemang

MHRA

Samera

Siddiqui

MHRA

Astellas Pharma Europe B.V.

Wybe

Hoffmann

Netherlands

United Kingdom

Gwyneth Rodrigues

Chriscilia

Tehupeiori

Sakura Finetek Europe B.V. Netherlands

United Kingdom

Lily

Martyn

Genomics plc

Tara

Fahy

Med-Di-Dia Limited

Ireland

Eva

Prevc

Amgen Ltd - Uxbridge

Austria

Module 19: Regulation of In Vitro Diagnostic Medical Devices 1 - 3 June 2021

LOCATION: ONLINE

Module Leader(s) : Nancy Consterdine

Date: 1 - 3 June 2021 Tuesday 1 st June 2021

Time: (BST)

Activity

Speaker

13.00 – 13.30

Introduction and Housekeeping

Stuart Angell

IVDeology

13.30 – 14.30

Lecture 1: Setting the Scene – EU Focus A regulatory and Industry Perspective To include UK CA

Stephen Lee

ABHI

Stuart Angell

IVDeology

14.30 - 15.30

Lecture 2: Classification of IVD Devices

Stephen Lee

ABHI

15.30 - 16.00

Refreshment Break

16.05 – 17.00

Lecture 3: Conformity Assessment:

Gill Morgan

What are the different routes and how does a manufacturer select the route which is appropriate for their device?

17.05 – 18.00

Lecture 4: Quality Management System

Stuart Angell

What is an ISO 13485 QMS? Why is it needed? In which countries is it recognised? What about CMCAS? What about MDSAP?

IVDeology

Date : Wednesday 2 nd June 2021

Module 19: Regulation of In Vitro Diagnostic Medical Devices 1 - 3 June 2021

Time: (BST)

Activity

Speaker

09.00 – 09.30

Review of Day 1: Interactive session to reflect on learnings from day 1, answer any questions and confirm understanding

09.30 – 10.30

Case Study: Apply learnings on classification, conformity assessment and QMS in a group setting using real life examples

Stuart Angell

Nancy Consterdine

10.30 – 10.45

Refreshment break

10.45 – 11.45

Lecture 5: Technical Documentation

Ben Jacoby

What is it? How should it be compiled? What is STED? How to write a DoC

Cambridge RA

11.45 – 13.00

Lecture 6: Performance Data & Product Claims: What is the difference between Scientific Validity, Analytical Performance and Clinical Performance and how should the data be collected and analysed? What is the significance of your claim?

Maurizio Suppo

Lunch

13.00 – 13.45

13.45 – 14.45

Lecture 7: Post Market Surveillance, Vigilance and FSCA

Stephen Lee

ABHI

14.45 – 15.45

Case Study including tea and coffee

Stephen Lee

Apply learnings on PMS, vigilance and FSCA in a group setting using real life examples

ABHI

15.30 – 15.45

Refreshment Break

15.45 – 16.45

Lecture 8: Risk Management

Stuart Angell

What is ISO 14179? When is it needed and why? How to establish a RM policy, procedure and plan. When is a risk acceptable?

IVDeology

Module 19: Regulation of In Vitro Diagnostic Medical Devices 1 - 3 June 2021

16.45 – 17.45

Lecture 9: Registration

Nancy Consterdine

What is required and why? What is EUDAMED and what are the requirements on UDI? Local country requirements versus EU – what is the difference?

IVDeology

Module 19: Regulation of In Vitro Diagnostic Medical Devices 1 - 3 June 2021

Date: Thursday 3 rd June 2021

Time: (BST)

09.00 – 09.30

Review of day 2 Interactive session to reflect on learnings from day 2, answer any questions and confirm understanding Case Study Apply learnings on performance data & product claims in a group setting using real life examples

Nancy Consterdine IVDeology

09.30 – 10.30

Refreshment Break

10.30 – 10.45

10.45 – 12.30

Lecture 10: Other Regulated Markets

Nancy Consterdine IVDeology

Which are they? How are they different? How can we drive harmonisation? Who are IMDRF

12.30 – 13.15

LUNCH

13.15 – 14.15

Lecture 11: Other Legislation Beyond IVDR. What about REACH, RoHS WEEE, GDPR, Machinery Directive and more

Nancy Consterdine IVDeology

14.15 – 14.45

Refreshment Break

Lecture 12: Companion Diagnostics and the IVDR What this means for co- development and personalised medicine

14.45 – 15.45

Shirley Hopper MHRA

15.45

Close of Module

02/06/2021

1

Module 19: IVD Regulation 1 - 3 June 2021

Stephen Lee Director, Diagnostic Regulation ABHI

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Setting the scene

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Setting the scene

• Why regulate? • EU context • IVDR features • EC system changes • Brexit

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Why regulate medical devices? “Regulation is primarily concerned with enabling patient access to high quality, safe and effective medical devices, and avoiding access to products that are unsafe. When appropriately implemented, regulation ensures public health benefit and the safety of patients, health care workers and the community.”

https://www.who.int/medical_devices/safety/en/

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UK Medicines and Medical Devices Act 2021

…the Secretary of State must have regard to— (a) the safety of medical devices; (b) the availability of medical devices; (c) the likelihood of the United Kingdom being seen as a favourable place in which to— (i) carry out research relating to medical devices, (ii) develop medical devices, or (iii) manufacture or supply medical devices.

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IVDR

I INTRODUCTORY PROVISIONS II MAKING AVAILABLE ON THE MARKET … III IDENTIFICATION AND TRACEABILITY OF DEVICES, REGISTRATION … IV NOTIFIED BODIES V CLASSIFICATION AND CONFORMITY ASSESSMENT VI CLINICAL EVIDENCE, PERFORMANCE EVALUATION AND PERFORMANCE STUDIES VII POST-MARKET SURVEILLANCE, VIGILANCE AND MARKET SURVEILLANCE VIII COOPERATION BETWEENMEMBER STATES… IX CONFIDENTIALITY, DATA PROTECTION, FUNDING AND PENALTIES X FINAL PROVISIONS

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Intended medical purpose

Now For the quantitative measurement of rhubarb in human serum on the SL+ instrument. For use in people with specific symptoms to help identify those with stage III rhubarb disease. Only for use by qualified laboratory professionals.

Previously For the measurement of serum rhubarb

Performance Evaluation Report

Analytical performance report

Clinical performance report Clinical performanc e studies Peer

Scientific validity report

Other device

Specimen type

Classification

IVDD risk categories

Examples

IVDR risk classification

Examples

Literature review

Annex II List A

ABO blood groups; HIV infections;

Class D ABO blood groups; HIV infections; Emergency epidemics

Accuracy

reviewed literature Published experience

Annex II List B

Blood glucose self tests PSA PKU Rubella, toxoplasmosis, CMV, chlamydia

Class C

Tests for cancer ; Tests for sexually

Sensitivity/ specificity Measuring range/ cut- off Novel markers

Expert opinion

transmitted infections ; Companion diagnostics; Human genetic tests; Most devices for self- testing Pregnancy self-tests; Cholesterol tests; Urine test strips;

Equivalence ?

Studies

Self testing Devices for self testing

Class B

General

Tests for cancer; Tests for sexually

Class A Clinical chemistry analyser;

transmitted infections; Companion diagnostics; Human genetic tests;

Specimen receptacles;

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https://ec.europa.eu/health/md_sector/contact_en

https://ec.europa.eu/health/md_sector/new_regulations_en

https://ec.europa.eu/health/md_sector/new_regulations/guidance_en

https://ec.europa.eu/docsroom/documents?locale=en&keywords=medical%20device

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EUDAMED

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EUDAMED3

actor registration UDI and device registration notified bodies and certificates clinical investigations and performance studies vigilance and post market surveillance market surveillance

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MDR/IVDR timelines

12 months

2016

2017

… 2020

2021

2022

… 2024

MDR

Original date of application

Revised date of application

Majority of AIMDD/MDD certificates

expire (c10K)

Regulations come into force

Text agreed

IVDR

Date of application IVDD certificates

IVDD certificates expire (c500)

start to expire*

Today

*Most IVDs (c10K+) have no certificate

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IVDR/MDR Notified Bodies

https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=35

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BREXIT, Medical Devices & IVDs

31 st December 2020 26 th May 2021

26 th May 2022

30 th June 2023

UK(NI) Mark UKCA Mark

UKCA Mark UK(NI) Mark

?Transition period?

MDR CE Mark

MDR CE Mark (NI only)

MDD CE Mark

IVDD CE Mark

IVDR CE Mark

IVDR CE Mark (NI only)

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Thank you for listening

Any Questions?

stephen.lee@abhi.org.uk

www.linkedin.com/in/steveleeivd

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Classification

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Classification (1 hour)

• Intended purpose • Risk classes • Classification rules • Case studies

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IVD function

Aid to diagnosis

Screening

Diagnosis

Monitoring disease status

Predisposition/ prediction

Prognosis

Companion diagnostic

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• Qualification – is it an IVD?

‘ in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, piece of equipment, software 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 on one or more of the following: (a) concerning a physiological or pathological process or state; (b) concerning congenital physical or mental impairments; (c) concerning the predisposition to a medical condition or a disease; (d) to determine the safety and compatibility with potential recipients; (e) to predict treatment response or reactions; (f) to define or monitoring therapeutic measures. Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices;

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• Qualification – is it an IVD?

‘accessory for an in vitro diagnostic medical device’ means an article which, whilst not being itself an in vitro diagnostic medical device, is intended by its manufacturer to be used together with one or several particular in vitro diagnostic medical device(s) to specifically enable the in vitro diagnostic medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the in vitro diagnostic medical device(s) in terms of its/their intended purpose(s);

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• MDR or IVDR?

Medical Device

MD accessory

IVD

IVD accessory

IVD accessory

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IVDR requirements

(c) the intended purpose of the device which may include information on: (i) what is to be detected and/or measured; (ii) its function such as screening, monitoring, diagnosis or aid to diagnosis, prognosis, prediction, companion diagnostic; (iii) the specific disorder, condition or risk factor of interest that it is intended to detect, define or differentiate; (iv) whether it is automated or not; (v) whether it is qualitative, semi-quantitative or quantitative; (vi) the type of specimen(s) required; (vii) where applicable, the testing population; (viii) the intended user; (ix) in addition, for companion diagnostics, the relevant target population and the associated medicinal product(s). Annex II 1.1c

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Intended purpose/ intended use

Now For the quantitative

Previously For the measurement of serum rhubarb

measurement of rhubarb in human serum on the SL+ instrument. For use in people with specific symptoms to help identify those with stage III rhubarb disease. Only for use by qualified laboratory professionals.

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Classification IVDD • 20/80

IVDD risk categories

Examples

Annex II List A

ABO blood groups; HIV infections;

Annex II List B Blood glucose self tests Rubella, toxoplasmosis, CMV, chlamydia Self testing Devices for self testing General Tests for cancer; Tests for sexually

transmitted infections; Companion diagnostics; Human genetic tests;

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Classification IVDR

• four risk groups (D,C,B&A) • B, C & D require Notified body scrutiny • significant change (80:20) IVDD risk categories Examples IVDR risk classification

Examples

Annex II List A Annex II List B

Class D ABO blood groups; HIV infections; Emergency epidemics Class C Tests for cancer ; Tests for sexually

ABO blood groups; HIV infections;

Blood glucose self tests PSA PKU Rubella, toxoplasmosis, CMV, chlamydia

transmitted infections ; Companion diagnostics; Human genetic tests; Most devices for self- testing

Self testing Devices for self testing

Class B Pregnancy self-tests; Cholesterol tests; Urine test strips; Class A Clinical chemistry analyser;

General

Tests for cancer; Tests for sexually

Specimen receptacles;

transmitted infections; Companion diagnostics; Human genetic tests;

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Classification IVDR

MDD/MDR

• significant change (80:20) • four risk groups (A,B,C &D) • B, C & D require Notified body scrutiny IVDD risk categories Examples IVDR risk classification

– Some up-classification (eg software) – Same risk groups (I, IIa, IIb, III)

MDD/MDR risk classification

Examples

Premarket scrutiny by a Notified Body

Examples

Annex II List A Annex II List B

Class D ABO blood groups; HIV infections; Emergency epidemics Class C Tests for cancer; Tests for sexually

Class III

Heart valve;

Yes

ABO blood groups; HIV infections;

Blood glucose self tests Rubella, toxoplasmosis, CMV, chlamydia

Class IIb Lung ventilator;

Yes

Bone fixation plate;

transmitted infections; Companion diagnostics; Human genetic tests; Most devices for self- testing

Self testing Devices for self testing

Class B Pregnancy self-tests; Cholesterol tests; Urine test strips; Class A Clinical chemistry analyser;

Class IIa Hypodermic needles;

Yes

Suction equipment; Bandages; Tongue depressors;

General

Class I

No

Tests for cancer; Tests for sexually

Specimen receptacles;

transmitted infections; Companion diagnostics; Human genetic tests;

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• Classification

CLASS

RISK LEVEL (IMDRF)

EXAMPLES

Low individual risk and Low public health risk

Clinical chemistry analyser Prepared culture media

A

10% self certify

Moderate individual risk and/or Low public health risk

Pregnancy self testing Urine test strips

B

R I S K

High individual risk and/or Moderate public health risk

Blood glucose self testing HLA typing PSA screening Rubella test ABO blood donor screening HIV blood diagnostic

C

90% NB scrutiny

High individual risk and High public health risk

D

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Courtesy of Philip Kelly, HPRA

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• Implementing rules

1.1. Application of the classification rules shall be governed by the intended purpose of the devices. 1.2. If the device in question is intended to be used in combination with another device, the classification rules shall apply separately to each of the devices. 1.3. Accessories for an in vitro diagnostic medical device shall be classified in their own right separately from the device with which they are used. 1.4. Software, which drives a device or influences the use of a device, shall fall within the same class as the device. If the software is independent of any other device, it shall be classified in its own right. 1.5. Calibrators intended to be used with a device shall be classified in the same class as the device.

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• Implementing rules (contd)

1.6. Control materials with quantitative or qualitative assigned values intended for one specific analyte or multiple analytes shall be classified in the same class as the device. 1.7. The manufacturer shall take into consideration all classification and implementation rules in order to establish the proper classification for the device. 1.8. Where a manufacturer states multiple intended purposes for a device, and as a result the device falls into more than one class, it shall be classified in the higher class. 1.9. If several classification rules apply to the same device, the rule resulting in the higher classification shall apply. 1.10. Each of the classification rules shall apply to first line assays, confirmatory assays and supplemental assays.

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• Classification rules

NPT classed in own right

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Words are important

Detecting the exposure to … / the presence of … Embryo/foetus/newborn/offspring Life-threatening Screening, monitoring Risk of propagation

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02/06/2021

Thank you for listening

Any Questions?

stephen.lee@abhi.org.uk

www.linkedin.com/in/steveleeivd

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24/05/2021

Conformity Assessment

 Gill Morgan

The Organisation for Professionals in Regulatory Affairs

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Learning Outcomes

 To identify the routes for conformity assessment allowed within the IVDR  To recognise routes linked to product risk classification  To explore the conformity assessment procedure for each route

The Organisation for Professionals in Regulatory Affairs

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Conformity

• Article 17 – EU declaration of conformity – statement that a device conforms with all the relevant requirements of the IVD Regulation. • Conformity assessment procedures are detailed in Annexes IV*, IX, X and XI of the IVDR. • Legal manufacturer chooses the appropriate conformity assessment route (Annex) which will usually include the involvement of a Notified Body to audit and verify that the device does conform to the requirements of the IVDR that apply to it. • Legal Manufacturer signs the DoC having followed the appropriate conformity assessment procedure.

* Annex IV – Declaration of Conformity

The Organisation for Professionals in Regulatory Affairs

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Involvement of a Notified Body

Device class determines Notified Body involvement Class A: Annex IV with no Notified Body involvement ● Exception: sterile Class A IVD Class B: Annex IX ● QMS audit, surveillance audit and unannounced audit ● Technical documentation (product) assessment: representative sample per category of device (not self test or near patient test) Class C: Annex IX or X + XI ● QMS audit with annual surveillance audit and unannounced audit ● Technical documentation assessment: representative sample per generic device group (not self test, near patient test or Companion Diagnostics) Class D: Annex IX or X + XI ● QMS audit with annual surveillance audit and unannounced audit ● Technical documentation assessment for each device ● Verification by Reference Lab ● Batch release managed through notified body

The Organisation for Professionals in Regulatory Affairs

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Conformity assessment options

A B

C

D

EU Declaration of Conformity Annex IV*

Quality Management

Quality Management

Quality Management

Type Examination Annex X (includes Technical Documentation)

Type Examination Annex X (includes Technical Documentation)

System Assurance Annex IX Ch I & III

System Assurance Annex IX Ch I & III

System Assurance Annex IX Ch I & III

* Except sterile

Assessment of Technical

Assessment of Technical

Assessment of Technical Documentation * Annex IX Ch II

Production Quality Assurance Annex XI

Production Quality Assurance Annex XI

Documentation per category device § - Annex IX Section 4

Documentation per generic device § - Annex IX Section 4

* Assessment of technical documentation - Class D, Class B, C, D self test and near patient tests and Companion Dx

For Companion Diagnostics CA consultation Annex IX 5.2 §

For Companion Diagnostics CA consultation Annex X 3

Verification by EU Reference Laboratory

Verification by EU Reference Laboratory

The Organisation for Professionals in Regulatory Affairs

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Definitions from MDCG 2019-13

MDCG 2019-13 is the guidance issued for sampling of IVDs for assessment of technical documentation. Allows manufacturers to group together Class B and C devices for the purpose of technical documentation review.

Category of Device – As defined by the relevant IVR codes according to Regulation (EU) 2017/2185 designation codes for Notified Bodies

Generic Device Group – 3rd level of the EMDN (one letter (W) plus 4 digits with the most appropriate IVP code. MDCG 2019-13 Guidance also allows manufacturer and NB to group using 4th level (W + 6 digits)

Only Generic Device Group is actually defined in the IVDR – having the same or similar intended purpose or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics

The Organisation for Professionals in Regulatory Affairs

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MDCG 2019-13 (EU) 2017/2185

3rd /4th level of EMDN

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – Class A ● Declaration of Conformity (Art. 17) and Annex IV Meets requirements of Regulation including: ● Risk Management and all relevant General Safety and Performance Requirements (Annex I) ● Performance evaluation (Art. 56 and Annex XIII) ● Quality Management System (Art 10.8) ● Technical Documentation (Annexes II and III) including lifecycle maintenance (Annex III and XIII) ● Incident / Vigilance reporting procedures (Art 82-84) ● No notified body certification required unless for sterile products (either under Annex IX or XI)

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – Class A

Manufacturer’s device

Sterile

Notified Body

Not sterile

Sterility (Annex IX or XI)

EC Declaration of Conformity (Annex IV)

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – Class B Annex IX only route available for Class B devices. Conformity Assessment based upon a Quality Management System and on assessment of Technical Documentation ● Technical documentation assessment prior to issue of EU QMS Certificate – At least one device per category of devices covered by application

● Technical documentation assessed of subsequent devices in group as part of NB surveillance audits over certification period

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – Class B

Notified Body

Manufacturer

Annex IX (Quality Management System and Assessment of TD)

Notified Body issues an EU Quality Management System certificate – including TD assessment

NB #

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – Class C ● EU Quality Management System certificate (Annex IX) – Technical documentation assessment of at least one device made by Notified Body according to the generic device grouping plan – Technical documentation assessed of subsequent devices in group as part of NB surveillance audits over certification period ● OR : EC Type Examination certificate (Annex X) coupled to EU production quality assurance certificate (Annex XI)

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – Class C

Notified Body

Manufacturer’s choice

Annex IX (Quality management system with assessment of technical documentation

EC Type Examination (Annex X)

Production QA (Annex XI)

Notified Body issues an EU Quality Management System certificate (includes TD assessment)

Notified Body issues an EU Type and Production Quality Assurance certificate

NB #

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – Class D

● EU Quality Management System certificate (Annex IX) and EU technical documentation assessment certificate. ● OR : EC Type Examination certificate (Annex X) coupled to EU production quality assurance certificate (Annex XI) ● No sampling, Technical Documentation reviewed and approved by NB for each device. ● Verification of design (conformity to Common Specifications) by EU Reference Lab (pre-approval) ● 60 day review period. NB must receive a positive opinion from the EU Ref Lab ● Batch verification (post-approval)

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – Class D

Notified Body

Manufacturer’s choice

QMS with technical documentation assessment - Annex IX and EU Ref Lab

EC Type Examination (Annex X) and EU Ref Lab

Production QA (Annex XI)

Notified Body issues an EU Quality Management System certificate and an EU Technical Documentation certificate

Notified Body issues an EU Type and Production Quality Assurance certificate

NB #

The Organisation for Professionals in Regulatory Affairs

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Conformity Assessment Procedures – special cases. Class B, C or D Devices for self-testing and near- patient testing ● NO sampling of technical documentation ● EU technical documentation assessment certificate issued for each device ● Specific requirements apply – Demonstrate usability – Show studies Class C or D Companion Diagnostics ● No sampling of technical documentation ● EU technical documentation assessment certificate issued for each device ● Involvement of European Medicines Agency (EMA) – guidance awaited

The Organisation for Professionals in Regulatory Affairs

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Art. 50 Mechanism for scrutiny of conformity assessment of Class D devices.

NB notifies the CA of certificates it has granted for all Class D devices.

CA may apply further procedures in ● Art. 40 Monitoring and re-assessment of NBs ● Art. 41 Review of NB assessment of Tech Doc and of Performance Evaluation ● Art. 42 Changes to designations and notifications ● Art. 43 Challenge to the competence of NBs ● Art. 89, 90 and 92 related to dealing with devices presenting an unacceptable risk to health and safety and non-compliant products MDCG may request scientific advice from experts

The Organisation for Professionals in Regulatory Affairs

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Annexes of Relevance

Annex IV EU Declaration of Conformity Annex IX Conformity Assessment based on a quality management system and on assessment of the technical documentation Annex X Conformity Assessment based on Type Examination Annex XI Conformity Assessment based on Production Quality Assurance Annex XII Certificates issued by a Notified Body

The Organisation for Professionals in Regulatory Affairs

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Annex IX – QMS and Techical Documentation

Chapter I: Quality Management System ● 1. QMS to be implemented according to art. 10.8 ● 2. Initial QMS assessment by NB. – Extensive list of QMS elements. – Audit will include processes for implementation of IVDR requirements (e.g. Art 10.8 (a) strategy for regulatory compliance) – Inform NB of substantial changes in the QMS ● 3. Surveillance – Surveillance audit at least every 12 months – Unannounced audit (at least once in 5 years) – Class B and C: include assessment of technical documentation based on sampling plan

The Organisation for Professionals in Regulatory Affairs

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Annex IX – QMS and Tech Doc

Chapter II: Assessment of Technical Documentation ● Section 4. Assessment of Technical Documentation by sampling for Classes B and C – Complete review in accordance with Annexes II and III – Class B and C NB will issue a report on the assessment for device sampled ● Technical documentation assessment for Class D – Performance evaluation testing by EU Reference Lab for Class D devices(opinion within 60 days) – NB issues Technical Documentation Assessment Certificate following positive Performance Evaluation Assessment Report from EU Lab – Approval of changes (possibly with reference lab involvement) – Batch release

The Organisation for Professionals in Regulatory Affairs

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Annex IX – QMS and Tech Doc

Chapter II: Assessment of Technical Documentation ● 5. Specific types ● 5.1. Class C self-tests and Class B and C near-patient tests – Test reports, including studies with intended user – Where practical an example of the device – Data showing suitability of the device in view of intended purpose – Labelling and instructions for use – NB Issues Technical Documentation Assessment Certificate – Changes to product – may require pre-approval ● 5.2 Companion Diagnostics – NB consults with medicinal product CA or EMA (opinion within 60 days) – NB issues a technical documentation assessment certificate

The Organisation for Professionals in Regulatory Affairs

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Annex IX – QMS and Tech Doc

Chapter III: Administrative Provisions ● Manufacturer or AR keep at the disposal of CA for at least 10 years after the last device has been

placed on the market: – the declaration of conformity,

– the documentation referred to in the fifth indent of Section 2.1 (QMS). and in particular the data and records arising from the procedures referred to in point (c) of Section 2.2., – the changes referred to in Section 2.4., – the documentation referred to in Sections 4.2 (TD required by Annex II

and III). and point (b) of Section 5.1., (ST/NPT) and – the decisions and reports from the notified body

The Organisation for Professionals in Regulatory Affairs

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Annex IX – QMS and Tech Doc

Chapter III: Administrative Provisions ● Each Member State shall make provision that this documentation is kept at the disposal of the competent authorities for the period indicated in the first sentence of the preceding paragraph in case the manufacturer, or his authorised representative, established within its territory goes bankrupt or ceases its business activity prior to the end of this period.

The Organisation for Professionals in Regulatory Affairs

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Annex X – EU-Type

Upon application the manufacturer will provide ● Technical documentation referred to in Annexes II and III and outlined in Annex X ● Representative sample(s) of device The NB will ● Review all documentation and arrange for tests to verify the devcie meets the relevant GSPRs. ● Arrange for tests to verify that applied harmonised standards have been applied. ● Class D devices – involvement of EU reference labs ● Companion Diagnostics – involvement of EMA ● Certification issued for the specific device type examined.

The Organisation for Professionals in Regulatory Affairs

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Annex XI – Production Quality Assurance

Annex IX Section 2.1 (QMS) applies in full and includes technical documentation required by Annex II and III for types approved Annex IX Section 2.2 a, b, d, and e apply (i.e. excludes section on design controls) Annex IX Section 2.3 audit requirements apply except for sampling

review of technical documentation Annex IX Section 2.4 applies in full

Annex IX Section 3 surveillance shall apply with the exception of sampling of technical documentation and design risk management Annex IX Section 4 does NOT apply (assessment of the technical documentation ) Verification of manufactured Class D devices required (batch release).

The Organisation for Professionals in Regulatory Affairs

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Manufacturer’s choice... Not all Notified Bodies will be designated for all Annexes. Check Nando listing to ensure your NB has been designated for your preferred choice of conformity assessment.

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Learning Outcomes: Recap

 To identify the routes for conformity assessment allowed within the IVDR  To recognise routes linked to product classification  To explore the conformity assessment procedure for each route

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Questions

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Masterclass

Quality Management Systems

Stuart Angell, IVDeology LTD

www.ivdeology.co.uk info@ivdeology.co.uk

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

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Learning Outcomes

 What is a Quality Management System  Why is it needed  MDSAP

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What does Quality actually mean?

Why do we need a Quality Culture?

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Why have a Quality Management System

Insight

“all manufacturers should have a quality management system and a post market surveillance systemwhich should be proportionate to the risk class and type of device in question” Art. 31

“There is no ‘one size fits all’ Quality Management System. The extent at which an organisation

controls their processes is

dependent on the nature, size and complexity of an organisation.”

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General Obligations

“The qualitymanagement system shall cover all parts and elements of a manufacturer's organisation dealing with the quality of processes, procedures and devices. It shall govern the structure, responsibilities, procedures, processes and management resources required to implement the principles and actions necessary to achieve compliance with the provisions of this Regulation” (paragraph 8)

Insight

“Establishing a documented, controlled, repeatable process for organisation operations is key to establishing a safe and effective product design, development and manufacture.”

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www.ivdeology.co.uk

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The Origins Backstory…

W. Edwards Deming: 14 Points for Quality Management

1.Create constancy of purpose for improving products and services.

2.Adopt the new philosophy.

3.Cease dependence on inspection to achieve quality.

4.End the practice of awarding business on price alone; instead, minimize total cost by working with a single supplier.

5.Improve constantly and forever every process for planning, production and service.

6.Institute training on the job.

7.Adopt and institute leadership.

8.Drive out fear.

9.Break down barriers between staff areas.

10.Eliminate slogans, exhortations and targets for the workforce.

11.Eliminate numerical quotas for the workforce and numerical goals for management. 12.Remove barriers that rob people of pride of workmanship, and eliminate the annual rating or merit system.

13.Institute a vigorous program of education and self-improvement for everyone.

This Photo by Unknown Author is licensed under CC BY-SA-NC

14.Put everybody in the company to work accomplishing the transformation.

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ISO13485:2016

ISO13485:2016 is still the standard of choice under IVD Regulation • Is specific for the In Vitro Medical Device and Medical Device industry • Not yet harmonized under IVDR • Concept of QMS has been extended to economic operators • Requirement for a QMS is included in the conformity assessment annexes IX, X and XI

This Photo by Unknown Author is licensed under CC BY-SA

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The Systematic Approach…

Insight

“Understanding your inputs and outputs are essential for effective Quality Management. The processes within ISO13485 are interconnected and work collectively to ensure quality.”

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Where to begin..

• What does quality mean to you (Quality Policy)?

• What do your customers or regulations need from you? • Defining quality objectives relevant to company vision • Describe how quality processes are run and interact with each other (Quality Manual, procedures) • Who is responsible for quality processes? • How are you recording your actions?

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The pushback…

Insight

“Why are we adding additional complexity?” “We can’t afford to do this!” “This is delaying getting products on market!” “We only have 3 people in the company!”

“Effective implementation of a QMS will add value to any organisation.

Much of what is described in the

standard is already performed as part of natural company growth.”

Here is why…

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The Benefits of a QMS: 3 examples

Document and Change Control

Risk Management

Supplier Management

Standardisation of processes and recording activity allows effective

Identification, assessing and controlling risk, allows the prevention of incidents that will have financial, safety and legal consequences

Organisations live or die on the quality of suppliers. A robust mechanism for supplier assessment and control will reduce risk of supply issues

delegation of actions, and enhanced ability to identify errors, risks and improvements

Consider the size, format and scope of the QMS specific to the requirements of the company

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Auditing…

A quality management system can be assessed by a notified body for conformity The certificate can be a useful mark of quality

Dave Spud

But

Internal auditing is essential to assess the state of the organization. The more you review the QMS the more efficient and compliant it will be.

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Medical Device Single Audit Programme

• Demonstrate conformity of Quality Management Systems • Based on ISO13485:2016 • Essential for Canadian registration • Supports Japan, Australia, USA and Brazil registration

Insight

“Good example of global harmonisation approach, this is highly recommend is these markets are required as part of the portfolio. There is an additional cost for this service will allow less audit pressure and ease market access routes”

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Learning Outcomes: Recap

 Quality Management Systems are essential for the IVD industry  How a QMS is used is highly dependent on the organisation, but based on ISO13485 requirements  An effective QMS can add real value  MDSAP is a useful addition to the process if applicable to your product portfolio

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Acknowledgements Mauricio Suppo - Qarad

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Tecs

Technical Documentation Documentation Module 19, Regulation of In Vitro Diagnostic Medical Devices Lecture 5 Ben Jacoby nd June 2021

Ben Jacoby, Cambridge RA Ltd.

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

The Organisation for Professionals in Regulatory Affairs

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Scope

The focus is on European legislation:

 Regulation (EU) 2017/746 on in vitro diagnostic medical devices  IVD Regulation, abbreviated ‘IVDR’

 Directive 98/79/EC on in vitro diagnostic medical devices  IVD Directive, abbreviated ‘IVDD’ More emphasis on IVDR than IVDD

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Learning Outcomes / agenda

General introduction Impact of Brexit Technical documenation – What is it? – How should it be compiled? – What is STED ? – How to write a DoC

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General introduction

Transition from Directive to Regulation

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Transition from Directive to Regulation

New MDR DOA May 2021

Source: MHRA, https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/640404/MDR_IVDR_guidance_Print_13.pdf

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Increased regulatory scrutiny under IVDR

IVD directive ~15% of IVD’s require intervention of notified body

IVDR ~85% of IVD’s require intervention of notified body (All except Class A)

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Review of technical documentation under IVDD

Annex II Most technical files reviewed by NB

Non-Annex II Few if any technical files reviewed by NB

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Notified body expertise under IVDD

Annex II NB’s generally familiar with these products

Non-Annex II NB’s mostly unfamiliar with these products which are self- certified by the manufacturer

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Notified bodies under IVDD

‘

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Notified bodies under IVDR (As of March 2021)

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Some potential transition issues (IVDD to IVDR)

• Impact on legacy devices especially re-classification • Conversion to IVDR and/or STED format • How far should technical documentation follow the exact order and structure of Annexes II and III? • Conformity with IVDR general safety and performance requirements rather than IVDD essential requirements • Number of technical files which might need revision • Availability and resources of notified bodies • How soon to engage with notified body • Additional clinical evidence which might be required • Impact of common specifications, implementing acts, updated guidance • Resources required to maintain technical documentation

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Technical documentation Impact of Brexit

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Technical documentation & Brexit

• In GB IVD’s will continue to be regulated by the IVD directive until June 2023. • But manufacturers of non-certificated CE- marked IVD’s must transition from the IVDD to the IVDR by 26 May 2022: • Unless they only want to market devices to Great Britain (GB) only. • Manufacturers can also obtain the UKCA mark by obtaining a certificate from a UK approved body or by self-certifying a general IVD.

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Technical documentation & Brexit

• The CE mark will continue to be accepted in GB until June 2023. • Northern Ireland will accept the CE mark or the CE UKNI mark. • But GB will transition to new regulations requiring a mandatory UKCA mark as of 1 July 2023. • Although no details have been made public it is possible that the new regulations will be based broadly around the existing IVDR.

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Technical documentation transition timelines

• It follows that it will be desirable to have a good understanding of IVDR requirements. • Notified bodies are under great pressure and may have long lead times. • In order to meet the timelines for NI / EU, manufacturers of legacy devices should have started work on their transition plan to IVDR already as the deadlines are: • Devices self-certified under IVDD, by 26 May 2022 • Devices with NB certificates under IVDD, by the expiry date of the certificate or 26 May 2024, whichever comes first.

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Technical documentation

What is it?

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Technical documentation IVDR

‘ 1.’When placing their devices on the market or putting them into service, manufacturers shall ensure that they have been designed and manufactured in accordance with the requirements of this Regulation. 4. Manufacturers shall draw up and keep up to date* the technical documentation for those devices. The technical documentation shall be such as to allow the conformity of the device with the requirements of this Regulation to be assessed. The technical documentation shall include the elements set out in Annexes II and III.’ Article 10 ‘General obligations of manufacturers’ * Highlighting added here to draw attention to this need.

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Technical documentation versus summary technical documentation Source: http://www.imdrf.org/documents/doc-ghtf-sg1

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Technical documentation

How should it be compiled?

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How should it be compiled?

‘The technical documentation and, if applicable, the summary thereof to be drawn up by the manufacturer shall be presented in a clear, organised, readily searchable and unambiguous manner and shall include in particular the elements listed in this Annex.’ (IVDR Annexes II and III)

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Comment on format of technical documentation

‘clear, organised, readily searchable …’ Whilst the wording of Annexes II and III don’t specifically exclude use of paper formats it could be interpreted to mean that electronic formats should be used

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How should it be compiled?

• How closely should summary technical documentation follow the order and content of IVDR Annexes II and III? • Will notified bodies expect a high level of concordance to make it easier to assess compliance (check-box approach)?

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The IVDD has no fixed format for technical documentation. By contrast IVDR Annexes II and III are quite prescriptive. This should drive more consistency around the content of technical documentation for example both within and between different manufacturers. Format of technical documentation

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Format of technical documentation

The following slides show the main headings of IVDR Annexes II and III. Comments are also provided in a few places in purple to highlight changes from the IVDD.

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