02 IVD-R Deep-Dive Deck New

the new EU
IVD-Regulation
deep dive
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The leading EU consulting/CRO company specialized in IVDs
our 4 key business areas
CE-mark Access Performance

Regulatory-Quality Evaluation Studies
Consulting & Technical Demonstrating Clinical
Writing Evidence for your IVDs
At the core
of your EU
success
e-Labeling EU-Authorized
web posting of your IFUs Representative
Slide 2 of 213
Key drivers of the new IVD-R
1. Emphasis on Traceability
2. Medical Vigilance
3. NB reinforcement plan
4. Extension to “Other Economic Operators”
All of the above changes are a

Essentially they respond to the consequence of the “immediate
need to ensure better control on measures which have been set
manufacturers/products and up as a consequence of the EU
better traceability of devices. PIP (breast implants) and metal-
on-metal prosthesis scandals.
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Scope of the IVD Regulation
• IVD
• General lab products with IVD use
• Accessories
• Specimen Receptacles
• Devices for Performance Evaluation
• Laboratory Developed Tests (LDT)
– some exceptions for the “True LDTs”
– Commercial labs / test services
– internet sales / distant sales
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Not in the scope !
• NOT in scope:
– General Laboratory Products
– RUO
– IVD for forensic or veterinary use
– Invasive sampling devices
– International certified reference materials
– Materials for EQAS
– IVD incorporating a Medical Device
• Regulated as a medical device
• But Annex I of IVD Regulation applies
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What is an In Vitro Diagnostic ?
“ ‘in vitro diagnostic medical device’ means any medical device which is
a
reagent
reagent product
calibrator
control material“… whether used alone or in combination,
kit intended by the manufacturer to be used in
instrument vitro for the examination of specimens,
apparatus
including blood and tissue donations, derived
from the human body, solely or principally for
equipment
the purpose of providing information :…”
software
or system….
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“…information
- concerning a physiological or pathological process or
state, or
- concerning congenital physical or mental impairments,
or
- concerning the predisposition to a medical condition or
a disease, or
- to determine the safety and compatibility with
potential recepients, or
- to predict treatment response or reactions, or
- to monitor therapeutic measures. “
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Specimen receptacles remain IVDs
•Products for general laboratory use and for research

use are not IVD, unless such products, in view of their
characteristics, are specifically intended by their
manufacturer to be used for in vitro diagnostic
examination
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•“Accessories” , whilst not being in vitro diagnostic

medical devices themselves, but intended by its
manufacturer to be used together with one or several
particular IVD to specifically enable the in vitro diagnostic
medical device(s) to be used in accordance with its/their
intended purpose(s) or to specifically and directly assist
the medical functionality of the in vitro diagnostic
medical device(s) in view of its/their intended purpose(s)
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Key Changes IVD-R vs IVD-D
1. wider scope
2. stronger supervision of & more powerful Notified
Bodies
3. Reclassification Revolution ! & Conformity Assessment
Procedures
4. Classification Rules
5. Understanding the Transition Period
6. new focus on Clinical Evidence
7. new Economic Operators
8. Vigilance and PMS
9. Eudamed and PRRC
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Scope Expansion of the IVD-R vs the
IVD-D
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scope expansion of the IVD-R
it covers more than the IVD-D !
• LDTs (with some exceptions)

• Tests providing information about the predisposition to a
medical condition or a disease (e.g. genetic tests) and
• Tests providing information to predict treatment response
or reactions (e.g. companion diagnostics), which are
considered as in vitro diagnostic medical devices ;
• Medical software, is now explicitly mentioned in the
definition of IVDs/MDs.
• New categories: POC IVDs (NPT = Near Patient Tests) / CoDx
• Test Services – Distant Sales – Internet Sales
• Claims
• Economic Operators
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exclusion for “true LDTs”
Article 5.5 specifies that the IVD-R doesn’t apply to devices

manufactured and used only within Health Institutions provided
that:
• Annex I GSPR are met
• devices are manufactured and used ONLY within EU Health
Institutions
• devices are not transferred to other legal entities
• lab of the HI complies with ISO 15189 (or applicable national
provisions including accreditation)
• there is no commercial product available - art. 5.5 (d)
• are not made on an industrial scale - art. 5.5 (2nd-last §)
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scope expansion: genetic tests
The “rapporteur” in the EU Parliament on the new IVD-R was

Dr. Peter Liese.
Medical Doctor particularly interested in genetic testing and
genetic diseases.
Art. 4: “Genetic Information, counselling and informed consent”

• the individual being tested is provided with genetic
counselling (relevant info on the nature, significance,
implications)
• particularly for those cases considered untreatable
• and obviously all in class C…
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scope expansion: test services and
distance sales
Article 6.1: Distance sales (or “internet sales”)
are covered by the IVD-R
Article 6.2: Test Services
Fast growing business model:
specimen collection kit distributed
specimens sent to lab
test performed
results delivered
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scope expansion: test services (contd.)
•Article 6 deals with those test services in which patient samples

are shipped to the labs (in or out of the EU) and testedthere and
the results are then provided to either physicians or directly to
patients.
•SUCH TEST SERVICES ARE WITHIN THE SCOPE OF THE IVD-R
•This is already the case with the IVD-D but the IVD-R makes this
super clear !
•These business models typically have a specimen collection kit
which is “placed on the market” and is used to collect the samples
and send them to the relative labs.
•This is a unique item which switches regulatory regime before /
after use !
•Before use: specimen receptacle / After use: biological specimen
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scope expansion: claims
•Article 7 indirectly introduces the potential obligation
to have all marketing/advertising material approved or
at least controlled (by whom?)
•Article 7: Claims
•In the labelling, instructions for use, making available, putting into service
and advertising of devices, it is prohibited to use text, names, trademarks,
pictures and figurative or other signs that may mislead the user or the
patient with regard to the device’s intended purpose, safety and
performance by:
•(a) ascribing functions and properties to the product which the product
does not have;
•(b) creating a false impression regarding treatment or diagnosis, functions
or properties which the product does not have;
•(c) failing to inform of a likely risk associated with the use of the product in
line with its intended purpose;
•(d) suggesting uses of the product other than those declared in the
intended purpose when the conformity assessment was carried out.
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scope expansion: claims (contd.)
• What does “prohibited” mean?
• NCAs can enforce (fines and retraction / rectification)

• Notified Body can write you up for a major non-
conformity (e.g. if the claim is made in the IFU or label)
• Under EU advertising law it means that competitors
have a direct action in court in the member states
• Will need to see how this affects current wide

differences between member states with regard to
private enforcement of claims regarding medical
devices
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scope expansion: new IVD categories
IVD-Directive IVD-Regulation
2 IVD categories: 4 IVD categories:
• professional use • professional use

• self test • NPT
• CoDx
•4 classes • self test
• Annex II List A
• Annex II List B 4 classes: A, B, C, D
• self-tests
• “all others”
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scope expansion: companion diagnostics
And finally the “cherry on the pie”

Definition: (Art. 2.7) '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
• identify, before and/or during treatment, patients likely to be at
increased risk for serious adverse reactions as a result of
treatment with the corresponding medicinal product;
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SCOPE EXPANSION: COMPANION DIAGNOSTICS
• (Whereas 11) Companion diagnostics are essential to define

patients’ eligibility to specific treatment with a medicinal product
through the quantitative or qualitative determination of specific
markers identifying subjects at higher risk of developing adverse
reaction to the specific medicinal product or identifying patients
in the population for whom the therapeutic product has been
adequately studied, and found safe and effective. Such
biomarker(s) may be present in healthy subjects and/or in
patients.
• (Whereas 12) Devices that are used with a view to monitoring a
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 companion
diagnostics.
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SCOPE EXPANSION: COMPANION DIAGNOSTICS
•Art. 48.4 2nd§: For companion diagnostics the notified body

shall consult the concerned competent authority designated in
accordance with Directive 2001/83/EC 24 or the European
Medicines Agency (EMA), as applicable, in accordance with the
procedures set out in point (k) of Section 3 of Annex X.
•Performance Evaluation Studies for CoDx are to be considered
as interventional studies
•They are in class C as per Classification Rule 3 point “f”
•The medicinal agency consulted (or EMA) shall give an opinion
within 60 days which could be extended for another 60 days.
•NB may (or may not) take into account such an opinion.
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Stronger !
Understanding the
new role of Notified Bodies
Fewer !
More Expensive!
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Key changes # 2 & 3: Notified Bodies
1. Emphasis on Traceability
3.NB reinforcement plan
4. Extension to “Other Economic Operators”
The absolute need to strengthen the controls of
NBs over manufacturers and the controls of the
Authorities over the competence and work of
NBs. This originated:
Action Box • enforcement of unannounced visits
Are we trained to handle unannounced
• establishment of the (multi-country)
audits?
joint committee for the assessment and
Have we extended this awareness /
periodic review of NBs.
readiness to our key suppliers ?
Are their responsibilities clearly defined?
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Key change 3: More power to NBs
• NBs will cover much more of the IVD market due to the new
classification rules
• They are responsible for assessing/inspecting the compliance of
the whole supply chain – importers & distributors – and 3rd
parties acting on their behalf for example: storage & distribution
companies
• They can and will perform unannounced inspections/audits &
physical-laboratory tests on devices
• They will verify the requirement that manufacturers & AR have
the qualified RA person
– university degree + 1 year RAQS experience –or
– 4 years RA RAQS experience
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Notified Bodies – who are they ?
Private or Governmental organizations which have been
demanded the task to review & authorized Medical
Devices and IVDs before they are placed on the market.
Not all classes are subject to NB review & approval. It depends of

the device classification:
Under the CURRENT DIRECTIVES NBs are involved in:
• MDs: Class I if sterile or with a measuring function, Class IIa, Iib

and III
• Class IIa, IIb, and III need NB involvement
• IVDs: Annex II List A or B and for self test products
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Continued Role of NBs…
• the dual role of Essential Requirements and Technical Details

(harmonized standards, other standards or own methods…).
– now the ERs are called: General Safety and Performance
Requirements (GSPR)
• The dual role of Competent Authorities and Notified Bodies
– Notified Bodies primarily involved in the pre-market review
– CAs primarily involved in the post-market review
• The importance of having a Quality Management System ISO
13485 “like”
• The concept of “State Of The Art”
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enforcement & monitoring of NBs
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enforcement & monitoring of NBs (contd.)
Representatives of designating authorities of two other Member States

shall, in coordination with the designating authority of the Member
State in which the conformity assessment body is established and
together with a representative of the Commission, participate to the
assessment of the conformity assessment body, including the on-site
assessment.
The designating authority of the Member State where the conformity

assessment body is established shall give those representatives timely
access to the documents necessary to assess the conformity assessment
body.
They shall produce within 45 days after the on-site assessment a report,
which shall contain at least a summary of identified non-compliances
with the criteria set out in Annex I and recommendation with regard to
the designation of the notified body
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Art. 5: Surveillance & Monitoring
The Designating Authority must monitor its NBs
• at least every year (for NBs w/ more than 100 clients)

• at least every 1.5 years (for NBs w/ less than 100
clients)
• NBs are available on the official EU Commission site:

NANDO
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Stronger monitoring of NBs
• Designation & monitoring of NBs is left to MS but

w/ stricter requirements
• Any new designation & monitoring will be subject to “joint
assessments” by experts nominated by EC & MS
• The “Joint Assessment Committee” is formed of:
– 2 Subject Matter Experts nominated by the European
Commission
– 2 Subject Matter Experts nominated by 2 EU Member State
countries
– Representative(s) from the Country Competent Authority
where the applicant NB has legal site of business.
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Stronger monitoring of NBs
• Designation & monitoring of NBs is left to MS but w/ stricter
requirements
• Any new designation & monitoring will be subject to “joint assessments” by
experts nominated by EC & MS
• The Member States shall levy fees for the designation and
monitoring of notified bodies to ensure sustainability of the
monitoring of those bodies by Member States and to establish a
level playing field for notified bodies
• The national authority responsible for notified bodies shall
continuously monitor the notified bodies to ensure ongoing
compliance / at least once a year on-site visits to each NB
• The EC has full authority to monitor & force the de-listing of the
NBs as well !
• Periodic rotation of NB assessors ! Slide 34 of 213
Unannounced – Audits Commission Recommendation
It was there !! In the IVD-Directive since the very beginning !

Annex IV “EC Declaration Of Conformity”
FULL QUALITY ASSURANCE SYSTEM
5.4. In addition, the notified body may pay unannounced visits to the
manufacturer. At the time of such visits, the notified body may, where
necessary, carry out or ask for tests in order to check that the quality system is
working properly. It must provide the manufacturer with an inspection report
and, if a test has been carried out, with a test report.
But nobody did it !
Now it’s too late and we have

EU Commission Recommendation
24 Sept. 2013 which essentially
changed the “may pay” in “will pay”
and industry will pay…
do you have a “UA” SOP ? ? ?

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Unannounced – Audits Commission Recommendation (contd.)
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Unannounced – Audits Commission Recommendation (contd.)
(c) To verify the day-to-day compliance with legal obligations, notified bodies
should, in addition to the initial, surveillance or renewal audits, visit the manu-
facturer or, if this is likely to ensure more efficient control, one of its
subcontractors in charge of processes which are essential for ensuring
compliance with legal requirements (‘critical subcontractor’) or a supplier of
crucial components or of the entire devices (both: ‘crucial supplier’) without
prior notice (‘unannounced audits’) in accordance with Annex III.
At least once every 5 years

Should increase the frequency for high-risk devices or for frequently non-
compliant devices or upon “specific information”…
Timing should be unpredictable
=< 1 day / 2 auditors
Should be foreseen in manufacturer/NB contracts (including subcontractors)
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Classification Revolution & new
Conformity Assessment Procedures
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The end of the self-certification era...
General Lab IVD
Instruments for IVD instruments culture media stains specimen recls
IVD-D: 85%
self-certification IVD-R: 90%?
under NBs
This is CLASSIFICATION REVOLUTION !!!

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The end of the self-certification era...
Think about the implications of re-classification…
• Enormous workload increase for NBs

• Fewer NBs available
• Potential for long waiting lists…
• Therefore what needs to be done ?
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IVD Directive 98/79/EC
Non-Annex II for
Annex II List A Annex II List B Self-Testing
• HIV-1 and HIV-2 • anti-Duffy, anti-
Kidd
• HTLV-I and HTLV-II
• Irregular anti-
• Hepatitis B, C, D erythrocytic
antibodies
• Blood groups: A B O, • Rubella, Non-Annex II for
Toxoplasmosis, Professional Use
Rhesus (C,c,D,E,e),
CMV, Chlamydia
anti-Kell
• Phenylketonuria
• HLA : -DR, -A, -B
• vCJD • PSA
• Trisomy 21
• self-tests for blood
sugar
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Classification in the new Regulation
• Based on 7 classification rules

• 4 classes:
– A is lowest risk – least regulated
• Self-Declaration
– D is highest risk – highest level of regulation
• Almost no products in Class A!
– Most products/manufacturers will require
Notified Body intervention
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Current vs. Future
Current Directive Future Regulation
Annex II List A Class D
Annex II List B Risk Class C
Level
Class B
Non-Annex II Class A
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Conformity Assessment Procedures
• Class A
– Declaration of Conformity (Art. 17)
– Product : Technical Documentation (Annex II & III)
– Incident reporting and post-production review
– Quality system, risk management and other general
requirements
– No notified body certification unless for sterile products
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Conformity Assessment Procedures –
Class A
Sterile EC Declaration of
Conformity
Not sterile
Sterility
(Annex IX or X)
Notified Body
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CAP – Class B
Notified Body CAP – Class C
Manufacturer
QA (Annex IX) w/out

review of TD (Chapt. 2)
+ TD review on generic EC Type Examination Production QA

device category
(Annex X) + (Annex XI)
No NB
surveillance *substantial changes of the
audits * QMS and of the product
range have to be
communicated to the NB,
which may decide to do an
audit.
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CAP – Class C
Notified Body
Manufacturer’s
choice
QA (Annex IX) w/out

review of TD (Chapt. 2)
+ TD review on generic EC Type Examination Production QA

device group
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Reference CAP Class D
Laboratories
Notified Body if no CS & new type MDCG Expert

Panels
Manufacturer’s
choice
QA (Annex IX) + review of

TD (Chapt. 2)
+ batch verification EC Type Examination Production QA

by Ref. Labs
+ batch verification
by Ref. Labs
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Art. 50: Scrutiny Procedure for Class D IVDs
Should apply only to

new Class D for
which no CS exist
EC: “it’s a transitional arrangement that would disappear once there is evidence that it’s no longer needed” (Commissioner
Slide 50 of 213 Mim
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General Safety and
Performance Requirements
• Important changes
– Extensive section on risk management
– Separate section on devices incorporating materials of
biological origin
– Devices with measuring function
• In current version: only instruments or apparatus
– Electronic programmable systems
– Near-patient testing: same requirements as self-testing
– GENERAL: more detail and more extensive
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Technical Documentation
• 10 pages (Annex II)

– Detailed description
• General
• Labeling
• Design and manufacturing
• General safety and performance requirements
• Risk management
• Product verification and validation
• “STED” (Summary Technical Documentation)
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Technical Documentation on Post-
Marketing Surveillance
• Annex III
• Post-Marketing Surveillance Plan
– Collection and utilization of information
– Content of the plan and documentation
• Periodic safety report
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Understanding the
Classification Rules
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IVD Classes & Classification Rules
• Four regulatory classes (based on 7 classification

rules)
– Class A: low patient risk/ no public health risk

(instruments, culture media, etc.)
– Class B: medium patient risk / no public health risk
– Class C: high patient risk / no or moderate public health
risk
– Class D: high patient risk / high public health risk
ALL EXCEPT CLASS A WILL REQUIRE NOTIFIED BODY INVOLVEMENT

(90%?)
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Classification (Annex VIII)
Implementing rules
Classification governed by intended use

If to be used in combination with another device, rules apply
separately to each device
Accessories are classified in their own right separately from the
device with which they are used.
Software, which drives a device or influences the use of a
device, falls automatically in the same class as the device. If
software is independent of any other device, it is classified in
its own right.
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Classification
Implementing Rules
Calibrators intended to be used with a device shall be classified
in the same class as the device
Standalone control materials with quantitative or qualitative
assigned values intended for one specific analyte or multiple
analytes shall be classified in the same class as the device
All rules have to be taken into consideration
If multiple intended uses: highest class applies
If several rules apply, the rule resulting in the highest
classification applies
Each rule applies to first line assays, confirmatory assays and
supplemental assay
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Classification Rules (made easy)
1. Transmissible agents in blood/tissues for transfusion/transplantation -> D
Transmissible agents causing a life threatening disease with high/undefined
risk of propagation -> D
2. Blood grouping / tissue typing -> immunological compatibility for
transfusion/transplant
-> C (except for ABO-Rhesus-Kell-Duffy-Kidd which are D)
3. - Sexually transmitted agents / infectious agents w-limited risk of
propagation or w-risk that wrong result may lead to death or severe
disability
- prenatal screening to determine mother status towards transmissible
agents
- CoDx / disease staging tests / cancer screening
All are C
- Human Genetic tests
- monitoring of medicinal products
- infectious disease patient management
- screening for congenital disorders in foetus
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4. Self-tests -> Class C
Except: pregnancy, fertility, cholesterol, detection of glucose,
erythrocytes, leucocytes and bacteria in urine) -> B
NPT = classified in their own right.
5. Instruments & specimen receptacles -> A
– products for general laboratory use, accessories which possess
no critical characteristics, buffer solutions, washing solutions
reagents, and general culture media and histological stains,
intended by the manufacturer to make them suitable for IVD
procedures related to a specific examination;
– Instruments intended by the manufacturer to be used for IVD
procedures
– Specimen receptacles
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6. Whatever is not covered by the above rules -> B

7. Controls w/out a quantitative/qualitative value -> B
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Understanding the
Transition Period
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Transition period
IVD-D / IVD-R timing overview

2024-05-26
Entry intoInto
Entry forceForce
of IVD-R IVD-R starts to “apply”
Full Applicability
(example: 2017-01)
2017-05-26 (example: 2022-01)
2022-05-26
↓ ↓
IVD-D – IVD-D – IVD-D – IVD-D – IVD-D – IVD-D – IVD-D – IVD-D
IVD-R - IVD-R – IVD-R – IVD-R – IVD-R – IVD-R – IVD-R – IVD-R – IVD-R -
. 5 years transition period .
TP extension for 2025-05-26
valid EC IVD-D
certificates
OK to sell IVD-D devices

already placed on the EU
market before 2025-05-26
NB-issued deadline for submission of application !
Slide 64 of 213
Additional considerations...
1. Reference Labs will NOT be designated until 18 months before the end
of the TP: this means they will be announced as of 2021-01-01.
2. Manufacturers may need to have 2 part numbers: one for the IVD-D
product / one for the IVD-R one.
3. Both certificates will have to be maintained and recertification
completed is required
4. Control of labeling for IVD-D vs. IVD-R would need to be demonstrated
5. No discussions have been held between NBs and CAs about the ground
rules to coordinate label changes
6. NBs plan to issue a “white paper” in order to explain these issues (and
others)
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The easiest definition made complex...
The TP is a defined-duration time during which both

legislative systems do apply (14 words)
Art. 110 of the IVD-R deals with the “Transitional Provisions”.

It has 7 sub-points / 460 words
let’s try to translate these words into common language...
Slide 66 of 213
Art. 110.1
• From the date of application of this Regulation any publication

of a notification in respect of a notified body in accordance with
Directive 98/79/EC shall become void
translation:
• at the end of the TP all the nominations of IVD-D notified

bodies will become void
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Art. 110.2 first §
• Certificates issued by notified bodies in accordance with

Directive 98/79/EC prior to the entry into force of this
Regulation shall remain valid until the end of the period
indicated on the certificate, except for certificates issued in
accordance with Annex VI of Directive 98/79/EC which shall
become void at the latest two years after the date of
application of this Regulation
translation:
• certificates issued before May.17 stay valid for their

duration
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Art. 110.2 second §
• Certificates issued by notified bodies in accordance with Directive 98/79/EC after

the entry into force of this Regulation shall become void at the latest two years
after the date of application of this Regulation
translation:
• IVD-D certificates issued during the TP will expire at the

latest in May. 2024 (2 years after end of TP)
Slide 69 of 213
Art. 110.3
• By way of derogation from Directive 98/79/EC, devices which

comply with this Regulation may be placed on the market
before its date of application
translation:
• IVD manufacturers are allowed to place their IVD-R

compliant (IVD-R CE marked) products in the EU market
during the TP
• Class B to D manufacturers will be able to do so once IVD-
R NBs will be nominated
Slide 70 of 213
Art. 110.4
• Devices which were lawfully placed on the market pursuant to Directive

98/79/EC prior to the date referred to in Article 90(2) may continue to be
made available on the market or put into service until three years after
that date
translation:
• IVD-D products placed on the EU market during the TP

may continue to be sold till 3 years after the end of the TP
(May 2025)
• “sold” = made available / put into service

Slide 71 of 213
Art. 110.6
• By way of derogation from Directive 98/79/EC, conformity

assessment bodies which comply with this Regulation may be
designated and notified before its date of application. Notified
bodies which are designated and notified in accordance with
this Regulation may apply the conformity assessment
procedures laid down in this Regulation and issue certificates in
accordance with this Regulation before its date of application.
translation:
• IVD-R CABs & NBs may be designated before end of the TP

and can operate as such
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Art. 110.7
• As regards the devices subject to the procedures laid down in Article 48, paragraphs
3 and 4, paragraph 5 applies provided that the necessary appointments to the
MDCG and expert panels and of reference laboratories have been made
Note: Art.48 §3 deals with Class D CAP; Art.48 §4 deals with the appointment
of MDCG, Expert Panels and Reference Laboratories
translation:
• IVD-R CABs & NBs may operate as such for Class D products
provided that MDCG, Expert Panels, and Ref. Labs have been
appointed (and are operational)
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Art. 110.9
• Authorizations granted by competent authorities of the Member States in

accordance with Article 9(12) of Directive 98/79/EC shall keep the validity
indicated in the authorization .
translation:
• “Orphan” IVDs approved by the Authorities w/out

complying with the IVD-D shall remain valid
Slide 74 of 213
Art. 110.10
• Until the Commission, in line with Article 24(2), has designated the UDI
assigning entities, GS1 AISBL, HIBCC and ICCBBA shall be considered as
designated UDI assigning entities.
translation: implementing acts
doesn’t need one… International Council for Commonality in Blood

Banking Automation
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Performance Evaluation &
Clinical Evidence
as per the IVD-R
Slide 76 of 213
How many IVD
manufacturers are
approaching
Clinical Evidence
as per the IVD-R ?
Slide 77 of 15
PERFORMANCE EVALUATION
“a continuous process”
Performance
Evaluation Plan
Pre-Market PMS
Performance
Evaluation Reactive
Complaints, Literature Reviews etc.
Scientific Clinical Vigilance

Validity performance
Analytical Proactive
Performance Clinical Studies, Surveys, Feedback
forms etc.
PMPF
Slide 78 of 213
CLINICAL EVIDENCE – SETTING THE SCENE
The IVD-R puts much more emphasis on the need for

manufacturers to demonstrate the CLINICAL EVIDENCE for their
devices (all of them!)
The prelim to the text of the regulation states
This Regulation sets high standards of quality and safety for
those devices by ensuring, among other things, that data
generated in clinical performance studies is reliable and robust
and that the safety of subjects participating in clinical
performance studies is protected.
Clinical expectations continue to increase
Slide 79 of 213
CLINICAL EVIDENCE
• There is a strong influence of the “pharma” approach.

• The concept of 'sponsor' is introduced
• clinical performance studies that do not pursue a regulatory
purpose are not covered by this Regulation = “post CE-
marking evaluations”
• every interventional clinical performance study and other
clinical performance study involving risks for the subjects of
the study shall be registered in a publicly accessible electronic
system which the Commission will set up
• new focus on “clinical evidence” which can be assessed by
“clinical performance studies”
• ISO standard available: ISO 20916 Clinical performance studies
for IVDs using specimens from human subjects.
Slide 80 of 213
CLINICAL EVIDENCE
Analytical
Scientific Performance Clinical
Validity Performance
Slide 81 of 213
CLINICAL EVIDENCE
• Scientific validity of an analyte means the association of

an analyte to a clinical condition or a physiological state;
• Analytical performance means the ability of a device

to correctly detect or measure a particular analyte
• Clinical performance means the ability of

a device to yield results that are
correlated with a particular clinical
condition or a physiological or
pathological process or state in
accordance with the target population
and intended user
Slide 82 of 213
Does the assay yield clinically meaningful
results?
Scientific Validity + Clinical + Analytical

Performance Performance
Why it makes clinical sense
To test such analyte ?
= How well (how precisely) the test

measures such analyte ?
Clinical
Evidence
which “pillar” is which “pillar” is assay

analyte specific? specific?
Test !
what conclusions do you draw from
your answers?
Slide 83 of 213
Analyte
Lab results with own assay Scientific

Analytical Performance Scientific Validity Literature
APR SVR
PER
IVD Clinical
Device Condition
Clinical Performance
CPR
Clinical Validation studies
or
Published Literature with own assay
Slide 84 of 213
Clinical Evidence
Three documents have been developed by the GHTF SG1 IVD subgroup and approved at
the GHTF SC meeting on Oct 30, 2012:
•SG5/N6:2012
– Clinical Evidence for IVD medical devices – Key Definitions and
Concepts
•SG5/N7:2012
– Clinical Evidence for IVD medical devices – Scientific Validity
Determination and Performance Evaluation
•SG5/N8:2012
– Clinical Evidence for IVD medical devices – Clinical Performance
Studies for In Vitro Diagnostic Medical Devices
Slide 85 of 213
Scientific Validity
• Definition: The association of an analyte to a clinical
condition/physiological state.
• Explanation: Scientific validity is often identified from academic research,

and is supported by studies evaluating the analyte for potential clinical
applications. Literature review and where applicable, feasibility and/or
scientific validity studies performed by the manufacturer will help to
establish the potential scientific validity.
For many analytes the scientific validity is well established. An example

would be calcium in serum. The scientific validity for this analyte is well
established as being linked to the diagnosis and treatment of parathyroid
disease, a variety of bone diseases, chronic renal disease and tetany.
However some IVD medical devices are developed when the scientific
validity of the analyte is still emerging. An example would be a newly
characterized biomarker that is potentially useful in monitoring recurrence
or progressive disease in patients with cancer.
Slide 86 of 213
Scientific Validity sources
• Information on IVD medical devices that measure the same
analyte and with the same intended use that have marketing
history (e.g. Instructions for Use)
• Literature searching: this information might be found in peer
reviewed articles, regulatory guidance documents, conference
proceedings, etc.
• Review of expert opinions: this information might be found in
sources that include textbooks, clinical guidance documents,
position statements from academic and professional organizations.
• Results from proof of concept studies: these studies are usually
smaller scale scientific studies to identify the fundamental
association of the analyte with the clinical condition/physiological
state.
• Results from clinical performance studies
Slide 87 of 213
Analytical Performance
• Definition: The ability of an IVD medical device to detect or measure a
particular analyte.
• Explanation: The demonstration of analytical performance supports the

intended use of the IVD medical device. Analytical performance is
determined by the collection of testing results (analytical performance
data) from analytical performance studies used to assess the ability of the
IVD medical device to measure a particular analyte. Analytical
performance may include analytical sensitivity (e.g. limit of detection),
analytical specificity (e.g. interference, cross-reactivity), accuracy (derived
from trueness and precision), and linearity.
• Content of analytical performance described in STED document
Slide 88 of 213
Clinical Performance
• Definition: The ability of an IVD medical device to yield results that are
correlated with a particular clinical condition/physiological state in
accordance with target population and intended user.
• Explanation: The demonstration of clinical performance supports the

intended use of the IVD medical device. Clinical performance
demonstrates that the IVD medical device, depending on its test purpose,
identifies an individual’s current or future state or evaluates changes in an
individual’s state. Clinical performance may include expected values,
diagnostic sensitivity and diagnostic specificity based on the known
clinical/physiological state of the individual, and negative and positive
predictive values based on the prevalence of the disease.
Clinical performance data can be derived from multiple sources such as

clinical performance studies, literature, or experience gained by routine
diagnostic testing.
Slide 89 of 213
Performance Study
‘performance study’ means a study undertaken to establish or

confirm the analytical or clinical performance of a device
They should be planned and documented this should include

• the rationale,
• objectives,
• design methodology,
• monitoring,
• statistical considerations,
• organisation and conduct of the study
Slide 90 of 213
Performance Study Plans
Performance Study Plans should be:
• preapproved
• executed by staff trained staff
• any changes approved before being executed
• non conformities documented and processed
accordingly
Slide 91 of 213
Requirements for Performance Evaluation
The performance evaluation shall be thorough and objective, considering

both favourable and unfavourable data.
This includes favourable and unfavourable literature and performance

study data
Its depth and extent shall be proportionate and appropriate to the

characteristics of the device including the risks, risk class, performance
and its intended purpose
Performance Evaluation Plan is required, if any element of the plan is not

completed because it is not appropriate due to the characteristics of the
device it should be justified
Slide 92 of 213
Performance Evaluation Plan should have:
• a specification of the intended purpose of the device

• a specification of the characteristics of the device
• a specification of the analyte or marker
• a specification of the intended use of the device
• identification of certified reference materials or reference
measurement procedures to allow for metrological traceability
• a clear identification of specified target groups with clear indications,
limitations and contraindications
• an identification of the general safety and performance requirements
• a specification of methods , including the appropriate statistical tools
• a description of the state of the art, including an identification of
existing relevant standards, CS, guidance or best practices documents
Slide 93 of 213
Performance Evaluation Plan should have:
• an indication and specification of parameters to be used to

determine the acceptability of the benefit/risk ratio
• for software qualified as an IVD device, an identification and
specification of reference databases and other sources of data
used as the basis for its decision making
• an outline of the different development phases including the
sequence and means of determination of the scientific validity,
the analytical and clinical performance, including an indication of
milestones and a description of potential acceptance criteria
• the post-market performance follow-up (PMPF) plan
Slide 94 of 213
Intended purpose
• 'intended purpose' means the use for which the device is

intended according to the data supplied by the manufacturer
on the label, in the instructions for use or in promotional or
sales materials or statements and as specified by the
manufacturer in the performance evaluation
• Where specific devices have no analytical or clinical

performance or specific performance requirements are not
applicable, it is appropriate to justify in the performance
evaluation plan, and related reports, omissions related to these
requirements.
Slide 95 of 213
Clinical Performance Study Plan (Annex XIII 2.3.2)
The clinical performance study plan (CPSP) defines the

rationale, objectives, design and proposed analysis,
methodology, monitoring, conduct and record-keeping of the
clinical performance study. It shall contain in particular the
information as laid down below. If part of this information is
submitted in a separate document, it shall be referenced in
the CPSP.
• (a) Identification of the clinical performance study and the

CPSP by the single identification number.
Slide 96 of 213
Clinical Performance Study Plan (Annex XIII 2.3.2)
• (b) Identification of the sponsor – name, address of the

registered place of business and contact details of the sponsor
and, if applicable, the name, address of the registered place of
business and contact details of his contact person/ legal
representative.
• (c) Information on investigator(s) (i.e. principal, coordinating,

other; qualifications; contact details) and investigation site(s)
(number, qualification(s), contact details) and, in the case of
devices for self-testing, the location and number of lay persons
involved.
Slide 97 of 213
Clinical Performance Study Plan (contd.)
• (d) The starting date and scheduled duration for the

clinical performance study.
• (e) Identification and description of the device, its
intended purpose, the analyte(s) or marker(s), the
metrological traceability, and the manufacturer.
• (f) Information about the type of specimens under
investigation.
• (g) Overall synopsis of the clinical performance study,
its design type (eg observational, interventional)
together with the objectives and hypotheses of the
study, reference to the current state of the art in
diagnosis and/or medicine.
Slide 98 of 213
• (h) A description of the expected risks and benefits of

the device and of the clinical performance study in the
context of the state of the art in clinical practice, the
medical procedures involved and patient
management.
• (i) The instructions for use of the device or test
protocol, the necessary training and experience of the
user, the appropriate calibration procedures and
means of control, the indication of any other devices,
medical devices, medicinal product or other articles to
be in- or excluded and the specifications on any
comparator or comparative method used as reference,
Slide 99 of 213
• (j) Description of and justification for the design of the clinical

performance study, its scientific robustness and validity,
including the statistical design, and details of measures to be
taken to minimise bias (e.g. randomisation) and management
of potential confounding factors.
• (k) The analytical performance according to point a) of Section
9(1) of Annex I with justification for any omission.
• (l) Parameters of clinical performance according to point b) of
Section 9(1) of Annex I to be determined, with justification for
any omission; specified clinical outcomes/endpoints
(primary/secondary) used with a justification and the
potential implications for individual health and/or public
health management decisions
Slide 100 of 213
• (m) Information on the performance study population:

specifications of the subjects, selection criteria, size of
performance study population, representativity to target
population and, if applicable, information on vulnerable
subjects involved (e.g. children, immuno-compromised,
elderly, pregnant women);
• (n) Information on use of data out of left over specimens
banks, genetic or tissue banks, patient or disease registries
etc. with description of reliability and representativity and
statistical analysis approach; assurance of relevant method for
determining the true clinical status of patient specimens.
• (o) Monitoring plan;
• (p) Data management;
Slide 101 of 213
• (q) Decision algorithms;

• (r) Policy regarding any amendments (incl. those according to
Article 71) to or deviations from the CPSP, with a clear
prohibition of use of waivers from the CPSP
• (s) Accountability regarding the device, in particular control of
access to the device, follow-up in relation to the device used in
the clinical performance study and the return of unused,
expired or malfunctioning devices.
• (t) Statement of compliance with the recognized ethical
principles for medical research involving humans and the
principles of good clinical practice in the field of clinical
performance studies as well as with the applicable regulatory
requirements.
Slide 102 of 213
• (u) Description of the informed consent process,

including a copy of the patient information sheet and
consent forms.
• (v) Procedures for safety recording and reporting,
including definitions of recordable and reportable
events, and procedures and timelines for reporting.
• (w) Criteria and procedures for suspension or early
termination of the clinical performance study,
Slide 103 of 213

• (w) Criteria and procedures for suspension or early termination

of the clinical performance study,
• (x) Criteria and procedures for follow up of subjects following
completion of a performance study, procedures for follow up
of subjects in the case of suspension or early termination,
procedures for follow up of subjects who have withdrawn their
consent and procedures for subjects lost to follow up.
Procedures for communication of test results outside the study,
including communication of test results to the performance
study subjects.
Slide 104 of 213

• (y) procedures for communication of test results outside the
study, including communications of test results to the
performance study subjects;
• (z) Policy as regards the establishment of the clinical
performance study report and publication of results in
accordance with the legal requirements and the ethical
principles referred to in Section 2.2
• (z) List of the technical and functional features of the device
indicating those that are covered by the performance study.
• (aa) Bibliography.
Where any of the above-mentioned elements are not deemed appropriate for
inclusion in the CPSP due to the specific study design chosen (e.g. use of left-
over samples versus interventional clinical performance studies), a
justification shall be provided.
Slide 105 of 213
Slide 106 of 213
details.. details..
• Need solid guidance on “interventional studies”
– CDx studies ? Interventional
– Prospective studies done ad-hoc for the study ? Interventional
– What about a larger volume of blood being taken from the patient ?
• 1 extra mL ?
Legacy
• 1 extra tube ?
• An extra venopuncture ?
• Legacy Products
WHAT ?!?
– ehm… yes, you know… those old products placed on the market long ago…
they DON’T EXIST !
– sorry but according to the IVD-R
Slide 107 of 213

Clinical evidence summary based on
GHTF published documents
Established and Established and non- Novel test
standardized test and standardized test (Annex VI 2.13)
class A IVD
Scientific Validity Derived from Derived from Derived from

literature literature literature, review of
Not for Class A expert opinions plus
some concept studies
Analytical Done at Done at Done at
Performance manufacturer’s manufacturer’s manufacturer’s
premises premises premises
Clinical Performance Not Needed Derived from Most likely

Surely not for Class A Literature or Performance study at
Routine diagnostic external site (one site
testing or can be manufacturer
Performance study at site)
external site (one site
can be manufacturer
site)
Slide 108 of 213
More emphasis on performance evaluation
•Article 5 Placing on the market and putting into service

•Demonstration of conformity with the general safety and performance requirements
shall include a performance evaluation in accordance with Article 47.
•Article 10 General obligations of the manufacturer

•Manufacturers shall conduct a performance evaluation in accordance with the
requirements set out in Article 56
and Annex XII, including post-market performance follow-up.
•(recital 62) As a general rule, clinical evidence should be sourced from performance
studies to be carried out under the responsibility of a sponsor who can be the
manufacturer or another legal or natural person taking responsibility for the
performance study.
Slide 109 of 213

Performance Evaluation - “What’s in a name”
•Performance Evaluation according to the IVDD

• Device for ‘performance evaluation’ means any device intended by the
manufacturer to be subject to one or more performance evaluation studies in
laboratories for medical analyses or in other appropriate environments outside his
own premises
•Performance Evaluation according to the GHTF
• Assessment and analysis of data to establish or verify the performance of an IVD
medical device.
•Performance Evaluation according to the IVDR

• 'performance evaluation' means the assessment and analysis of data to establish or
verify the scientific validity, the analytical and, where applicable, the clinical
performance of a device
Slide 110 of 213

What does this mean?
• You need to carefully described the intended use e.g.
• Purpose screening/ diagnostic

• Who is the intended user?
• Intended population if applicable
• Specimen type
• You need to have the data to support this
• Claims/ marketing information/ websites all need to match and there needs to be
supporting data
Slide 111 of 213

Meeting clinical evidence requirements
• You will need objective evidence to support all 3 pillars

• No grandfathering
• Required for all products
• For near patient (point of care) testing data from suitable user
groups required nurse/ doctor/ hospital/ out patient
• For self testing lay user studies required from a representative
patient group
• This can be derived from a mixture of literature and data but data
will be required
• Existing data can be used provided the validity of the data can be
assured
• Studies could include PMS/ reimbursement studies
Slide 112 of 213
Understanding
Vigilance &
Post Market Surveillance
Slide 113 of 213

PERFORMANCE EVALUATION
“a continuous process”
Performance
Evaluation Plan
Pre-Market PMS
Performance
Evaluation Reactive
Complaints, Literature Reviews etc.
Scientific Clinical Vigilance

Validity performance
Analytical Proactive
Performance Clinical Studies, Surveys, Feedback
forms etc.
PMPF
Slide 114 of 213

Slide 115 of 213
Slide 116 of 213
manufacturer !
manufacturer !
competent authorities !
Slide 117 of 213

IVD-R Definitions
Post-Market Surveillance:
• means all activities carried out by the
manufacturers in cooperation with other
economic operators to institute and keep up to
date a systematic procedure to proactively
collect and review experience gained from their
devices placed on the market, made available
or put into service for the purpose of
identifying any need to immediately apply any
necessary corrective or preventive actions.
Slide 118 of 213
IVD-R Definitions
PMS:
• The purpose of PMS is also
to ensure that the device
continues to be compatible
with the “State of the Art”.
Slide 119 of 213

details.. details..
• State of the art is quoted 20 times in the IVD-R // it needs to be formalized in a

document as per a defined process!
– whereas #13
• The requirement to reduce risks as far as possible should be fulfilled
taking into account the generally acknowledged state of the art
– Art. 56.3
• The clinical evidence shall be such as to scientifically demonstrate, by
reference to the state of the art in medicine, that the intended clinical
benefit(s) will be achieved and that the device is safe.
– Art. 58.5(m)
• in the case of clinical performance studies, the analytical performance
has been demonstrated, taking into consideration the state of the art;
– Annex I – Chapt. II, 9.1:
• Devices shall be designed and manufactured in such a way that they are
suitable for the purposes referred to in point (2) of Article 2, as specified
by the manufacturer, and suitable with regard to the performance they
are intended to achieve, taking account of the generally acknowledged
state of the art.
Slide 120 of 213
details.. details..
• Annex IX – Chapt. 1, point 2.1 (last indent):

– a description of the procedures in place to keep up to date
the performance evaluation plan, taking into account the
state of the art.
• Annex XIII, Part A, 1.1 (PEP):
– a description of the state of the art, including an
identification of existing relevant standards, CS, guidance
or best practices documents
• Annex XIII, Part A, 1.3.2 (PER):
– the clinical evidence as the acceptable performances
against the state of the art in medicine;
Slide 121 of 213

There is no official definition in the IVD-R but…
Warning zone !
State of the art
Marketing Edge
Top Performers
Critical area !
This is where you don’t want to be!
Slide 122 of 213

IVD-R Definitions
Vigilance:
• No official definition in the IVD-R. However

“vigilance” is intended to be the: “Reporting of
serious incidents and field safety corrective
actions”.
• The IVD-R has practically incorporated the
MEDDEV 2.12-1 rev 8
• with the exclusion of the reporting forms
Slide 123 of 213

Vigilance Reporting
Complex Supply Chain can result in communication hurdles
Distributor End User
Importer
Own
Distributor
subsidiary
Own
Manufacturer
subsidiary
Distributor
Own End User
subsidiary Own
subsidiary
End User
Slide 124 of 213
IVD-D vs IVD-R
• 2 days (serious public  2 days (serious public
health threat) health threat)
• 10 days (death or  10 days (death or
unanticipated serious unanticipated serious
deterioration of deterioration of
health) health)
• no later than 30 days  no later than 15(*)
(others) days (others)
(*)This “small” change will have a profound impact on reporting practices.
More notification of “initial reports” to be followed by “false alarm” final reports.
Justification rationale moves from being an internal decision only to be one scrutinized by
the Health Authorities. Slide 125 of 213
IVD–R
DEFINITIONS
• The interpretation of what it
means for the manufacturer
“becoming aware” of the
incident is changing !
• too often the potential
vigilance case takes too
long to work its way up the
complex logistic chain !
Slide 126 of 213

IVD–R DEFINITIONS
Market Surveillance:
• means the activities carried out and measures taken by
public authorities to check and ensure that devices
comply with the requirements set out in the relevant
Union harmonisation legislation and do not endanger
health, safety or any other aspect of public interest
protection.
• Manufacturers are NOT directly responsible but…
• are impacted by the Authorities performance studies (TD)
• must be prepared to facilitate such studies in case requested
by the Authorities (who does what, how)
Slide 127 of 213

PMS Data Elements
Where to find data and how reliable is the data?
Surveys
(Product /
Customer)
PMPF
Competitive
Information
or Actions PMS Analysis
Published Literature
Service Reports, Customer

Discussions
Complaints and Incidents
Slide 128 of 213

PMS Data Elements
Proactive and Reactive elements
QMS
PMS
Reactive A comprehensive Post Market
Surveillance System looks at various
Complaints, Literature Reviews etc. data elements and consists of a:
• Reactive System
Vigilance • Proactive System (level and type of
activity dependent upon product
Proactive risk)
Clinical Studies, Surveys, Feedback

forms etc.
PMPF
Slide 129 of 213

Post Market Surveillance (PMS)
A good PMS process must be based on a Plan:

• An obligation of Art. 79, the Plan shall be based on the requirements given
in Section 1 of Annex III (TD for PMS)
• Shall be part of the TD as per Annex III requirements!
• PMS Plan shall addresses the collection and utilisation of information
coming from:
✓ serious incidents, including information from PSURs, and field safety corrective
actions
✓ records referring to non-serious incidents and data on any undesirable side-
effects,
✓ trend reporting,
✓ relevant specialist or technical literature, databases and/or registers,
✓ feedbacks and complaints, provided by users, distributors and importers
✓ publicly-available information about similar medical devices.
Slide 130 of 213

PMS Plan shall at least cover:
✓a proactive and systematic process to collect any information
referred above. The process shall allow a correct characterization of
the performance of the devices and shall also allow a comparison to
be made between the device and similar products available on the
market;
✓effective and appropriate methods and processes to assess the
collected data;
✓suitable indicators and threshold values that shall be used in the
continuous reassessment of the benefit-risk analysis and of the risk
management
✓effective and appropriate methods and tools to investigate
complaints and analyse market-related experience collected in the
field
✓methods and protocols to manage the events subject to the trend
report, including the methods and protocols to be used to establish
any statistically significant increase in the frequency or severity of
incidents as well as the observation period;
Slide 131 of 213
PMS Plan shall at least cover (contd.):

✓methods and protocols to communicate effectively
with competent authorities, notified bodies,
economic operators and users;
✓reference to procedures to fulfil the manufacturers
obligations of the post-market surveillance
✓systematic procedures to identify and initiate
appropriate measures including corrective actions;
✓effective tools to trace and identify devices for
which corrective actions might be necessary
✓a PMPF plan or a justification as to why a PMPF is
not applicable.
Slide 132 of 213

PMS flow-chart
Customer Competitor
Feedback (similar) products
Vigilance Complaints
FSCA
Post Market
Surveillance Plan
Scientific
Literature Review
PMPF Plan
PMPF Evaluation
Report
Performance Evaluation Risk Management

& Clinical Evidence TD Report
Slide 133 of 213

Post-market surveillance report:

• For class A and B devices
• It is the summary of the results and conclusions of the
analyses of the post-market surveillance data gathered as a
result of the post-market surveillance plan together with a
rationale and description of any preventive and corrective
actions taken.
• To be made available to the notified body and the competent
authority upon request.
• To be included in the Technical Documentation.
Frequency: once, max 2 years after launch

Slide 134 of 213
Periodic Safety Update Report (PSUR):
• For class C and D devices (for each device and where
relevant for each category or group of devices)
• It is the summary of the results and conclusions of the
analyses of the post-market surveillance data gathered as a
result of the post-market surveillance plan together with a
rationale and description of any preventive and corrective
actions taken.
• It shall set out:
✓the conclusions of the benefit-risk determination;
✓the main findings of the PMPF;
✓the volume of sales of the device and an estimate of the size
and other characteristics of the population using the device
and, where practicable, the usage frequency of the device.
Slide 135 of 213
Periodic Safety Update Report (PSUR) (cont.):

• To be updated annually
• For class D submitted annually to NB and
published in EUDAMED(*) together with the NB
evaluation
• For class C made available to the notified body and
the competent authority upon request
• To be included in the Technical Documentation
This means that TD more than ever has to be a living set of

documents !
Slide 136 of 213
Post Market Report For A
Do it once (before 2 years after launch) -> File it
(PMS) &B
For C Do it once a year -> File in T.D.

Periodic Safety
Update Report (PSUR)
For D
Do it once a year -> Send it to N.B. -> File in
T.D. to be published in EUDAMED
Risk/Benefit
PMPF Sales Volume Vigilance/FSCAs
report
Clinical Evidence
Report
Slide 137 of 213
IVD–R DEFINITIONS
PMPF: Post Market

Performance Followup
A specific process which is part of the PMS
process (Art. 10).
Indirectly defined by Art. 70.1 as: “…a performance study
conducted to further assess, within the scope of its
intended purpose, a device which already bears the CE
marking in accordance with Article 18(1) (‘PMPF study’)”.
Slide 138 of 213
IVD–R DEFINITIONS
PMPF is addressed by Part B of Annex XIII of the

IVD-R.
It belongs to the proactive part of PMS (the part
which is under the initiative of the manufacturer)
It can be thought as a post-launch continuation of
the performance studies made to support the CE-
marking
Note: PMPF can also be mandated by the NB! (Art.
51.3)
Art. 56.6: The performance evaluation and its documentation shall be updated
throughout the life cycle of the device concerned with data obtained from
implementation of the manufacturer's PMPF plan in accordance with Part B of
Annex XIII and the post-market surveillance plan referred to in Article 79.
Slide 139 of 213
Post Market Performance Follow-up
(PMPF)
PMPF Process:
• Proactive collection and evaluation of the performance
and relevant scientific data from the use of a device which
bears the CE marking
• To be addressed in the Post-market surveillance plan
• To be performed pursuant to a documented method laid
down in a PMPF plan
• the findings of the PMPF shall be analyzed and the results
documented in a PMPF evaluation report
• The PMPF evaluation report shall update the performance
evaluation report (clinical evidence) that is part of the
technical documentation
• If PMPF is not deemed appropriate for a specific device
then a justification shall be provided and documented
within the performance evaluation report
Slide 140 of 213
(PMPF)
PMPF Study isn’t needed when:
• There has been no change in the state of the art
• There has been no change in the biological/clinical

environment related to the device in question
Slide 141 of 213

(PMPF)
A clever way to use your PMPF Plan
• PMPF Plan can be used to strengthen you

Performance Evaluation Studies in those cases in
which clinically relevant sample availability is rare.
Slide 142 of 213

(PMPF)
PMPF objectives:
• confirm the safety and performance of the
device throughout its expected lifetime
• identify previously unknown risk or limits to
performance and contra-indications
• identify and analyse emergent risks on the
basis of factual evidence
• ensure the continued acceptability of the
clinical evidence and of the benefit-risk ratio
• identify possible systematic misuse
Slide 143 of 213

Plan
must include:
a.The general methods and procedures of the PMPF to be
applied, such as gathering of clinical experience gained,
feedback from users, screening of scientific literature and
of other sources of performance or scientific data;
b.The specific methods and procedures of PMPF to be
applied, such as ring trials and other quality assurance
activities, epidemiological studies, evaluation of suitable
patient or disease registers, genetic databanks or post-
market clinical performance studies;
c. A rationale for the appropriateness of the methods and
procedures referred to in points (a) and (b);
d.A reference to the relevant parts of the performance
evaluation report and to the risk management
Slide 144 of 213
Post Market Performance
Follow-up Plan
must include (continued):
e. The specific objectives to be addressed by the PMPF;
f. An evaluation of the performance data relating to
equivalent or similar devices, and the current state of
the art;
g. Reference to any relevant Common Specifications,
harmonised standards when used by the manufacturer,
and relevant guidance on PMPF, and;
h. A detailed and adequately justified time schedule for
PMPF activities, such as analysis of PMPF data and
reporting, to be undertaken by the manufacturer
Common Specifications (CS) means a set of technical and/or clinical requirements other
than a standard, that provides a means of complying with the legal obligations
applicable to a device, process or system (IVD-R Art. 2 – Definitions – (74)).
Slide 145 of 213
PMS & PMPF flow-chart
Performance
Performance Evaluation Procedure
Evaluation Plan (PEP)
Analytical
Scientific Validity Clinical Performance
Performance
SV method AP Protocol CP Study Plan
SV Report AP Report CP Study Report
Performance
Evaluation PMS Process
Report (PER)
Procedure
Report
PMPF Evaluation
Report
Slide 146 of 213

C O N C L U S I O N S (1 OF 2)
1. Manufacturers must set up a flawless PMS

process
2. This is multi-functional & multi-parties and
requires the cooperation of the Economic
Operators involved (particularly for the
Vigilance part).
a. between entities of same group (corporation)
RAQS roles & responsibilities can be covered
by global procedures
b. between different legal entities (“pure”
distributors) QA/RA roles & responsibilities
must be contractually defined or covered by
QA/RA Annexes linked to contracts.
Slide 147 of 213
C O N C L U S I O N S (2 OF 2)
3. The PMS process is complex and should not be

underestimated and shall be taken into consideration
with adequate training, skills and resources with
adequate authority.
4. It includes:
• Reactive Analysis: complaints, vigilance cases, FSCAs, literature
review, EQAS results, etc.
(anything that it is not initiated by the manufacturer)
and
• Proactive Analysis: post-market performance evaluation studies,
customer surveys, feedback forms, etc.
(anything that it is initiated by the manufacturer)
5. It needs to be proceduralized in the Corporate & Sites

QMS (who does what, when & how)
Slide 148 of 213
Implications of the
IVD-R Clinical Evidence
requirements on
legacy products
Slide 149 of 213

6 major areas of IVD-R impacts on legacy products:
1. IVD-R impact on instrument installed base

2. IVD-R impact on legacy reagents
3. The need to have Scientific Validity Reports for all products
4. Learn to work with economic operators in a new way
5. Much more demanding and sophisticated Post Market Surveillance
process
6. Product Liability coverage
Slide 150 of 213

Slide 151 of 213
IVD-R impact on instrument installed base
1. Instruments which have been placed on the EU market in compliance

with the IVD-Directive requirements are allowed to stay on the market
and to continue to provide good results
2. Obviously the majority of such instruments can provide good results only
in conjunction with good reagents.
3. Most of the IVD reagents (except the Annex II ones(*)) will have to comply
to the IVD-R requirements as of May 27th, 2022.
a. IVD manufacturers must have evidence that these reagents work well (in
compliance with all IVD-R applicable requirements) with the IVD-D
compliant instruments
4. Directive-compliant instruments can be moved freely from lab to
lab within the EU (as long as they are not “fully refurbished”).
a. They cannot be sourced from outside EU into the EU after the DOA (Date of
Applicability)
(*) after 27 May 2024 there will be no more valid IVD-D CE certificates.
Slide 152 of 213

Special case for “particular” instruments
1. The concept that instruments are “Class A” derives essentially from the
general understanding that the analytical results they provide is driven
from the analyte-specific reagents(*) that are running on the instrument.
a. But what if there are no analyte-specific reagents ?
2. Current IVD-R is not specific about this point.
3. However the interpretation that it is likely to emerge (possibly via an
implementing or delegated act) is that such instruments will be classified on the
base of the diagnostic result they do provide
a. Hematology Analyzers (for example)
b. IVD Instruments which do not need any reagent
4. What will be the impact ?
a. for reagents the lot # is taken into account for the definition “placed on the market”
b. for instruments this is driven by serial number
5. Implications of having a NB involved in the assessment of the instrument
technical documentation: DHF, DMR, technical drawings etc.
(*) Not to be understood in the ASR terminology of FDA

Slide 153 of 213
Slide 154 of 213
IVD-R impact on legacy reagents
1. There is NO GRANDFATHERING !
a. (exactly like it happened for the IVD-Directive)

b. All IVD devices which will be placed on the EU market from 2022-05-27
onward will have to comply with the IVD-R (be “IVD-R CE-marked”).
c. This will apply to all new lots even for those products which have been
launched on the market many years ago.
d. The “lot number” defines the device when it comes to reagents.
Slide 155 of 213

Define an IVD-R compliance strategy

a. IVD-R project definition
i. Define the sponsors, the functional leaders, the doers and the overall
timing
b. first pass on what’s IN and what OUT (prepare for hot debates)
c. mapping of the intended uses (as they are)
• This is NOT just what’s written in the “intended use” section of the
IFU !
d. Have the IVD-R project confirm such intended use / purpose
e. Implement a Gap-Analysis on the confirmed intended use /
purpose
• Do we have enough data to support the intended use/purpose ?
f. Executive decision on what to do to address gaps (next slide)
Slide 156 of 213

Gap filling decisions
Slide 157 of 213

How much clinical evidence data can rely on
scientific literature ?
Clinical Evidence
Scientific Analytical Clinical

Validity Performance Performance
Intended Purpose
Slide 158 of 213
Clinical Evidence
The three pillars of Clinical Evidence - Definitions
Scientific validity of an analyte means the association of an analyte to a clinical

condition or a physiological state;
Scientific
Validity
is based on scientific literature
Analytical performance means the ability of a device to correctly

detect or measure a particular analyte
Analytical
Performance
must be based on laboratory data !
Clinical performance means the ability of a device to yield

results that are correlated with a particular clinical
Clinical condition or a physiological or pathological process or
Performance state in accordance with the target population and
intended user
the jury is still out debating it…
Slide 159 of 213
3. Scientific Validity
a. Perhaps one of the major impacts on legacy products
b. Typically IVD manufacturers do NOT have Scientific
Validity Reports (SVR) for legacy products
c. NBs have already clearly stated that they expect data on
all of the 3 pillars of Clinical Evidence
d. The SVR provides evidence for the association between
analyte and clinical conditions, which could originate
from different sources. Most used are:
a. scientific (peer-reviewed) literature;
b. consensus expert opinions/positions from relevant professional
associations
Slide 160 of 213

Scientific validity report - Definitions
• IVD-R Art. 2, Def. 38: ‘scientific validity of an analyte’ means the association of an
analyte with a clinical condition or a physiological state
• IVD-R Annex XIII 1.2.1: Demonstration of the scientific validity
The manufacturer shall demonstrate the scientific validity based on one or a
combination of the following sources:
— relevant information on the scientific validity of devices measuring the
same analyte or marker;
— scientific (peer-reviewed) literature;
— consensus expert opinions/positions from relevant professional
associations;
— results from proof of concept studies;
— results from clinical performance studies.
The scientific validity of the analyte or marker shall be demonstrated and
documented in the scientific validity report.
Slide 161 of 213

Scientific validity report - Definitions
• IVD-R Art. 2, Def. 12: ‘intended purpose’ means the use for which a device is
intended according to the data supplied by the manufacturer on the label, in the
instructions for use or in promotional or sales materials or statements or as specified
by the manufacturer in the performance evaluation;
• IVD-R Annex I 20.4.1(c)(ii-iii): The intended purpose statement (in the instructions
for use) shall contain its function (e.g., diagnosis, monitoring) and specific
information that is intended to be provided in the context of the physiological or
pathological state.
• The two latter pieces of information suggest a need for consistency in how a
manufacturer addresses the clinical conditions that are being tested with the assay.
The terms for clinical conditions should be the same across documentation, whether
it is internal or available for customers. There is not necessarily a need for extreme
caution but simply good consistency.
Slide 162 of 213

Scientific validity report – Process
Intended purpose statement
= the 4 documents Qarad prepares for each

SVR
Literature search
protocol
Systematic literature search

Literature selection report
Additional sources
Literature evaluation report
Scientific Validity Report
Slide 163 of 213

Scientific validity report – Process (contd.)
• Identification of clinical conditions: The initial step is to define

the analyte (easy) and the clinical conditions that are being
diagnosed / screened / monitored with the assay.
– The identification of those clinical conditions is not trivial in many cases.
• Identification of function type: The function type (e.g.,
monitoring, screening, diagnosis) is also a central component of
the scientific validity claims.
• Once the clinical conditions and function type are identified,
they can be put into the intended purpose statement. The
following slides provides some examples:
Slide 164 of 213

• The free thyroxine (T4) assay quantitatively measures

free thyroxine in serum and is intended:
– for use as an aid in the diagnosis of hypothyroidism

– for use as an aid in the diagnosis of hyperthyroidism
– for screening of neonates for congenital hypothyroidism
– for monitoring of patients with hypothyroidism
– for monitoring of patients with hyperthyroidism
Slide 165 of 213

• The C-reactive protein assay is intended for the in vitro

quantitative measurement of C-reactive protein in human
plasma or serum and is intended:
– for use as an aid in the diagnosis of infections and non-

infectious inflammatory diseases
– for the prognosis of postoperative inflammatory complications
– for the monitoring of patients with chronic inflammatory
disease or on antibiotics treatment
Slide 166 of 213

• The measles IgG assay is used for the semi-quantitative

determination of anti-measles virus IgG antibodies in
human serum or plasma and is intended to be used
– as an aid in the diagnosis of measles

– in the diagnosis of measles immunity
Slide 167 of 213

• This identification step is very important.

• Qarad highly encourages IVD manufacturers to think about the exact
terms they use for the clinical conditions that are being measured.
– Example: ferritin is a marker for iron deficiency, not anemia, even if the two
conditions are closely related.
• The idea is to choose the conditions to be broad and to-the-point (to

avoid mentioning too many conditions), specific enough (to avoid
claims that cannot be supported) and uncontroversial if possible.
– Example: background information in an IFU for C-reactive protein mentions
more than 10 different applications for the assay. If all of them would be
incorporated in the intended purpose statement, scientific validity for each
of them would have to be provided and it could also have consequences for
the clinical and analytical performance studies.
– These 10-15 scientific validity claims can be grouped into 3 official claims
which are a better approximation of what the C-reactive protein assay can
be used for (medically and clinically speaking)
Slide 168 of 213
• Clinical conditions should be included in the intended

purpose statement !
– This intended purpose statement is the guiding factor for the
performance evaluation.
• Literature search process: Once the clinical conditions are
identified, a literature search procedure is started that aims
to provide evidence for scientific validity.
– This process is straightforward and involves setting up the protocol,
retrieving and reviewing the literature through a selection process,
and documenting the whole process in the protocol, selection
report and search report.
– Additional sources can be included only if very significant and
authoritative, like relevant guidelines from European organizations.
Slide 169 of 213
Scientific validity report – Content
Scientific validity report: is ideally based on two types of association:

• biological background
• clinical validation
Biological component: when the function of the analyte (e.g., ferritin: iron
storage) is known to be closely related to the condition (e.g., iron
deficiency)
Clinical component: information from reviews, guidelines, clinical studies or
case reports on the measurement of the analyte in a clinical setting
Justification of the assay by associating the analyte with (highly) relevant

pathological or physiological states
Slide 170 of 213

Biological background:
• C-reactive protein is involved in the recognition of damaged cells or bacterial cells and its synthesis
strongly correlates with inflammation (clinical condition: infectious and non-infectious
inflammation)
• Ferritin is an iron-binding protein involved in the storage of excess iron (clinical condition: iron
deficiency)
• Thyroid-stimulating hormone (TSH) is a hormone that stimulates the production of thyroid
hormones. However, a feedback mechanism takes place in which the thyroid hormones suppress
the TSH (to prevent overproduction of thyroid hormones). Low TSH levels generally indicate high
thyroid hormone levels and are a sign of hyperthyroidism.
Biological background information explains the reason why there is correlation and sometimes even
causation between analyte and clinical condition. It is also the only part that is highly distinct from
the clinical performance study which overlaps somewhat with the clinical validation aspect of the
SVR.
Slide 171 of 213

Clinical validation:
• Validation of the link between analyte and clinical condition can also come from clinical studies or
systematic reviews/guidelines that cover those clinical studies.
• Clinical validation is not assay-independent. Many of those studies could also be used for the
literature aspect of the clinical performance study.
• To avoid repetition, manufacturers could focus on expert consensus sources, mainly guidelines, in the
scientific validity report (‘thrust the messenger’) while discussing technical aspects and performance
statistics in the clinical performance report (‘thrust the data’).
The order of preference for literature sources should be:

• guidelines,
• reviews/systematic reviews and
• case reports/individual clinical studies.
Slide 172 of 213

Scientific validity report – example
Ferritin is an iron-binding protein involved in the storage of excess iron
Intended purpose:
The ferritin assay is used for the quantitative measurement of serum ferritin and intended
(1) as an aid in the diagnosis of iron deficiency
(2) as an aid in the diagnosis of iron overload
(3) for the monitoring of patients at risk for iron deficiency or iron overload, and for the monitoring of
the response to iron chelation, iron supplementation, blood transfusion or phlebotomy therapy.
Search:
PubMed search: “Iron deficiency” OR “Iron overload”
Filters: Year of publication: not older than 10 years
Language: English
Species: human
Article type: guidelines
42 articles retrieved (22 retained)
1 additional article included (systematic review)
Output: Scientific validity report that supports the three claims of the intended purpose statement
Slide 173 of 213

IVD-R impact on legacy products
4. Economic Operators
1. The IVD-R places more emphasis on the control over
economic operators & third parties
• vigilance / good distribution practices (traceability)
2. Quality & Regulatory agreements (annexes to contracts)
have to be put in place
• Manufacturer – own subsidiary (country organization)
• Manufacturer – Importer and/or Distributor
• Manufacturer – “maker” (contract manufacturer)
• Manufacturer – 3PL (third party logistic provider)
3. Heightened control on outsources processes
• It’s key to understand the difference from a supplier and a 3rd
party that provides an outsourced process/product.
Slide 174 of 213
MD/IVD-R Parties Involved
Economic Operators - Supply Chain - MAID
Manufacturer
Economic Economic Operators
Operators covered in Directives
covered in Regs Authorized
Representative
Importer Importer Distributor
Distributor
User User User User

Slide 175 of 213
Supply Chain
Upstream and downstream Suppliers
Verify Compliance Verify Compliance
End-Users
Supplier Manufacturer Importer Distributor
contract service
manufacturers providers
consultants Downstream Key Suppliers
Upstream Key Suppliers consultants 3PLs
contract R&D
Slide 176 of 213
Economic Operators
Some potential overlapping roles will need to be contractually defined
Manufacturer EU AR Importer Distributor

• QMS • PRRC • QMS • QMS
• PRRC • Verify and Keep Tech • Verify and Keep DoC • Verify DoC
• Design Doc • Verify CE mark • Verify CE mark
• Draw up Tech. Doc. • Verify and Keep DoC • Verify Manufacturer • Verify Importer “label”
• Draw up DoC • Verify Conformity and AR identified • Verify Labelling and IFU
• Conformity Assessment • Verify Labelling and IFU • Verify UDI assigned
Assessment • Register as AR • Verify UDI assigned • Keep complaint & vigilance
• Assign UDI • Verify manufacturer • Verify device register
• Affix CE mark registration registration • Transmit complaints
• Register as • Verify device • Register as Importer • CAPA
Manufacturer registration • Add Importer “label” • Correct storage &
• Register Device • Transmit Complaints • Keep complaint & transportation
• Keep complaint & • CAPA vigilance register
vigilance register • Liability coverage • Transmit complaints
• CAPA • CAPA
• Liability coverage • Correct storage &
transportation
Slide 177 of 213
Supply Chain Implications
Strengthened controls around traceability and transparency affecting all
contact points in the supply chain
Supply Chain Flow
Monitor Compliance
IMPACT ON Patients
SUPPLIER Manufacturer Importer Distributor
AGREEMENTS
INCREASED
SCRUTINY OF Authorised
SUPPLY CHAIN Representative
UNANNOUNCED Post Market Surveillance and Vigilance

AUDITS
Regulatory compliance of devices
Regulatory Authorities
Key changes:
• Increased level of information retained, ready and available for inspection
• Co-operation amongst regulators to ease burden (EUDAMED)
• Harmonised unique device identifier (UDI) guidance Slide 178 of 213
5: PMS Data Elements
Proactive and Reactive elements
QMS
PMS
Reactive A comprehensive Post Market
Surveillance System looks at various
Complaints, Literature Reviews, EQAS etc. data elements and consists of a:
• Reactive System
Vigilance • Proactive System (level and type of
activity dependent upon product
Proactive risk)
Clinical Studies, Surveys, Feedback

forms etc.
PMPF
Slide 179 of 213

PMS Data Elements
Where to find data and how reliable is the data?
Surveys
(Product /
Customer)
Competitive
Information
or Actions PMS Analysis
Published Literature
Identify:
• What requires immediate
Service Reports, Customer Action?
Surveys – Discussions etc. • Conflicting information?
• What requires further analysis?
• What to monitor?
Complaints and Incidents
Slide 180 of 213

Post-Market Surveillance, Vigilance and Market Surveillance
Vigilance Reporting
But there is another very important aspect to vigilance reporting:
• Article 82 (3): Manufacturers shall report any serious incident immediately after the
manufacturer has established the causal relationship with their device or that such causal
relationship is reasonably possible, and not later than 15 days after they have become
aware of the serious incident.
• The interpretation of what it means for the manufacturer “becoming aware”

of the incident
– too often the potential vigilance case takes too long to work its way up the complex
supply chain !
Periodic Summary Reports:

For similar serious incidents that occur with the same device or device type and for which
the root cause has been identified or a field safety corrective action implemented or where
the incidents are common and well documented, the manufacturer may provide periodic
summary reports instead of individual serious incident reports, on condition that the
competent authority has agreed with the manufacturer on the format, content and frequency
of the periodic summary reporting.
Slide 181 of 213
Vigilance Reporting
Complex Supply Chain can result in communication hurdles
Importer
Own
Distributor
subsidiary
Own
Manufacturer
subsidiary
Distributor
Own End User
subsidiary Own
subsidiary
End User
Slide 182 of 213
Post-Market Surveillance, Vigilance and Market Surveillance
Key Points
• Your PMS and Vigilance processes have to be flawless
• It’s about time to consider a full-time PMS and Vigilance position/department?
• PMS has to be proactive!

– Post Market Surveillance Plan / Periodic Safety Update Reports
• New incident reporting timelines:
IVDD 98/79/EC IVDR 2017/746

❑ 2 days (serious public health ❑ 2 days (serious public health
threat) threat)
❑ 10 days (death or ❑ 10 days (death or
unanticipated serious unanticipated serious
deterioration of health) deterioration of health)
❑ no later than 30 days (others) ❑ no later than 15 days (others)
Slide 183 of 213

IVD-R impact on legacy products
6. Liability Insurance !
– should not be overlooked
– it shall cover all IVD-R products (including the legacy ones)
– can be rather costly
Slide 184 of 213

Understanding the
new role of Economic Operators
Slide 185 of 213

Key driver 4: improve coverage
Action Box
Do we have RAQS contract (annexes
to contracts) with all
distributors/subsidiaries?
Are their responsibilities clearly
1. Emphasis on Traceability defined?
3. NB reinforcement plan
4.Extension to “Other Economic Operators”
Extension to importers and distributors
following the same strategic need of
increasing/improving the traceability of
MD/IVDs.
• New controversial rules (art. 9.4a) for EU Ars
• Overlapping obligations to be clarified (who
needs to have copy of TD ?)
• Labeling requirement for importer ?
Slide 186 of 213
scope expansion: economic operators
• Definition 28: ‘economic operators’ means the manufacturer, the authorized

representative, the importer and the distributor;
• The IVD-R sets out the obligations of the relevant economic operators:
(manufacturers, authorised representatives of non-EU manufacturers,
importers and distributors).
• Definitions:
• Importer: 'importer' means any natural or legal person established within the
Union who places a device from a third country on the Union market
• Distributor: 'distributor' means any natural or legal person in the supply
chain, other than the manufacturer or the importer, who makes a device
available on the market
• In reality there may be several “importers”. Which one has the responsibility?
• pragmatic solution given by the cosmetic industry is: the “first” importer.
Will it be followed also for MDs & IVDs?
Slide 187 of 213
MD/IVD-R Parties Involved
Economic Operators - Supply Chain - MAID
Manufacturer
Economic Economic Operators
Operators covered in Directives
covered in Regs Authorized
Representative
Importer Importer Distributor
Distributor
User User User User

Slide 188 of 213
Economic Operators
Some potential overlapping roles will need to be contractually defined
Manufacturer EU AR Importer Distributor

• QMS • PRRC • QMS • QMS
• PRRC • Verify and Keep Tech • Verify and Keep DoC • Verify DoC
• Design Doc • Verify CE mark • Verify CE mark
• Draw up Tech. Doc. • Verify and Keep DoC • Verify Manufacturer • Verify Importer “label”
• Draw up DoC • Verify Conformity and AR identified • Verify Labelling and IFU
• Conformity Assessment • Verify Labelling and IFU • Verify UDI assigned
Assessment • Register as AR • Verify UDI assigned • Keep complaint & vigilance
• Assign UDI • Verify manufacturer • Verify device register
• Affix CE mark registration registration • Transmit complaints
• Register as • Verify device • Register as Importer • CAPA
Manufacturer registration • Add Importer “label” • Correct storage &
• Register Device • Transmit Complaints • Keep complaint & transportation
• Keep complaint & • CAPA vigilance register
vigilance register • Liability coverage • Transmit complaints
• CAPA • CAPA
• Liability coverage • Correct storage &
transportation
Slide 189 of 213
Supply Chain
Upstream and downstream Suppliers
Verify Compliance Verify Compliance
End-Users
Supplier Manufacturer Importer Distributor
contract service
manufacturers providers
consultants Downstream Key Suppliers
Upstream Key Suppliers consultants 3PLs
contract R&D
Slide 190 of 213
The “MAID” syndrome...
Authorized
Representative
Manufacturer
? Importer
Distributor
Slide 191 of 213

Clarifying and documenting who’s
doing what…
The imperative requirement set by the EU MD/IVD regulations is that
the roles and responsibilities between the different EOs are clearly
established and monitored.
This essentially can happen in two ways:

a) either by the establishment of RAQS Agreements (which are
typically annexes to the financial contracts between the 2 EOs) –
or
b) via the respective QMS of the EOs with procedures which define
who’s responsible for what and how.
Slide 192 of 213

doing what…
Solution a) = formal RAQS Agreement
This is typically the solution of choice when the EOs truly belong to
different companies e.g.: different legal entities not belonging to the
same group or corporation. This is the case when the Legal
Manufacturer commercially interacts with a 3rd party not belonging
to its group of companies.
This solution involves considering such 3rd party company as a
supplier of either products or services and thus triggers the “supplier
management” process with all its consequences: Supplier
qualification, monitoring, requalification.
Slide 193 of 213

doing what…
Solution b) = demonstrate control of RAQS roles/responsibilities via
respective QMS
This solution is more and more the solution of choice used by large
corporations among different EOs belonging to the same group.
Mind that these EOs very frequently are different legal entities but
they are all part of the same larger group.
This solution is also been sponsored by the MedTech Europe
organization (EU trade association of MD/IVD manufacturers) which
recently published a position paper on this matter.
This position paper clearly states that intra-company quality agreements, IT systems and
QMS can be used to ensure proper controls for placing products on the EU market and for
fulfilling PMS requirements.
Slide 194 of 213

Mapping who’s who…
From a regulatory point of view we have therefore to “map” each EU country organization to
understand which EO roles are applicable to it.
To do so a simple questionnaire could be sent out to all such legal entities asking them
questions like:
1. are you invoicing customers directly ?

2. do you import TFS products from non-EU countries ? *
3. do you import non-TFS products from non-EU countries ? *
4. do you distribute (sell, directly invoicing customers) non-TFS products sourced from EU
countries ?
5. do you store (even if only temporary) finished products (instruments/reagents) ?
6. do you receive (even if only occasionally) products returned from customers ?
Or from 3rd party distributors ?
* Keep Brexit in mind. As of 2019-10-31 UK may become a non-EU country.
Slide 195 of 213

Mapping who’s who…
7. do you manage (have relationship) with EU distributors ?

8. do you receive performance-related complaints from customers (end users) ?
9. do you receive logistic/financial complaints from customers (end users) ?
10. do you receive complaints from distributors ?
11. do you have a dedicated RAQS resource even if only part-time ?
12. Please list all countries in which your organization performs commercial activities (invoicing
instruments/reagents).
Slide 196 of 213

some considerations…
(once clarified) the respective roles & responsibilities will need to

be formally described in legal contracts (or Annexes to such
contracts):
• manufacturer – authorized representative
• manufacturer – importer (for non EU manufacturers)
• importer – authorized representative ?
• importer – distributor(s) ?
It may also be possible to rationalize some of the importation

activities (for example via a single EU legal entity) rather than
having too many country subsidiaries acting as importers.
Slide 197 of 213

Key change 6: TRACEABILITY
• UDI: manufacturers must fit their devices with a Unique Device
Identification (UDI) which allows traceability. The UDI system will be
implemented gradually and proportionate to the risk class of the
devices
• The traceability of in vitro diagnostic medical devices by means of a

Unique Device Identification (UDI) system based on international
guidance should significantly enhance the effectiveness of the post-
market safety of in vitro diagnostic medical devices due to improved
incident reporting, targeted field safety corrective actions and better
monitoring by competent authorities
• Registration of importers & distributors in Eudamed
• Inspections of Notified Bodies on storage & transportation processes
to ensure traceability and proper storage / transportation conditions
Slide 198 of 213

Understanding
the new EUDAMED
Slide 199 of 213

Key change 5: new EUDAMED
• This is directly linked to what is perceived as the main

shortcoming of the current EU legislative system: lack of
transparency and traceability
• Economic operators shall be able to identify who supplied

them & who they supplied
• manufacturers fit their devices with a Unique Device
Identification (UDI) which allows traceability
• obligation for manufacturers of high-risk devices to make
publicly available a summary of safety and performance
with key elements of the supporting clinical data
Slide 200 of 213

Key change 5: new EUDAMED (contd.)
• Further development of the European databank on

medical devices (Eudamed), set up by Commission
Decision 2010/227/EU12, will contain:
• registration of economic operators
• registration of devices / UDI
• NB EC certificates
• clinical performance studies
• vigilance and market surveillance data
• etc.
• A large part of the information in Eudamed will become publicly available in
accordance with the provisions regarding each electronic system
Slide 201 of 213

(whereas 42 & Art. 23): To facilitate the functioning of the European Databank
on medical devices (Eudamed), an internationally recognised medical device
nomenclature should be available free of charge to manufacturers and other
natural or legal persons
(recital 41): One key aspect is the creation of a central database that should
integrate different electronic systems to collate and process information
regarding:
• in vitro diagnostic medical devices on the market,
• relevant economic operators,
• certain aspects of conformity assessment,
• notified bodies,
• certificates,
• performance studies,
• vigilance and market surveillance.
Slide 202 of 213

The objectives of the database are:

• to enhance overall transparency, including through better access to
information for the public and healthcare professionals,
• to streamline and facilitate the flow of information between economic
operators, notified bodies or sponsors and Member States as well as
between Member States among themselves and with the Commission,
• to avoid multiple reporting requirements and to enhance the coordination
between Member States.
Within an internal market, this can be ensured effectively only at Union level
and the
Commission should therefore further develop and manage the European
databank on medical devices (Eudamed) by further developing the databank
set up by Commission Decision 2010/227/EU of 19 April 2010 on the
European Databank for Medical Devices.
Slide 203 of 213
(recital 43) Eudamed's electronic systems regarding devices on the market, the
relevant economic operators and certificates should enable the public to be
adequately informed about devices on the Union market.
The electronic system on performance studies should serve as tool for the cooperation
between Member States and for enabling sponsors to submit, on a voluntary basis, a
single application for several Member States and to report serious adverse events,
device deficiencies and related updates.
The electronic system on vigilance should enable manufacturers to report serious

incidents and other reportable events and to support the coordination of their
assessment by competent authorities.
The electronic system regarding market surveillance should be a tool for the exchange
of information between competent authorities.
what are these points above? Design Input Requirements !
Slide 204 of 213

Art. 26 (process for registration of devices) Before placing a device on the

market, the manufacturer shall:
• assign a Basic UDI-DI
• submit to the Eudamed database the information referred to in section 2
of part A of annex V (information related to the devices)
Art. 29 (Summary of Safety and Performance)

• For class C and D devices the SSP shall be made available to the public via
Eudamed
Slide 205 of 213

Art. 30 (EUDAMED) shall include the following electronic systems
for
• registration of devices
• UDI
• registration of economic operators
• notified bodies and their certificates
• performance studies
• vigilance & PMS
• market surveillance
• For CoDx, Cancer tests, class C genetic tests: IFUs shall link to a
website where the SSP is made available to the public via
EUDAMED
Slide 206 of 213

Understanding
the new role of the PRRC
(Person Responsible for Regulatory Compliance)
Slide 207 of 213

Person Responsible for Reg Compliance
• Requirements defined in Art. 15

• Looks like a pharma QP but isn’t
• Manufacturers shall have available within their organisation at least one
person responsible for regulatory compliance who possesses the requisite
expertise in the field of medical devices
• Role may be split over persons

• Qualifications necessary in MDR / IVDR
• Can you outsource the role?
• Unsure what “available within their organisation” means but SMEs
and ARs are not required to have the person responsible for
regulatory compliance within their organisation but shall have such
person permanently and continuously at their disposal.
• Suggests that SMEs and ARs can outsource but bigger companies
cannot
Slide 208 of 213
What “SME” means ?
• The size of (Medium) Small & Micro Enterprises is defined by

Commission Recommendation 2003/361/EC
• Medium Company = < 250 employees / < 50 MM € annual turn-

over
• Small Company = < 50 employees / < 10 MM € annual turn-over
• Micro Company = < 10 employees / < 2 MM € annual turn-over
Slide 209 of 213

Person Responsible for Reg Compliance (contd.)
The person responsible for regulatory compliance shall at least be responsible

for ensuring the following matters:
(a) that the conformity of the devices is appropriately checked in accordance
with the
quality management system under which these devices are manufactured
before a
product is released;
(b) that the technical documentation and the declaration of conformity are
drawn up and kept up-to-date;
(c) that the post-market surveillance obligations in accordance with Article
10(9) are
complied with;
(D) that the reporting obligations in accordance with Articles 82 to 86 are
fulfilled;
Slide 210 of 213
Person Responsible for Reg Compliance (contd.)
(e) in the case of devices for performance studies intended to be

used in the context of interventional clinical performance studies
or other performance studies involving risks for the subjects, that
the statement referred to in point 4.1 of Annex XIV is issued;
If a number of persons are jointly responsible for regulatory

compliance in accordance with paragraphs 1, 2 and 3, their
respective areas of responsibility shall be stipulated in writing.
3. The person responsible for regulatory compliance shall suffer no

disadvantage within the manufacturer's organization in relation to
the proper fulfilment of his duties, regardless of whether or not he
is an employee of the organization.
Slide 211 of 213

what you can start doing as of next week…
1. pre-classify your products as per the IVD-R

2. lay-out EU UDI strategy: who? what? how? when?
3. challenge your Medical Vigilance & PMS processes
a. do they cover all your supply chain structure?
4. assess existence (!) -> quantity / quality of data in support of clinical evidence for
all your products
5. extend your QMS to cover:
a. key suppliers (particularly on unannounced audit obligations)
b. importers
c. country subsidiaries
d. distributors
Do you have quality/regulatory agreements with everyone?
6. start discussions with your current or future NB
a. if you don’t have one now you surely will need one for the IVD-R !
7. strengthen your international RAQS network – all part of a single team regardless
of reporting lines (functional vs. local)
8. Start thinking about the Person Responsible for Regulatory Compliance
Slide 212 of 213

Key Take-Away Points
1 Understand that a much stronger/stricter regulatory scenario is coming!
Understand that a much stronger/stricter regulatory scenario is partly

2 already here!
3 Working with NBs will be different and will require a higher budget!
Start reassessing your relations with your key suppliers, importers,

4 distributors.
5 Train and identify a dedicated person for Medical Vigilance - PMS
Slide 213 of 213

Key Take-Away Points
6 Start re-assessing the clinical validity of your products !
7 Define your UDI strategy!
8 Stay tuned in order not to be caught unprepared
Slide 214 of 213

Dr. Maurizio Suppo
maurizio.suppo@qarad.com
ph: +39-348-785.6529
end of IVD-R
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the new EU

CE-mark Access Performance

All of the above changes are a

Specimen receptacles remain IVDs

•Products for general laboratory use and for research

•“Accessories” , whilst not being in vitro diagnostic

• LDTs (with some exceptions)

Article 5.5 specifies that the IVD-R doesn’t apply to devices

The “rapporteur” in the EU Parliament on the new IVD-R was

Art. 4: “Genetic Information, counselling and informed consent”

•Article 6 deals with those test services in which patient samples

• What does “prohibited” mean?

• NCAs can enforce (fines and retraction / rectification)

• Will need to see how this affects current wide

2 IVD categories: 4 IVD categories:

• professional use • professional use

And finally the “cherry on the pie”

• (Whereas 11) Companion diagnostics are essential to define

•Art. 48.4 2nd§: For companion diagnostics the notified body

Not all classes are subject to NB review & approval. It depends of

• MDs: Class I if sterile or with a measuring function, Class IIa, Iib

• the dual role of Essential Requirements and Technical Details

Representatives of designating authorities of two other Member States

The designating authority of the Member State where the conformity

Art. 5: Surveillance & Monitoring

The Designating Authority must monitor its NBs

• at least every year (for NBs w/ more than 100 clients)

• NBs are available on the official EU Commission site:

• Designation & monitoring of NBs is left to MS but

It was there !! In the IVD-Directive since the very beginning !

But nobody did it !

Now it’s too late and we have

do you have a “UA” SOP ? ? ?

At least once every 5 years

This is CLASSIFICATION REVOLUTION !!!

Think about the implications of re-classification…

• Enormous workload increase for NBs

• Therefore what needs to be done ?

• Based on 7 classification rules

Current Directive Future Regulation

Annex II List A Class D

Annex II List B Risk Class C

QA (Annex IX) w/out

+ TD review on generic EC Type Examination Production QA

QA (Annex IX) w/out

+ TD review on generic EC Type Examination Production QA

Notified Body if no CS & new type MDCG Expert

QA (Annex IX) + review of

+ batch verification EC Type Examination Production QA

Should apply only to

• 10 pages (Annex II)

• Four regulatory classes (based on 7 classification

– Class A: low patient risk/ no public health risk

ALL EXCEPT CLASS A WILL REQUIRE NOTIFIED BODY INVOLVEMENT

Classification governed by intended use

6. Whatever is not covered by the above rules -> B

IVD-D / IVD-R timing overview

OK to sell IVD-D devices

NB-issued deadline for submission of application !