The European Commission’s scienceand knowledge service

Joint Research Centre

Connecting the dots: globally applicable adverse event terminology,

signal detection and the novel MIR formDr. Claudius Griesinger

Group leader ‘Health technologies’

European Commission, DG Joint Research CentreDirectorate F: Health Consumer, Reference Materials

Unit F.2: Consumer Products Safety

Conferenza Nazionale sui Dispositivi Medici, Rome, 18-19 December, 2017

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OutlineJoint Research Centre

MIR form

IMDRF adverse event terminology

Signal detection & management

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• One of the 33 Directorate Generals of the Commission

• About 3000 staff, ca 75% are researchers

• HQ in Brussels, research facilities in 5 Member States

Examples:

• Migration & demographic change

• Water resources

• ‘Copernicus’ - satellite data analysis

• Chemical safety

• Alternative methods to animal models

• Nanobiosciences

• Vehicle emissions & electromobility

• Renewable energy

• Reference materials & measurements

• Medical technology

JRC online: ‘EU science hub’

https://ec.europa.eu/jrc/en

The Joint Research Centre's mission is to

support EU policies with independent

evidence throughout the whole policy cycle.

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• Directorate "Health, Consumer,

Reference Materials"

• Unit "Consumer Products Safety"

• JRC Medical Medical Devices Task Force

Life sciences buildings, JRC, Ispra campus, Italy

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Conception Implementation Adaptation to technical

progress

JRC JRC

Ca 30% Ca 70%

JRC is involved throughout the policy cycle of EU legislation

JRC

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Joint managementby Commissionservices

Regulation on Medical Devices (MD)

Regulation on in vitrodiagnostics

DG GROW DG SANTE DG JRC

Policy leadNB assessment with MS

Scientific & technical aspects

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• Medical technology: Increasing importance for modern healthcare: improving health and healthy ageingWide range of products – ca 500’000 to 1 million on EU market.

• Creating jobs: > 600'000 people in EU medical technology sector• Competitive: 100 billion in annual sales• Agile industrial fabric: 95% of companies are SMEs

…robotic surgery...diagnostics…imaging …prosthetics…plasters

Medical Technology: key facts

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The silver society: a challenge with considerable global opportunities

UN / WorldBank

China

2028: aged

2035: hyper aged

Emerging markets

will have major

Share of >65

Chart: Standard Chartered (2017) Ageing – Passing the Baton to Asia

Developing socioeconomic models

addressing the challenges:

policies, products & services

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OutlineJoint Research Centre

MIR form

IMDRF adverse event terminology

Signal detection & management

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Why?Manufacturers, regulators and other relevant actors, want to

make sure that cost-effective devices are

safe and efficient/performing as intended.

Patients should receive devices that

• do not cause unnecessary harm ("acute") and

• do not pose unknown or unjustifiable risks ("longer term”)

• improve their health & well-being

Thus, it is important to look out for information that may

indicate specific patterns, trends or that signals risks/concerns

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Post-market & ‘real world data’

Benefit

Risk

Benefit

Risks

Collecting, monitoring data post-market

‘real world data’ is critical:

pre-market clinical data reflect very controlled use and

are often very limited, especially in context of EU model

of fast market access of novel technologies.

BRc = ?

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Evidence Pathway

downstreamupstream

Life cycle assessment

In vitro / in vivo

Toxicity

Bio-compatibility

Modelling/Simulation

Pharmaco-/toxicokinetics

Feasibilitystudies

FIM / phase 0

Patient registries

Incident Reporting, FSCA, PSR etc.

News

Scientificliterature

Extra EU information

Materialcharacterisation

REACH

PROs /UROs

PMCF

Pre-market space Post-market space

Pivotal Studies

preclinical

clinical

Market surveillance/

vigilance

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Regulatoryrecipient

DB

DB

Database (DB)

Member StatesEU level

MIR form

EUDAMED

Manufacturers(serious

incidents)

Sponsors(serious

adverse events)

…

MIR form

SAE form

MS coordination

Improved detection & management of signals;

Detection of trends and patterns

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Background: EU pilot on novel MIR formusing categorised reporting (ISO)

Online:

Search ‘EU bookshop’.

Search for title keywords

MIR form

Pilot MIRform

Voluntary participants from

industry, analysis JRC

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MIR form working group

COMPETENT AUTHORITIES

• Tony Sant, MHRA, UK (co-chair WG)• Paras Shah, MHRA, UK• Audrey Sierra, ANSM, France• Rosaria Boldrini, Ministry of Health, Italy• Bernhard Bichsel, Swissmedic, Switzerland• Kelly Decaluwe, FAGG, Belgium• Christophe Driesman, FAGG, Belgium• Helena Dzojic, MPA, Sweden• Andrea Hanson, HPRA, Ireland• Ulrike Meyer, Swissmedic, Switzerland• Patrick Murphy, HPRA, Ireland• Carmen Ruiz-Villar, AEMPS, Spain• Ekkehard Stösslein, BfArM, Germany

EUROPEAN COMMISSION

• Claudius Griesinger, DG JRC (co-chair WG)• Tim Raemaekers, DG JRC• Marco Nocita, DG JRC• Jean-Francois Roche, DG GROW

(Vigilance WG Chair)

INDUSTRY ASSOCIATIONS

• Philippe Auclair, Abbott• Marta Carnielli, Ortho Clinical Diagnostics• Nicole Denjoy, COCIR• Frederic Melchior, COCIR• Jean-Charles Moreau, Medtronic • Philippe Soly, Philips Healthcare• Dario Pirovano, MedTech Europe• Laure-Anne Thieren, Eucomed• Sophie Vaillot, GE Healthcare• Petra Zoellner, MedTech Europe

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MIR form working group - scope

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Key novelties of the MIR form

Adverse Event Terminology (IMDRF)

Back reporting of similar incident

Clear structure – user friendliness

Fit for novel Regulation

1.Administrative Information2.Medical Device Information3.Information derived from

healthcare professional / user

4.Manufacturer analysis

1.Open comments

1.Adverse Event ‘ footprint’ (AUTO FILL IN)

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OutlineJoint Research Centre

MIR form

IMDRF adverse event terminology

Signal detection & management

Powdery mildew

Rustdisease

Mouldy core

Rustdisease

Mouldy core

Powdery mildew

Rustdisease

Mouldy core

Powdery mildew

Rustdisease

Mouldy core

Powdery mildew

Critical importance of data structureProducts Problems

Medical device problem

Device,IVD

Patient, User,Consumer

Patient problem

Adverse Event Terminology

Cause investigation

Adverse Event terminology: data structure to support

signal detection / pattern recognition & communication

IMDRF “Health Effects”

Terminology set No. 3: Health Effects

Annex E Clinical conditions /symptoms / signs

Annex F Health

impact

E | F ‘Brain haemorrhage’ | ‘extended surgery’

Structured according to organ system / physiological system, e.g. • Cardiovascular• Nervous system • Hormonal system• Reproductive system

Downstream impact, e.g. ‘death’, ‘hospitalisation’, ‘unexpected medical intervention’, ‘wrong intervention due to incorrect diagnosis’

IMDRF Adverse Event Working GroupMeeting at JRC campus, Ispra, Italy, May 2017

2015 Basic issues(methodology,mapping…)

EU proposal:MD problems

2016 EU proposal:Cause investigation

1st Meeting:MD problems

2nd Meeting:Cause investigation

IMDRF consultation:MD problems

2017

IMDRF consultation:cause investigation

PUBLISHED:MD problems EU proposal:

Patient Problems

4th Meeting:Patient problems

PUBLISHEDCause investigation

3rd meeting@ JRC

2018IMDRF consultationPatient Problems

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PUBLISHED:Patient problems ?

Use of terminology: data interrogation, signal detection, confirmation, exchange of information…

Data structure

Data query (Boolean operators)…Device Device Problem Health effectAND AND

Pacemaker X In back-up mode bradycardiaAND AND

Time

f (I

nci

de

nts

)Visualisation…

Data extraction for further analysis…

associations

Product Health effect Product Product problems

Trends, patterns, signals

associations

Product problems

…over time …over time

Location

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Definition of signal

Signalconveyinginformationon…

…specific occurrence orpresence that is of concern / interests

…and promptsaction

Signal

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f Data structure

‘Qualitative’ ‘Quantitative’

Signal detection is about using information thatcan help identify problems related to the use of medical devices

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Legal anchor: MDR article 90 – vigilance data

• Trends

• Patterns

• Signals

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1 basic aspects

Definitions & basic concepts

2 data sources

Mapping and possible use

3) qualitative

SDExpert

judgment

4 data mining

Quantitativesignal

detection

5) processSignal

management6 data

quality to

enable efficient signal

detection

7 Legal tools linked

to SD

MDR EUDAMED

Open Conceptual Framework

Open = adaptable, amenableto innovationConceptual = based on commonlyunderstood concepts, principles,practicesFramework = providing the theoretical frame for building practical approaches, e.g. …Integrated approach:Integration of1) … data 2) … methods: qualitative &

quantitative (data mining)

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Staged approach

Time

Initial phase• Horizon

scanning• Extra-EU

information • IMDRF AE

terminology• Collection of

MS data

Strategic planning document & Survey of CAs

Kick-off workshop in Ispra

Elaboration of Open Conceptual Framework (7 modules) – further workshops

EUDAMED vigilance gr.

Vigilance expert group

Develop-ment of Integrated Approach

Po

ssib

le

acto

rs International partners (NCAs)

Stakeholders

Info

rmed

&

po

ssib

le li

nks

MDEG / MDCG*

CAMD & MS Joint Action on Market Surveillance

CIE expert group

IVD expert group

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Kick-off workshop: agreements & follow-up

Presentation & discussion of SURVEY

Presentation & discussion of

JRC collection of MS data1) basic aspects

Definitions & basic concepts

2) data sources

Mapping and possible use

3) qualitative

SDExpert

judgment

4) data mining

Quantitativesignal

detection

5) processSignal

management6) data

quality to

enable efficient signal

detection

7) Legal tools linked

to SD

1) basic aspects

Definitions & basic concepts

2) data sources

Mapping and possible use

3) qualitative

SDExpert

judgment

Data management

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Breakout group work: signal definition

JRC proposal:A signal is understood as information arising from one or multiple sources, which prompts concerns and demands attention regarding a medical device or device category and which may justify subsequent verification; {… examples}

Final agreement :

A signal is an indication from any source, which suggests a concern regarding one or multiple medical devices and justifies subsequent action.

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Pharmacovigilance: signal management process

Signal detection ValidationConfirma-

tion

Analysis & prioriti-sation

Assessment Action

EMA

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Integrated approach for SD & management• ‘Integrated’ approaches have been developed in the area of

chemical safety & in particular in the area of alternative (non-animal)

methods for testing chemical hazards (…through data integration).

• They provide strategic outline of how to generate, use, combine data

in view of decision making

Milestones:

REACH Integrated Testing Strategies (ITS) – introduced in 2006/7 with

REACH implementation project 3.3 (led by JRC)

Now accepted and used as

‘Integrated Approaches forTesting & Assessment (IATA)’

by OECD

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Integrated approach for SD & management

Data sources

Methods: qualitative / quantitative

Prioritisation

(Type of) action

compare

weigh

assess

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JRC DATA COLLECTION: increase in incidents

Will very likely increase

further due to

reduction of 30 to 15 days

time window for MIR

under MDR.

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DATA COLLECTION: most reported devices

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“I never made a mistake in my life. I thought I did once, but I was wrong.”

Charles M Schulz,

Creator of ‘ The Peanuts’

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