Module 18 2021

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

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Module 18 Drug Device and other Combination Products

First Name

Last Name

Company

Tess

Barker

Cara PM Consulting

Juliet

Boylett

Precipio Consulting

Stephanie

Brams

UZ Leuven

Phillip

Davenport

MHRA

Chris

Emmott

Shionogi B.V.

Faye

Grundy

Vectura

Christina

Hansen

Ralex Consulting

Kelly

Jackson

Mi3

Brennan

Kirk-Bratchie

QP-Services

Andrea

Krause

AbbVie Deutschland

Kadi

Kuuskmae-Perry

DLRC

Ruth

Lloyd-Williams

MHRA

Tanja

Megens

Santen Oy

George

Moore-Arthur

MHRA

Ana

Pires

Tillotts Pharma

Sarah

Robertson

Endo Ventures

Anna

Somuyiwa

Guidehouse

Robert

Wakeford

QP-Services

Yvonne

Wilding Woods

Broughton Nicotine Services

Elilzabeth

MMM

Module 18: Drug Device Combinations and other Technology 8 th – 10 th February 2021

Location: Online

Module Leader(s) : Jason Collins and Helen Erwood – ESPL Regulatory Consulting

Date: Monday 8 th February 2021

Time GMT (CET - hour)

Activity

Speaker

08.45

Registration

09.00 – 09.30

Welcome & Introduction to the Module Overview of the regulatory environment for combination products

Jason Collins and Helen Erwood

EU MDR, IVDR and US

09.30 – 10.15

Lecture 1: Drug Device Combinations including Ancillary Medicinal Products

Helen Erwood

10.15 – 10.45

Refreshment Break

10.45 – 11.45

Case Study 1: Classification of DDC’s

Jason Collins and Helen Erwood

Integral v non-Integral Medicine or Device Pathway Lecture 2: IVDR and Companion Diagnostics

11.45 – 12.45

Volker Franzen Maranna Sweeney Qiagen

12.45 – 13.45

Lunch

13.45 – 14.45

Lecture 3: Borderline Products

Sarah Tang MHRA

14.45 – 15.00

Refreshment Break

15.00 – 15.45

Lecture 4: Overview of the medicines pathway Case Study 2: Borderlines/Manual of Decisions/Algorithms

Jason Collins

15.45 – 16.30

Jason Collins and Helen Erwood

Module 18: Drug Device Combinations and other Technology 8 th – 10 th February 2021

Date: Tuesday 9 th February 2021

Time

Activity

Speaker

09.00 – 09.30

Introduction and review of case study 2

Chairperson Helen Erwood

09.30 – 10.15

Lecture 5: Software as a medical device: A different development approach

David Horton GSK

10.15 – 10.30

Refreshment Break

10.30 – 11.15

Lecture 6: Innovative Manufacturing – Rapid Prototyping – the Challenges of Designing and Testing prototypes

Sukie Whitehall Oval Medical Technologies

11.15 – 12.00

Lecture 7: Devices and ATMPS – Examples and Challenges

Shaun Stapleton Reneuron

12.00 – 13.00

Lunch

13.00 – 13.45

Lecture 8: Human Factors for Drug Device Combination Products

Greg Thay

13.45 – 14.30

Case Study 3: Considerations when planning your registration activities

Jason Collins and Helen Erwood

14.30 – 14.45

Refreshment Break

14.45 – 15.30

Lecture 9: Biological Assessments

Stuart Freeman Farino Consulting

Module 18: Drug Device Combinations and other Technology 8 th – 10 th February 2021

Date: Wednesday 10 th February 2021

Time

Activity

Speaker

09.00 – 09.15

Introduction to day 3

09.15 – 10.00

Lecture 10: Clinical Evidence

Richard Holborow BSi

10.00 – 10.15

Refreshment Break

10.15 – 11.00

Case Study 4: Evidence base for different products

Jason Collins / Helen Erwood

11.00 – 11.45

Lecture 11: Notified Body Role and Expectations for DDCs

Theresa Jeary BSi

11.45 – 12.45

Lunch

12.45 – 13.30

Lecture 12: Regulatory Considerations and Experiences when working with Multi- faceted Products Lecture 13: And now for something completely different: The impact of Brexit

Jason Collins and Helen Erwood

13.30 – 14.15

Jason Collins and Helen Erwood

14.15 – 14.30

Refreshment Break

14.30 – 16.15

Case study information and recap

Helen Erwood

07/02/2021

Drug-Device Combinations (including ancillary medicinal products)

Helen Erwood / ESPL

The Organisation for Professionals in Regulatory Affairs

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Learning Outcomes

To understand and describe: ● Devices incorporating ancillary medicinal substances ● The role of Notified bodies and Medicines CAs ● The regulatory process for assessment of DDCs ● Post-consultation requirements ● Borderline and classification issues ● MDR related uncertainties

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We are going to mainly focus on EU requirements after 26 May 2021

MDR (EU) 2017/745

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As of now (Feb 2021)…

Not all of the regulatory aspects and changes have been worked out yet!

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Traditionally…..

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Primary Mode of Action

Antibiotic cement

Primary Mode of Action • Cement for fixation of prostheses Secondary Action • Drug reduces risk of infection

Device

Antibiotic eluting beads

Primary Mode of Action • Antibiotic to treat infection Secondary Action • Temporary filling of cavity

Drug

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DDC examples

• Absorbable Collagen Sponge with Genetically Engineered Human Protein • Antibiotic Bone Cement • Biological Product Gel for Surgical Hemostasis • Cysview for Intravesical Solution and Photodynamic Diagnostic System • Iontophoretic Drug Delivery Patch and Controller • Paclitaxel-Eluting Coronary Stent System • Photodynamic Therapy • Surgical Mesh with Antibiotic Coating

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Drug Device Combinations (DDCs)

Regulation 2017/745

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Drug Device Combinations (DDCs)

TWO TYPES • SINGLE INTEGRAL DDC • Supplied pre-filled with the medicinal product

• NON-INTEGRAL • Use for delivery of medicinal product • .. But can be supplied separately

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Drug Device Combinations (DDCs)

• SINGLE INTEGRAL DDC

• e.g. prefilled insulin pen

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Drug Device Combinations (DDCs

• NON-INTEGRAL • Insulin injection pen, for use with cartridges

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Medical devices that deliver medicines…

Single integral product Non-reusable

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MDR 2017/745… effective 26.05.2021

Within the definition of scope..

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MDR 2017/745…

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MDR 2017/745… Article 117

• THE DEVICE REGULATION AMENDS THE MEDICINES DIRECTIVE !

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Article 117 of the MDR

• “…where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device”

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Article 117 of the MDR

• “If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question”

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Article 117

Who is involved?

EU Commission

Manufacturer

Competent Authorities

Notified Body

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With thanks to BSi

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Current guidance (not yet replaced)

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Article 117 of the MDR

• FOR THE DEVICE ASPECT OF A DDC: • General Safety and Performance (GSPR) checklist requirements apply • MDR Annex I

• Notified Body Assessment Report required • For inclusion within the MAA

• APPLIES TO ALL NEW SUBMISSIONS AFTER 26.05.2021

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MDs incorporating ancillary medicinal substances

1. Notified body consultation

2. Consultation with EU Medicines CA • NB and manufacturer choose CA • consultation on • drug substance aspects alone and • as incorporated into the device • variable procedures and timelines 3. Consultation with EMA • mandatory • human blood derivatives (human albumin, thrombin) • products derived from biotechnology • voluntary • drug substance authorised via centralised procedure

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MDs incorporating ancillary medicinal substances Two connected regulatory procedures  Regulation of medicines ● Scientific advice ● Clinical trials Authorisations (CTAs) ● Marketing Authorisations ● Post marketing safety monitoring ● Inspections ● Enforcement and prosecution

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MDs incorporating ancillary medicinal substances  Regulation of medical devices ● NB / CA consultation ● Clinical trial notifications (CTNs) ● Overseeing notified bodies – CE marking – NBOp ● Post market surveillance/inspection ● Enforcement and prosecution

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EMA consultations

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UK consultations: 2017

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.. An emerging process..

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Article 117 NB Assessment {device aspects}

• Quotation and contract with NB

Contract

• NB technical assessment

Technical File

• Technical specialist recommendation

Questions / Responses

Certificate Decision

• Independent review

Summary document/ report

• Issued to manufacturer

With thanks to BSi

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The DDC technical file (STED) – device aspects

Same as for any other Medical device • Structure and content as per IMDRF guidelines

• Including

• GSPR checklist • Clinical evaluation report • Human factors data • Manufacturing / control information

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IMDRF

http://www.imdrf.org/

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The DDC technical file (STED) – device aspects

Manufacture and control in accordance with ISO standards

• Evidence of compliance with ISO standards, including: • ISO 14971 (Risk Mgt)

• ISO 13485 (Quality Mgt system) • ISO 10993 – relevant sections (Biological evaluation of medical devices) • Clinical evaluation report • Labelling, etc..

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Clinical evaluation data

May be: • Published literature / meta-analyses • Clinical investigations • In vitro studies (microbiological etc – relevant to product)

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1. Validation: 20 working days 2. 1 st round review by NB: 40 working days 3. CLOCK STOP 4. 2 nd round review by NB: 60 working days 5. CLOCK STOP 6. 3 rd round review by NB: 70 working days 7. CLOCK STOP 8. NB finalises report and makes submission for decision making 9. Final decision issued: 80 working days Timelines – Example NB review timelines

Up to 250 working days : 13 months

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Medicines aspects

Jason will present these aspects…

• Quality

• Safety

• Efficacy

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Clinical studies with DDCs

1. Factor in device and meds expectations

2. Look at Performance / Efficacy of the Device ● As well as the drug product formulation

3. Human Factors studies

● Collected within the CTA protocol

4. Monitor safety of DEVICE and DRUG

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Clinical Investigations:

“Similar” (predicate) products CE marked

• In-vitro/in vivo data may be sufficient • But needs to be fully justified • Risk evaluation

• Observational data in humans • Claims in ‘Instructions for Use’ - consistency of approach?

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Clinical Investigations:

Devices containing a “New active” substances

• More robust data needed • Pre-clinical studies important • Clinical studies required

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Common DDC file issues

Quality – Insufficient drug substance data – Control of elution of drug substance – Validation of analytical methods – Stability: accelerated testing; no degradation product testing Clinical – Data presented do not support the claims proposed – Benefit/risk not clearly defined – Poor/ lack of usefulness report from Notified Body

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Common DDC file issues

 Lack of supportive data provided initially  CTD headings not addressed

Summarised data as evidence that finished product can be reproducibly manufactured and stored within specifications established from safety and clinical data

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EMA consultation procedures

• The EMA is the CA for substances derived from human blood or human plasma or that fall under the scope of the Centralised procedure. • NBs may consult the EMA for other substances • e.g. if the Agency has already evaluated a medicine containing the same drug substance. • For a new MD, the NB acts as the applicant on behalf on device manufacturer in an initial consultation procedure with EMA. • It should provide an 'intention to submit' letter, preferably at least six months before it expects to submit the application.

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EMA consultation procedures

• When changes are made to an ancillary substance for which EMA has already given an opinion, in particular to its manufacturing process, the NB should consult the Agency to confirm that quality and safety are maintained. • This is called a post-consultation procedure with EMA.

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• Published following CE marking • Similar to EPAR for medicinal products • Confidential information removed

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National Consultation procedures e.g. MPA, Sweden : 210 day procedure

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BORDERLINE CLASSIFICATION ISSUES

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Guidances – still MEDDEVs

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Borderline precedents

MANUAL OF DECISIONS ● https://ec.europa.eu/health/sites/health/files/md_topics- interest/docs/md_borderline_manual_05_2019_en.pdf

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Manual of Decisions… example precedents

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Learning Outcomes

To understand and describe: ● Devices incorporating ancillary medicinal substances ● The role of Notified bodies and Medicines CAs ● The regulatory process for assessment of DDCs ● Post-consultation requirements ● Borderline and classification issues ● MDR related uncertainties

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Acknowledgements

Janine Jamieson BSi TUV Sud

helen@espl-regulatory.com

Thank you! Questions ??

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1. The IVDR and 2. Companion Diagnostics

Volker Franzen / Maranna Sweeney

The Organisation for Professionals in Regulatory Affairs

February 2021

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Learning Outcomes

To understand and describe: ● The definition of an IVD ● The current issues with implementation of the IVDR ● Classification of IVDs under IVDR ● Where they might be used in association with DDCs ● Companion Diagnostics – what, when, and how they are used.

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Medical devices are typically used on or in humans

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Human body

Medical evaluation

Take a sample

Testing outside of the human body

Anamnesis Info

IVD

Imaging Info

Information

Endoscopic Info

Using a Medical Device

Other Info

IVD 1 IVD 2 IVD 3 IVD 4

Information

Specimens are never reintroduced into the human body

Information

Information

Information

Using an IVD

Diagnosis/ treatment decisions

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In vitro diagnostic medical devices

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Test of human specimens like e.g. blood, plasma, urine, sputum

Some typical IVD medical devices

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There’s a huge change coming along…

© HS2

Not only some improvements. Experts see it more as a revolution

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• Operational since 2000

• Becomes operational in May 2022

IVD Directive

• IVDD is transposed into the

IVD Regulation

• The law text is in force in

national laws by the member

all member states

states

• Not 1:1 and with different national

• Higher classification of most of the IVD

interpretations

products

• Weaknesses like

• Stricter and extensive pre-market and post-

 Inadequate classification system  No transparency of what is on the EU market  Most of the products are self- certified by the manufacturer  Unprecise pre-market and post market documentation requirements

market documentation requirements

• Clear transparency of what is on the market

• Will strengthen the image and value of CE

marked devices

The new IVDR passport for Europe

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Reagent

… whether used alone or in combination ,

Calibrator

intended by the manufacturer to be used in

Control

vitro for the examination of specimens

Piece of equipment

It can be

Kit

including blood and tissue donations, derived

from the human body, solely or principally for

the purpose of providing information

Software or System

Instrument

Apparatus

 see next slide

What means in vitro diagnostic medical device

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under the IVDR ?

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a physiological or pathological state

congenital physical or mental impairments

The specific information that is intended to be provided by the manufacturer in the context of

the predisposition to a medical condition or a disease

the determination of the safety and compatibility with potential recipients

the prediction of treatment response or reactions

the definition or monitoring of therapeutic measures

Specific information for what ?

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The medical interpretation becomes more important

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Class A sterile, class B,C and D come under Notified Body review

There will be no grandfathering of IVDs

With thanks to FAMHP

Classification changes with IVDR (see your notes for the new classifications)

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2025, May 26 Sell-off provision

2022, May 26 Full Applicability

2024, May 26 Grace period List A/List B

2017, May 26 IVDR entry into force

IVD-R

5 years transition period

Devices that are still in the supply chain before May 25, 2022 and have not reached their final user are marketable until May 25, 2025

IVD-D

IVD-D List A and List B devices with valid IVDD certificates can be further manufactured under specific requirements

Transition timelines from the Directive to the new IVD Regulation

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‘Companion diagnostic' means ’ a device which is essential for the safe and effective use of a corresponding medicinal

product to :

- identify , before and/or during treatment

- patients who are most likely to benefit from the corresponding medicinal product; or

- patients likely to be at increased risk for serious adverse reactions as a result of treatment with

the corresponding medicinal product

Class C / Classification Rule 3 (f) = Devices intended to be used as companion diagnostics

IVDR introduces a definition for Companion Diagnostics for the first time in the EU

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Blood glucose monitoring devices are intended for the quantitative measurement of blood glucose levels in freshly collected capillary blood samples. Such monitors provide immediate information to the user on whether the blood sugar is too high (hyperglycaemia) or too low (hypoglycaemia). In cases of hyperglycaemia, the test result is then used to calculate an adequate insulin dosage to be administered to the patient Devices that are intended to be used for monitoring treatment with a medicinal product in order to ensure that the concentration of relevant substances in the human body is within the therapeutic window are not considered to be CDxs

⇨ Annex VIII, rule 3 (k), class C: Devices intended for management of patients suffering from a life-threatening disease or condition. Example from the Medical Device Coordination Group (MDCG) classification guidance: HbA1c and blood glucose tests for the management of patients with diabetes

What are NOT companion diagnostics ? Example No 1

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Cyclosporine, Sirolimus, Tacrolimus as Therapeutic Drug Monitoring Devices (TDM ) to measure cyclosporine, sirolimus or tacrolimus blood concentrations to enable the dose of the drug individualized to the patient to improved transplant outcome for transplants of liver, kidney, heart, pancreas, lung, and intestines, and for prevention of graft-versus-host disease

Annex VIII, Rule 3 (j), class c: Devices intended for monitoring of levels of medicinal products, substances or biological components, when there is a risk that an erroneous result will lead to a patient management decision resulting in a life-threatening situation for the patient or for the patient's offspring

Example from the MDCG classification guidance: Devices intended for monitoring of iimmunosuppressive (anti-rejection) medicinal products e.g. cyclosporine, sirolimus, tacrolimus

What are NOT companion diagnostics ? Example No 2

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Its function screening, diagnosis, monitoring, prognosis, companion diagnostic , prediction

The International Non- proprietary Name (INN) of the associated medicinal product

1

for which it is a companion test

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TUse Specific information in th context of

What is detected and /or measured

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Testing population

Prediction of treatment response or reactions

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Type of specimens

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Several CDx specific intended purpose requirements

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The KRAS PCR Kit is a real-time qualitative PCR test for the

detection of seven somatic mutations

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(Codon 12: G12A, G12D, G12R, G12C, G12S, G12V, and Codon 13: G13D) in exon 2 of the human KRAS

gene using genomic DNA (gDNA) extracted from

specimens of formalin-fixed paraffin-embedded (FFPE)

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human colorectal cancer (CRC) tumor tissue.

What is detected and /or measured

The (…) PCR Kit is indicated for use as a

companion diagnostic test, to aid clinicians in the

1

identification of patients

with metastatic colorectal cancer (mCRC) who are

less likely to respond

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3

positively to treatment with the anti-EGFR biological therapeutics Erbitux (

cetuximab) or Vectibix

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(

panitumumab), on the basis of a

KRAS Mutation Detected result.

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Type of specimens

KRAS kit is a predictive marker of cetuximab efficacy KRAS wild-type tumors benefit from cetuximab

IVD CDx example

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IVD-R Class C CDx device under NB and MPA review

IVDD self declaration

MPA/ European Medicines Agency (EMA)

Medicinal Products Authority (MPA)

QMS plus TD assessment Audit

Quality Management System Notified Body Audit

Marketing Authorisation Application (MAA)

MAA

NB

Self-certification based on the Technical Documentation

EU Technical Documentatio n assessment

IVD Manufacturer

Pharma

IVD Manufacturer

Pharma

The new CDx conformity assessment procedure is a very complex one

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

Which NBs are designated for devices intended to be used as CDx ?

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– demonstrate the following in accordance with Intended Use Statement:

Scientific Validity Analytical Performance

Clinical Performance

The association of an analyte to a clinical condition or a physiological state

The ability of a device to correctly detect or measure a particular analyte

The ability of a device to yield results that are correlated with a particular clinical condition or a pathological

process or state in accordance with the target population and intended user

Performance Indicators for IVDs

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Companion Diagnostics clinical performance studies

CDx CPSs can be pro- or retro-spective, normally conducted at an accredited central laboratory. Prospective studies involve testing clinical samples collected during a clinical trial Retrospective studies involve testing clinical samples collected from patients for research purposes

The route to an approved CDx is a simultaneous one between Pharma sponsor and Diagnostic sponsor

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CDx requirements under IVDR – Clinical Affairs Challenges & Questions

a. Following gap analysis of existing CE-IVDs, additional clinical validation data may be needed to meet IVDR requirements - do we have enough time? b. Come May 2022 FDA PMA data may/may not fulfill Annex XIV requirements. Therefore, consideration must be made for supply of CE-IVD kits in RoW where the CE-Mark cannot be maintained under IVDR c. Also, how do we continue supply kits to existing interventional CDx clinical trials conducted in EU with a non CE-marked kit? d. Label Performance Evaluation Only? – who obtains CA approval for this? Pharma or Diagnostic Sponsor, both?

1. Can the clinical evidence gaps be filled in time?

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CDx requirements under IVDR – Clinical Affairs Challenges & Questions

CAs are not ready to accept Clinical Trial Applications for review with IVDR in mind

Nor are NBs and EMA/National CAs ready to accept submissions for conformity assessments and scientific opinions respectively, as required for CE marking under IVDR Since the roadmap is not ready, combined with impact of Coronavirus pandemic, a delay to IVDR implementation has been proposed by Labs and Hospitals among other authorized representatives Meanwhile, we are getting ready for May 2022 but continue to seek the guidance needed on how to implement all aspects of the IVDR into our current and future CDx studies.

2. Can a clinical trial be initiated today under IVDR?

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CDx requirements under IVDR – Challenges for clinical

• MedTech Europe has and continues to develop(ed) guidance documents. E.g. eBooklet CDx section helpful, but many questions remain unanswered. See MedTech eBook ref at end • ISO 20916: 2019 IVD medical devices — Clinical performance studies using specimens from human subjects — Good study practice is available but not EN standard and not harmonized by European Commission to IVDR • Guidance docs from the Medical Device Co-ordination Group (MDCG) due 2021:  IVDR Performance evaluation – extremely specialist, expertise needed  IVDR SSP (Summary of Safety & Performance)  IVDR Qualification of assays used in clinical trials of medicinal products1

3. Not all guidance on ‘how to’ meet requirements is available

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Potentially.. A train crash waiting to happen.. (we will have to see what happens over the next few months)

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Acknowledgements

Many thanks to the national IVD Manufacturers Associations and to MedTech Europe in Brussels, representatives of the national Medical Device Authorities, Notified Bodies and the European Commission for the many helpful discussions over the past years

Volker Franzen / Maranna Sweeney

Thank you! Questions ??

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NANDO List of Notified Bodies for Conformity Assessment https://ec.europa.eu/growth/tools- databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=35

Medical Device Coordination Group (MDCG) http://ec.europa.eu/transparency/regexpert/index.cfm?do=groupDetail.groupDetail&groupID=3565

Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR: https://ec.europa.eu/docsroom/documents/37581

MDCG 2020-16 Guidance on Classification Rules for in vitro Diagnostic Medical Devices under the Regulation (EU) 2017/46 https://ec.europa.eu/health/sites/health/files/md_sector/docs/md_mdcg_2020_guidance_classifi cation_ivd-md_en.pdf MedTech Europe eBooklet about the ‘Clinical Evidence Concept’ under the Regulation 2017/746/EU on In-vitro Diagnostic Medical Devices https://www.medtecheurope.org/wp-content/uploads/2020/05/MedTech-Europe-Clinical-Evidence- Requirements-for-CE-certification-eBook-2020.pdf

References Part I

The Organisation for Professionals in Regulatory Affairs

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06/02/2021

ISO 20916:2019 In vitro diagnostic medical devices — Clinical performance studies using specimens from human subjects — Good study practice: https://www.iso.org/standard/69455.html

IVDR- and MDR Factsheets from the European Commission https://ec.europa.eu/health/md_newregulations/publications_en

MedTech Europe, the overall association of the European medical technology industry (members of the diagnostic industry and the medical technology industry): http://www.medtecheurope.org/

European Medicines Agency http://www.ema.europa.eu/ema/

Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0746&from=EN

References Part II

The Organisation for Professionals in Regulatory Affairs

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Classification and Borderlines for Medical Devices Sarah Tang Regulatory Affairs Manager

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Overview

• UK regulation of medical devices as of 1 Jan 2021 • Classification of medical devices

• Borderlines with medical devices

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UK regulation of medical devices – 1 January 2021

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EU Exit & EU MDR/IVDR delay

• Regulation 2017/745 (EU MDR) entered into force on 25 th May 2017 • Original date of full implementation: 26 th May 2020 • Date of full application of MDR fell within EU Exit transition period

• Regulation 2020/561 amending the MDR • Full implementation of MDR delayed to 26 th May 2021 – outside the EU Exit transition period • MDR and IVDR not automatically retained by EU Withdrawal Agreement Act

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MDR & IVDR will not apply in Great Britain

MDR

IVDR

• Applies in the EU on 26 May 2021 – outside of transition period

• Applies in the EU on 26 May 2022 – outside of transition period

• Not automatically retained by the EU

• Not automatically retained by the EU

Withdrawal Agreement Act

Withdrawal Agreement Act

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Legislation that will apply in Great Britain

Medical Devices Directive

Active Implantable

Medical Devices Directive

In vitro Diagnostic Medical Devices Directive

UK Medical Devices Regulations 2002 (in the form they exist on 1 January 2021)

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CE marking

• Valid until 30 June 2023

• Class I and General IVD manufacturers can continue to self-declare

• Existing certificates by UK Notified Bodies valid in GB

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UKCA marking

• Valid from 1 January 2021 and mandatory from 1 July 2023

• Requirements – MDD, AIMDD, IVDD

• UK Approved Body must be used

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Classification

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Definition of Medical Device ‘medical device’ means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, together with any accessories, including the software intended by its manufacturer to be used specifically for diagnosis or therapeutic purposes or both and necessary for its proper application, which – (a) is intended by the manufacturer to be used for human beings for the purpose of: (i) diagnosis, prevention, monitoring, treatment or alleviation of disease, (ii) diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap, (iii) investigation, replacement or modification of the anatomy or of a physiological process, or (iv) control of conception; and (b) does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means , even if it is assisted in its function by such means, and includes devices intended to administer a medicinal product or which incorporate as an integral part a substance which, if used separately, would be a medicinal product and which is liable to act upon the body with action ancillary to that of the device;

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Exclusions

Certain things are excluded from the remit of the medical device regulations and therefore products containing certain things cannot be considered as Medical Devices: e.g.

• Most human derived products • Viable animal tissues

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UK Medical Devices Regulations 2002

Transposes into UK law the three EU Medical Devices Directives

• Medical Devices (93/42/EEC) – Part II of UK MDR • Active Implantable Medical Devices (90/385/EEC) – Part III of UK MDR • In Vitro Diagnostics Medical Devices (98/79/EC) – Part IV of UK MDR

A product may be a Medical Device, but could be regulated as an Active Implantable Device or an In Vitro Diagnostic Medical Device.

Active Implantable Devices must be both (i.e. active and implanted).

In Vitro Diagnostic Medical Devices are intended for the examination of specimens derived from the human body and thus may not come into contact with the body.

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Manufacturer’s Responsibilities

A ‘manufacturer’ under the UK MDR is the person or company placing the product on the market in their own name.

The manufacturer is responsible for:

• determining if their product is a Medical Device and what classification applies. • review and comply with relevant Essential Requirements • implement the systems required • if applicable: apply to a Notified Body or UK Approved Body for Assessment and / or testing of devices • register the product with relevant Competent Authority

• make a Declaration of Conformity • apply CE Marking/ UKCA marking • operate Post Market Surveillance and Vigilance systems

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Risk Classes

• The UK MDR classifies all medical devices as per the level of risk associated with their use.

• There are 4 classes of medical devices, sorted I to III in order of increasing risk: Class I – low risk Class IIa and Class IIb – medium risk Class III – high risk • Which class a device fits into is determined by the rules laid out in Annex IX. – Part II of the Medical Devices Regulations 2002, Annex IX [as modified by Part II of Schedule 2A to the Medical Devices Regulations 2002]

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Risk Classification - IVDs

• There are 4 main groups of IVD medical devices: “General” IVDs – considered low risk IVDs for self-testing – medium risk

Annex II, List B – high risk Annex II, List A – high risk

• Which class a device fits into is determined by the intended purpose and whether it is listed in Annex II.

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Risk Classification

Low Risk : General IVDs, Plasters, Walking Sticks, Wheelchairs, Stethoscopes, Medicine Spoons, Administration Sets, Syringes, Re- usable Surgical Instruments Medium Risk: Needles, Dental Filling Materials, Contact Lenses and Solutions, Diagnostic and Monitoring Equipment, Self Test IVDs, Condoms, Infusion Pumps, Blood Bags, Haemodialysis Concentrates, Hearing Aids, Ventilators, Incubators, Surgical Lasers, Anaesthetic Machines, Nebulisers, Specified IVDs (eg Rubella, Chlamydia, PSA, Downs Syndrome) High Risk: Pacemakers, Cochlear Implants, Breast Implants, Devices containing Medicinal Substances, Devices containing Animal Materials, Cardiovascular and Devices, Neurological Implants, Absorbable Sutures, IUDs, HIV and Hepatitis Test Kits, Blood Grouping Reagents

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Classification

If it is a Medical Device..

• Is it an IVD, MD or AIMD?

• How long is it intended to be used for? • Is it invasive? • Is it implantable? • Is it ‘active’? • How does it work? (physically?) • Does a ‘special’ rule apply?

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Other Factors influencing classification

- Does the Device contain a medicinal substance? - Does the Device contain animal derived tissue? - Does the Device contain tissue derived from TSE susceptible species? - Does the Device contain a human blood derivative?

Classification rules : General medical devices (Part II): Regulation 7 and Annex IX

IVD (Part IV): Regulation 40 and Annex II AIMD (Part III): All the same class – Class III

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Special Rules – Annex IX

These are classification rules covering specific products which give specific products a specific classification:

Rule 13 – Rule 14 – Rule 15 – Rule 16 – Rule 17 – Rule 18 –

devices containing Medicinal Products

devices for contraception or prevention of STDs

devices for disinfecting

devices intended for recording X-ray images

devices containing animal tissues

blood bags

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Borderlines

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What is a Borderline ?

Borderline products are those where is it initially unclear what regulations should apply to the specific product.

• Could it be a Medical Device? • Does it fit the definition?

• What is the intended purpose? • How does it work? (physically?) • Is it clearly ‘something else’ (e.g. a medicinal product). • What other regulations might apply?

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Borderlines

Key determination factors: • manufacturer’s intended purpose for the product • associated claims • product’s mode of action

It is possible to argue that almost anything is a Medical Device

To be a Medical Device:

• The product must fit the definition of a medical device; • The product must have an appropriate mode of action; and • There must be a ‘medical purpose’ for the product.

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Borderlines

Not everything used or intended to be used in a healthcare environment are medical devices:

Patient identity bracelets, chairs for use in surgeries and hospitals, healthcare professionals’ clothing (except sterile theatre drapes etc), porters’ chairs (wheelchairs for transporting patients), portable ramps, pyjamas and other bedclothes or materials claiming anti-microbial action

Things for use in the home or at work may be medical devices:

Hypo allergenic bedding, orthopaedic mattresses (with specific claims)

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Are these medical devices?

Heating Gel for pain release

Pill dispenser

Toothbrush

Safety glasses

Acupuncture needles:

Tattoo needles:

Incontinence pads

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Borderlines with what?

• Medicinal products • Cosmetics • Biocides • Personal Protective Equipment • Food • General Products

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What is a medicinal product?

a)

Any substance or combination of substances presented as having properties of preventing or treating disease in human beings ; or Any substance or combination of substances that may be used by or administered to human beings with a view to – i. restoring, correcting or modifying a physiological function by exerting a pharmacological, immunological or metabolic action, or ii. making a medical diagnosis .

b)

- The Human Medicines Regulations 2012 (S.I. 2012/1916)

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Borderlines with Medicinal Products

Most (if not all) medical devices will ‘fit’ the definition of a medicinal product at least under the first part.

Thus determining whether a product is a medical device or a medicinal product can be a complex process.

Key areas:

• Mode of action (pharmacological, immunological, metabolic or physical?) • The intended purpose for the product • The claims being made for the product • The ingredients contained in the product

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Borderlines with medicinal products

There are two main borderlines with medicinal products.

1. A single product intended for a medical purpose, where it is not immediately clear whether it should be classed as a medicinal product or a medical device. 2. A combination product which includes a medical device component and a medicinal product component, e.g. i. Intravascular stents which have been coated with heparin (which prevents blood clots forming on the stent) ii. Subdermal contraceptive implants (a small device slow- releasing a medicinal product)

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Borderlines with medicinal products

How can you decide?

Remember the definitions:

• A medicine works by exerting a pharmacological, immunological or metabolic action • A medical device 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 So: • If the primary action of the product is physical or mechanical , it is a medical device . • If the primary action is pharmacological, immunological or metabolic , it is a medicinal product .

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Classification Rule 13

Classification rule 13 states that: • devices incorporating as an integral part, • a substance which used separately, can be considered to be a medicinal product • which is liable to act on the human body with action ancillary to that of the devices • are Class III.

Key issues: Is the substance a medicinal product in its own right? Is the medicinal substance acting in an ancillary manner? Is it liable to act on the body?

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Products on the drug-device borderline

Integral combination product (medicine)

Integral combination product (device)

Co-packaged drug & device

Non-integral, re- usable (drug- delivery) device

Applicable legislation

• Combination product falls under Medicines legislation • Device component to meet essential requirements for safety & performance

• Combination falls under Devices legislation • Consultation with Medicines authority required for medicinal component

• Drug and

• Drug and

device each fall under the

device each fall under the

respective legislation

respective legislation

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What is a cosmetic product?

“Any substance or mixture intended to be placed in contact with the external parts of the human body (epidermis, hair system, nails, lips and external genital organs) or with the teeth and the mucous membranes of the oral cavity

with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance, protecting them, keeping them in good condition or correcting body odours;”

- from Cosmetic Products Regulation (EU) 1223/2009

In short, it’s for cosmetic purposes – keeping things clean, maintaining condition, or making them look or smell better.

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