Module 18 - Drug Device Combinations and Other Technologies

Module 18: Drug Device Combinations and Other Technologies

Date: 6th – 8th December 2023 Module: 18 of the TOPRA MSc Design Development and Certification of Medical Devices

Module Leader: Phil Warner

©The Organisation for Professionals in Regulatory Affairs 2023 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

Module 18: Drug Device Combinations and other Technology

Date: 6 – 8 December 2023

LOCATION: TOPRA OFFICE, LONDON, UK / ONLINE Module Leader: Phil Warner

Day 1: Wednesday 6 th December 2023

Time (GMT)

Activity

Speaker

08.45

Registration

09.00 – 09.30

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

Phil Warner

EU MDR, IVDR and US

09.30 – 10.15

Lecture 1: Drug Device Combinations including Ancillary Medicinal Products

James Pink, Element Materials Technology

10.15 – 10.45 Morning break 10.45 – 11.45

Case Study 1: Classification of DDCs

Phil Warner and James Pink

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

11.45 – 12.45

Richard Bassett, DLRC

12.45 – 13.45 Lunch

13.45 – 14.45

Lecture 3: Borderline Products

Daniel Hill, MHRA

14.45 – 15.00 Afternoon break

15.00 – 15.45

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

Pete Gough, NSF - Health Sciences

15.45 – 16.30

Phil Warner

Module 18: Drug Device Combinations and other Technology

Date: 6 – 8 December 2023

Day 2: Thursday 7 th December 2023

Time

Activity

Speaker

09.00 – 09.30

Introduction and review of case study 2

Phil Warner

09.30 – 10.15

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

Celia Cruz, Complear Health

10.15 – 10.30 Morning break

10.30 – 11.15

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

Tom Wood, JensonR+

11.15 – 12.00

Lecture 7: Devices and ATMPS – Examples and Challenges

Shaun Stapleton, Amryt Pharma

12.00 – 13.00 Lunch

13.00 – 13.45

Lecture 8: Human Factors for Drug Device Combination Products

Greg Thay, Thay Medical

13.45 – 14.30

Case Study 3: Considerations when planning your registration activities

Phil Warner

14.30 – 14.45 Afternoon break

14.45 – 15.30

Lecture 9: Biological Assessments

Chris Carr, Catapult

Module 18: Drug Device Combinations and other Technology

Date: 6 – 8 December 2023

Day 3: Friday 8 th December 2023

Time

Activity

Speaker

09.00 – 09.15

Introduction to day 3

Phil Warner

09.15 – 10.00

Lecture 10: Clinical Evidence

Giovanni Di Rienzo, Q Serve Group

10.00 – 10.15 Morning break

10.15 – 11.00

Case Study 4: Evidence base for different products

Phil Warner

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

Mehryar Behizad, Endomag

13.30 – 14.15

Mehryar Behizad, Endomag

14.15 – 14.30 Afternoon break

14.30 – 15.45

Course summary and wrap up.

Phil Warner

13/12/2023

Drug-Device Combinations (including ancillary medicinal products)

Helen Erwood / ESPL

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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

2. Companion Diagnostics

Richard Bassett DLRC

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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 Clinical Trials for medicinal products ● Companion Diagnostics – what, when, and how they are used Learning Outcomes

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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

LW0

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In vitro diagnostic medical devices

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Slide 4

LW0

Some have tiny slide numbers and most don’t, either add to all or remove Laura Wright, 2023-11-27T15:09:50.913

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

Some typical IVD medical devices

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Huge change has arrived…

© HS2

Not only some improvements its more of a revolution

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• Operational since 2000

• Became 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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Classification changes with IVDR

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2022, May 26 All new products must comply

2026, May 26 Transition period Self-Declared to Class C

2027, May 26 Self-Declared Class B, Sterile A

2025, May 26 Transition period Self-Declared to Class D

2017, May 26 IVDR entry into force

IVD-R

8 years transition period

26 May 2025 for Class D devices 26 May 2026 for Class C devices 26 May 2027 for Class B devices 26 May 2027 for Class A devices placed on the market in sterile condition

IVD-D

REGULATION (EU) 2023/607 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 March 2023 amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards the transitional provisions for certain medical devices and in vitro diagnostic medical devices

Transition timelines from the Directive to the new IVD Regulation

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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 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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‘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 the context of

What is detected and /or measured

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2

Testing population

Prediction of treatment response or reactions

3

Type of specimens

4

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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

2

(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

Self-certification based on the Technical Documentation

Marketing Authorisation Application (MAA)

MAA

NB

EU Technical Documentation assessment

IVD Manufacturer

Pharma

IVD Manufacturer

Pharma

The new CDx conformity assessment procedure is a very complex one

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EUROPA – European Commission – Growth – Regulatory policy - SMCS

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

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• Process of Performance Evaluation • Done according to a Performance Evaluation Plan • Collated as a Performance Evaluation Report • Sum total = Clinical Evidence

• Continuous during life-time of the device

Performance Evaluation for IVDs

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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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• The flow of a blinded clinical trial with two treatment arms, where the key processes for which assays might be utilised are highlighted. • The processes in blue are used for medical management decisions of trial subjects. • The processes in pink are likely not to impact the medical management of the trial subjects.

2. What assays used in clinical trials are considered IVDs under the IVDR?

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CDx requirements under IVDR – Challenges for clinical

34% of the devices on the market are CE marked under IVDR. 66% of devices remain uncertified under the IVD Regulation or discontinued.

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

Richard Bassett - DLRC

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

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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

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Working with Multi-Faceted Products

… complex drug-device products

Introduction

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Combination Products…

● DRUG DEVICE COMBINATIONS ● DEVICE DRUG COMBINATIONS ● MULTIFACETED PRODUCTS – DEVICE – DRUG – SOFTWARE – ACCESSORIES

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Drug-device combinations

FDA examples • “single-entity” combination products Device coated or impregnated with a therapeutic drug product ● Drug-eluting stent (e.g. sirolimus-eluting coronary stent)

● Pacemaker lead with steroid-coated tip ● Catheter with an antimicrobial coating ● Condom with spermicide ● Transdermal patch

Prefilled drug delivery systems ● Syringes, insulin injector pens, metered dose inhaler

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Drug-device combinations

FDA examples (continued) • “co-packaged” combination products ● Drug or vaccine packaged with a delivery device ● Surgical tray with surgical instruments, drapes and anaesthetic or antimicrobial swabs ● First aid kits containing devices (bandages, gauze) and drugs (antibiotic ointments, pain relievers)

“Cross-labeled” combination products ● Photosensitising drug and activating laser / light source

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Acknowledgment: Philips Medisize Corporation

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EU Drug-device combinations

• Drug Product – primary action • EMA / national CA reviews the dossier • Typically administration devices only

• Separate administration devices must be CE marked • If integrated administration devices (not separate) must meet GSPR. Do not need CE mark but do need NB opinion • Additional information needed • Compatibility, functionality, safety / tox

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Device-Drug combination

FDA examples • “single-entity” combination products Device coated with a metabolic or cellular action inhibitor ● E.g. Nanoparticle devices

The term used is “ Combination Product ” with “Device Primary mode of action”

FDA is unique in having this definition. No equivalent EU definition exists.

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EU Device-drug combinations

• Medical device – primary action • In the EU… the NB is the main regulating body

• Typically Class III devices (highest risk) • QUALITY SYSTEM control • Declared procedures and GSPR checklist • The MANUFACTURER has responsibility for safety and product liability (through the declaration of conformity) • Clinical benefit / risk (efficacy) of the ANCILLARY MEDICINAL SUBSTANCE must be evident

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MDCG Guidance on Borderline Products

https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed documents-and-other-guidance_en#mdcg-work-in-progress

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The regulatory framework is evolving…

https://www.ema.europa.eu/en/human regulatory/overview/medical-devices

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Software as a medical device

If the software is part of a hardware medical device • It does not meet with definition of Software as a Medical Device

Software as a medical device… • Must have a medical purpose in its own right.

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Guidance on Software as a Medical device

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• In the US it is estimated that

• A hospital

patient is on average linked to 15 interacting medical devices during their treatment

close to 200 patients may have died in 2022 due to cybersecurity issues.

• Many are

combination devices that are interlinked via software

Acknowledgement: http://www.mukoland.de/ photophereseteil3.htm

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EMAs remit [from TOPRA SYMPOSIUM 2017]

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EMAs remit [from TOPRA SYMPOSIUM 2017]

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EMAs remit [from TOPRA SYMPOSIUM 2017]

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There are some exciting developments in new drug-device and device-drug combination products…

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Rebismart Injection System

Injection of Rebif ® (Interferon beta-1a, SC)

• Software • Hardware • Biological DP

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Digital therapeutics..

Example – Software as a medical device supporting.. Behavioural and Music Based Interventions for Neurological Disorders • Systems under development for the treatment of epilepsy

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Examples – multifaceted products Ophthalmics: Corneal collagen crosslinking..

PHOTREXA Viscous

PHOTREXA

KXL system

Device

Software

Drug UVA activated

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Example 1 – regulatory management of a multifaceted product

Complex Class III Medical Device  Contains a reservoir of medicinal product  Performs in situ treatment.

 Contains software that manages the treatment The drug component is licensed separately as a pharmaceutical and is administered via the device during treatment.  Drug component cannot be used without the device

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Example 2 – regulatory management of a multifaceted product

Complex Class III Medical Device  Makes the biopharmaceutical (e.g. targeted DNA/RNA)  Performs in situ treatment.  Contains software that manages the treatment The drug component is licensed separately as a biopharmaceutical and is administered via the device during treatment.  Drug component cannot be made/used without the device

What would be involved if a regulatory agency identified an issue based on adverse event feedback from using the device, and requests a change to the labelling?

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tslimx2 + Dexcom G6

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tslimx2 + Dexcom G6

The tslimx2 / Dexcom G6 combination is an example of a continuous glucose monitoring (CGM) system and an infusion pump, using:  A diagnostic device  An insulin pump  Connected using custom software, which takes the IVD result, applies an algorithm and translates that at the pump interface to make an adjustment of the continuous insulin in respect to the interstitial glucose level. A true ‘hybrid” closed loop system.

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Multifaceted Example

If the labelling for the device requires updating, does the labelling for the drug? ● If the products are based on the same indication(s), then yes .

What will this involve?

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Multifaceted Examples

For the Device: • The labelling for the device requires updating • This will need to be filed as part of the STED, and • May need to be reviewed by the Notified Body ● A field safety notice may need to be issued to inform users ● Does this impact the way treatment is performed? ● are there any impacts on the software? For the Drug Product: • A variation to update the SmPC and PIL would be required. • If the product is part of a DCP/MRP, then this will involve all the relevant countries and national labelling

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Multifaceted Example

Points for consideration • A change affecting one part of the Drug-Device combination, may impact on the other • For Example 2: • CMC/TPP aspects of Near Patient Manufacture will/may have to be clarified through scientific advice from EMA and/or specific country CA • Risk Management file for the medical device has to identify all primary and secondary risks associated with the change. …therefore the wider implications of any change should always be considered

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Medical Device regulations .. Impact for combination products

• New guidances under development / to be finalised • NB assessment of delivery devices • Without the need for CE marking

• Emerging new guidances on QUALITY aspects for drug-device combination products.

• Both US and EU • Need for improvement in regulatory assessments… driven by the MDRs in the EU

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BREXIT: Sowhat happens now?

Mehryar Behizad, Regulatory Director, Endomagnetics Ltd

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Learning Outcomes

• “Understand” the UK regulations for Medical Devices and Medicines • What are the changes from the current EU-wide system

Masterclass Lecture 13

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Brexit

• 1 st January 2021 • UK left the EU with current legislation being translated to UK law • For Devices, this means the UK will continue to follow the Medical Device, IV and AIMD Directives as MDR is not fully implemented • For Medicines, there would be no changes to the legal requirements other than those associated with the national implementation

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Medical Devices

• MHRA is now the agency responsible for medical devices in the UK • UK Notified Bodies will have their designations rolled over for certifying UK products • UK will adopt it’s own UKCA marking system, as it will no longer be part of the EU CE marking system

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Registering devices with the MHRA

• All devices will need to be registered with MHRA from 1 Jan 2021 • Can be done from 1 Jan • Must be done from 1 May for Class III and Class IIb Implantables, active implantables and IVD List A • Must be done from 1 Sep for other Class IIb, Class IIa, IVD List B and self-test IVDs • Must be done from 1 Jan 2022 for Class I and general IVDs • Custom-made devices should be registered based on risk class of the device

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UKCA Marking

• Continue to be valid until 30 June 2023 • Certificates from UK Notified Bodies are acceptable • Class I and General IVD self declarations remain acceptable

• Applicable from 1 Jan 2021 • From 1 Jul 2023 , all UK devices must have UKCA • Only UK Approved Body can issue UKCA mark and must be used Big But…..

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Big But 1

On 27th April 2023, the MHRA officially accepted EU extension for MDD and AIMDD certificates as valid for placing CE-marked devices on the Great Britain market as follows: • Class III and IIb implantable non-WET devices 31st December 2027 • Class IIb WET, Class IIa, Class I devices until 30th June 2028 In addition, the MHRA officially extended the standstill period for compliance with UKCA to 1st July 2025 for all Medical Devices and In Vitro Diagnostic Medical Devices on the Great Britain market.

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• In August 2023 UK manufacturers of 12 categories of products persuaded the government to accept CE marking indefinitely • This does not include Medical devices or IVD yet…. So…. Are you sitting comfortably?…. Can you guess what’s going to happen next?.... Big But 2

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Let’s look at a few perspectives

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1. EU-based manufacturer

CE marked product: • EU manufacturers will need to appoint a UK Responsible Person as soon as possible after 1 Jan 2021 • UK Responsible person to register devices as per schedule • Import into UK for up to 2 years under current EU CE mark ( extension applies ), then the product must have a UKCA mark issued by a UK NB ( standstill applies ) • UK responsible person details will need to be included on the product labelling (this does not apply to CE-marked devices)

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2a. UK-based manufacturer

If using a UK Notified Body: • Can continue with CE mark for up to 2 years • Can transition to UKCA mark with existing NB during this time (standstill applies) • Will need to find an EU Notified Body and EU Authorised Representative in the EU in order to retain and sell in the EU under CE mark In Practice NB migration to EU offices.

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2b. UK-based manufacturer

If using an EU Notified Body: …As with EU manufacturers Can continue with CE mark in the EU, and in UK for up to 2 years After that, will need a UK NB to review and issue a UKCA mark for the product

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And then there is the Northern Ireland Protocol…

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Northern Ireland Protocol

• Northern Ireland able to access the EU Single Market and as a results, NI will continue to align with specific EU rules. • To enable NI businesses to access the UK market, the UK government committed to “unfettered access”

• So how does this work…

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