Report NB MED 2016

What are the news from the

clinical field?

Brussels, 2016-10-12

Dr. Bassil Akra

Global Director
Clinical Centre of Excellence
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EAG Leadless/TAVP MHRA Guidance

The MHRA is a leading authority on initiating the

development of new guidance documents

2 Working Groups are already in place (TAVP and EAG

Leadless)

The WG are supported by english Physicians that are

mainly reflecting the view of the UK Medicine

Notified Body and Industry Representatives are allowed

to attend the open meetings and comment accordingly

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EAG Leadless MHRA Guidance

Advers CE-approval Study Post-approval Studies/Registries

e event
rate Sample size to give 80% power to Sample size to give 90% power to
under
have a 95% CI with an upper have a 95% CI with an upper
test (%
patient bound below z% bound below z%
Approx z Appropriat z max Min Approx Approp z max Min
s)
(upper e sample linked patient z riate linked to patient
bound CI) size range to min follow- (Upper sample min follow-up
% (patient sample up bound size sample duration
number) size in duratio CI) % (patient size (months)
range n s
(month number
s) )
1 4.5 150 4.8 2.3 > 900 2.5
250
PMCF
2 7.0 130-200 7.7 4.0 > 700 4.3 Study
3 9.2 100-150 10.0 3 years
12 5.5 > 600 5.7

4 12 90-120 12.5 7.2 > 500 7.6

Registry
5 14 80-110 15.7 9.0 > 400 9.4 5 years
6 16.5 70-100 17.8 10.7 > 300 11.3

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Implementation of the new MEDDEV 2.7.1 Rev. 4

TEAM NB
Representative

Suggestion to Suggestion to
Suggestion to EU
TEAM NB and CIE Working
Commission
NB MED Group

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Implementation of the new MEDDEV 2.7.1 Rev. 4

Step 1:
Manufacturers should prepare an impact assessment and an implementation plan within six months
after publication of this document. This evidence should be subject to an audit during the next
scheduled audit at the manufacturer's place from January 2017.

Step 2:
Manufacturers should start implementing the new revision of the MEDDEV by updating their clinical
evaluation reports (CERs) accordingly by beginning of January 2017 at the latest. The CER update
schedules should be prioritized based on the establishment level of the device and the risk level
associated with the device. New device submissions shall be prepared from January 2017 following
the new MEDDEV revision requirements.

Step 3:
December 31, 2018 at the latest, all CERs should be reflecting the new MEDDEV revision
requirements.

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Implementation of the new MEDDEV 2.7.1 Rev. 4

In case of compliance issues regarding requirements of the directives 93/42/EEC,

90/385/EEC and 2007/47/EC, notified bodies will of course continue to apply case
specific deadlines. Earlier action may be necessary in order to resolve compliance
issues.

This suggestion is based on current public information and has been prepared to the
best of our knowledge. Additional recommendations of the European Commission or
the European Member States may influence the implementation of this guidance
document by notified bodies and manufacturers.

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MEDDEV 2.7.1 rev. 4

Overview of Changes
Documentation requirements
Detailed information for
including plans/protocols for
sources of literature
appraisal, methods, clinical
Life Cycle Methodology Examples (MEDLINE, EMBASE,
investigation, PMCF studies,
CENTRAL, ICTRP and
registries and for related
clinical Trials.gov)
reports

Points for sufficient clinical

evidence (intended purpose,
Literature research: on device Reference to relevant GAP analysis on compliance
Detailed principals of clinical clinical performance and
in question/equivalent device Directives in more details and of clinical data generated
evaluation benefits, risk
and on State of the art) better structure outside of EU
mitigation/avoidance,
usability, target population)

Requirements for updating Need and concept of PMCF Qualification requirements of Scope of clinical evaluation
Risk/benefit profile
CER studies evaluator or evaluator team before and after CE marketing

Analysis to demonstrate the

State of the art /Current
Scientific validity Relevance of data Weightening criteria for data compliance to Essential
knowledge concept
Requirements

Considerations for a clinical

Equivalence (clinical, investigation and state of the
Release criteria for a CER Structure and content of CER Role of NB
technical, biological) art, compare to alternative
methods

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MEDDEV 2.7.1 rev. 4

Equivalence Approach

Clinical Data Source and

Significance

Clinical Expertise (Evaluator

Expectations)

Clinical Update

Devices based on performance

data

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Equivalence Approach per MEDDEV 2.7.1 rev. 4

Clinical, technical and biological characteristics shall be taken

into consideration for the demonstration of equivalence

For assuming equivalence:

only be based on a single device
all three characteristics (clinical, technical, biological)
no clinically significant difference in the performance and safety of the device
the differences between the device under evaluation and the device presumed
to be equivalent need to be identified, fully disclosed, and evaluated
manufactured via a special treatment (e.g. a surface modification, a process
that modifies material characteristics)
if measurements are possible, clinically relevant specifications and properties
should be measured both in the device under evaluation and the device
presumed to be equivalent

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MEDDEV 2.7.1 rev. 4

Demonstration of equivalence

Biological
Use the same materials or substances in contact with the same
human tissues or body fluids.

Exceptions can be foreseen for devices in contact with intact skin

and minor components of devices.

In these cases risk analysis results may allow the use of similar
materials taking into account the role and nature of the similar material.

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Same material Is this new?

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Equivalence Approach per MEDDEV 2.7.1 rev. 4

The notified body should challenge

the ability of the manufacturer to
access information that are relevant
to the demonstration of equivalence.
Demonstration of equivalence might
be difficult or impossible in case of
limited access to the technical
documentation of the devices.

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MEDDEV 2.7.1 rev. 4

Examples of studies that lack scientific validity for demonstration of

adequate Clinical Performance and/or Clinical Safety

Lack of information on elementary aspects

Numbers too small for statistical significance

Improper statistical methods

Lack of adequate controls

Improper collection of mortality and Serious

Adverse Events data

Misinterpretation by the authors

Illegal activities

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MEDDEV 2.7.1 rev. 4

Who should perform a clinical evaluation?

The evaluators should possess knowledge of the following
the device technology and its application;
research methodology (including clinical investigation design and biostatistics);
diagnosis and management of the conditions intended to be managed or diagnosed by the device,
knowledge of alternative treatments, treatment standards and technology (e.g. specialist clinical
expertise in the relevant medical specialty);
information management (e.g. scientific background or librarianship qualification; experience with
relevant databases such as Embase and Medline)
regulatory requirements; and
medical writing (e.g. post-graduate experience in a relevant science or in medicine; training and
experience in medical writing, systematic review and clinical data appraisal);

Least experiences in relavent field

A higher degree & 5 years of documented professional experience
10 years of documented professional experience (if higher degree is not a prerequisite

Note: There may be circumstances where the level of evaluator expertise may be less or different; this should be documented and duly justified.

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Updating Clinical Evaluation Report MEDDEV 2.7.1 rev. 4

when the manufacturer receives new

information from post-market
surveillance that has the potential to
change the current evaluation;
if no such information is received, at
Typically least
the clinical annually if the device carries
evaluation significant risks and/or is not yet well
is updated: established;
every 2 to 5 years if the device is not
expected to carry significant risks and
is well established;
Justification

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Updating Clinical Evaluation Report MEDDEV 2.7.1 rev. 4

When updating the clinical evaluation, the evaluators should verify:

if the benefit/risk profile, undesirable
side-effects (whether previously known
or newly emerged) and risk mitigation correctly addressed in the information
correctly addressed by the
measures are still compatible with a materials supplied by the manufacturer
manufacturer's current PMS plan
high level of protection of health and of the device
safety and acceptable according to
current knowledge/ the state of the art

if existing claims are still justified

if new claims the manufacturer intends to use are justified

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Updating Clinical Evaluation Report MEDDEV 2.7.1 rev. 4

If the manufacturer concludes there is not sufficient clinical evidence to be able

to declare conformity with the Essential Requirements, the manufacturer will
need to :
stop placing the devices on the market until conformity is restored, and
take necessary corrective and preventive action.

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MEDDEV 2.7.1 rev. 4

Devices for Unmet Medical Needs

Medical conditions that are life threatening, or cause

permanent impairment of a body function,

and for which current medical alternatives are insufficient or

carry significant Risks.

Explanations why current

PMCF Plan to further
medical alternatives are Explanations of the
Clear IFU presenting the evaluate the Clinical Including all patients in
Exact indication considered to be benefits delivered by the
clinical evidence level Performance and Clinical PMCF Studies
insufficient or to carry device
Safety of the device
significant Risks

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MEDDEV 2.7.1 rev. 4

Demonstration of conformity based on clinical data is not deemed appropriate

Where demonstration of conformity with Essential

A clinical evaluation is still required and the above
Requirements based on clinical data is not deemed
information and evidenced justification should be
appropriate, adequate justification for any such
presented in the clinical evaluation report.
exclusion has to be given:

The justification must be based on the output of the risk

management process.

The device/body interaction, the clinical performances

intended and the claims of the manufacturer have to be
specifically considered.

Adequacy of demonstration of conformity with the Essential

Requirements based on performance evaluation, bench
testing and pre-clinical evaluation in the absence of clinical
data has to be duly substantiated.

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MEDDEV 2.7.1 rev. 4

The CEAR at a minimum should address the notified bodys assessment of

manufacturers application relating to the following:

Device description and product specification

Intended purpose of the device
Classification proposed for the device
Pre-clinical evaluation data presented by the manufacturer
Risk analysis and risk management and alignment with the CER
Clinical evaluation process
Clinical evaluation report authors
Clinical equivalence assessment if data from equivalent is used
Clinical investigation assessments and reports
Justification if no clinical investigation performance
Instructions for use, labelling and training
Justification if no post-market clinical follow up is planned
Post-market surveillance
Post-market clinical follow up
Planned frequency/criteria for updates to the clinical evaluation
Summary of review
Conclusion on clinical benefit/risk profile
Conformance of the device to the relevant Essential Requirements

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MEDDEV 2.7.1 rev. 4

The systematic review of clinical evidence by notified

bodies being extended to IIa and IIb medical devices.

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Thank you

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