ELLEN NEVEN MARCH, 2022

Regulatory Medical Writer

CLINICAL
EVALUATION

FOR MEDICAL DEVICES

UNDER MDR
TABLE OF

CONTENTS

INTRODUCTION 03
1. CLINICAL EVALUATION - WHAT AND WHY? 04
2. CLINICAL EVALUATION - WHEN? 05
3. CLINICAL EVALUATION - UPDATES 06
4. CLINICAL EVALUATION - DOCUMENTATION 07
4.1 CEP - ROADMAP OF THE CLINICAL EVALUATION STRATEGY 07
4.2 CER - A MUST-HAVE FOR ALL DEVICE CLASSIFICATIONS 08
4.2.1 CER - State-of-the-art 09
4.2.2 CER - Equivalence 10
4.2.3 CER - Pre-clinical data 11
4.2.4 CER - Clinical data 11
4.2.5 CER- Risk Assessment 12
5. CLINICAL EVALUATION - WHO? 13
6. CER - COMMON GAPS AND HURDLES TO TAKE 14
6.1 POOR LITERATURE REVIEW 14
6.2 MISSING CRITICAL DOCUMENTS RELATED TO THE CER 14
6.3 INCONSISTENCY BETWEEN ESSENTIAL DOCUMENTS 14
6.4 INPUT FROM DIVERSE EXPERT TEAMS 14
6.5 TEMPLATES COMPLIANT TO MDR AND MEDDEV 2.7/1 REV 4 15
7. HOW CAN QBD ASSIST IN THE CLINICAL 16
EVALUATION OF YOUR MEDICAL DEVICE?

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INTRODUCTION

Clinical evaluation of a medical device - defined

as an ongoing collection, generation, appraisal
and analysis of clinical data related to your device
- is central to getting and maintaining market
approval in the EU.

The regulatory documents required to support

credible clinical evidence for safety and
performance of your device are essential for
device development and approval and should
comply with strict regulatory guidelines (MDR
2017/745 and MEDDEV 2.7/1 version 4).

In this whitepaper, we will guide you through

crucial regulatory documents pertaining to the
clinical evaluation process of your device.

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CHAPTER ONE

CLINICAL EVALUATION:
WHAT AND WHY?

To obtain a CE mark for a medical device,

manufacturers are obliged to perform a clinical
evaluation verifying the performance, safety, and
clinical benefits of their device when used
according to the Instructions For Use (IFU).

Clinical evaluation of a medical device aims to

show that the device offers more benefit and/or
poses less risk than state-of-the-art
treatments or is at least comparable to state-of-
the-art technologies.

Clinical evidence may come from literature,

clinical investigations, and post-market
surveillance (PMS). Both favorable and
unfavorable data are to be considered in the
clinical evaluation of the device.

The implementation of the MDR entails essential

changes in the clinical evaluation process, its
documentation, and PMS requirements.

In comparison with the Medical Device Directive

(MDD), the clinical evaluation as such and the
integration of PMS and risk management gain
in importance under MDR, with more stringent
requirements and subject to increased scrutiny by
the Notified Bodies.

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CHAPTER TWO

CLINICAL EVALUATION:
WHEN?

Clinical evaluation starts during the development For initial CE marking, clinical evaluation provides
phase and is an ongoing process throughout the clinical evidence needed to demonstrate
life cycle of a medical device. In the pre-market conformity with relevant safety and performance
phase, the clinical evaluation identifies clinical requirements when your device is used as
safety and performance data that need to be intended and identifies aspects that should be
generated for the marketing of the device. At this addressed during PMS
early stage, gap analysis establishes which data
still need to be generated with your device and For example, residual risks and remaining
whether clinical investigations are required. questions (rare complications, long-term
performance, safety under wide-spread use)
An early start of the clinical evaluation process is proportionate and appropriate to the nature,
of utmost importance as it pinpoints the classification, intended purpose, and risks of the
questions to be answered by a clinical device, as well as to the claims in respect of your
investigation and feeds the clinical strategy to be device.
followed to get the required clinical data for CE
marking.

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CHAPTER THREE

CLINICAL EVALUATION:
UPDATES

Throughout the life cycle of the device, the clinical

evaluation and its documentation should be
updated with clinical data obtained from the PMS
and post-market clinical follow-up (PMCF) to pro-
actively collect and evaluate the safety and
performance data of your device after being
placed on the market. The frequency of updates
depends on the risk classification of your device
and the output of the PMS.

The clinical evaluation should actively be

updated:

Whenever new information from

PMS affects the clinical evaluation
or its conclusion (accounts for all
risk classes), particularly on the
benefit-risk profile of the device
If no new information is received,
then
At least annually for high risk
(class III) or not yet well-
established devices
Every 2 to 5 years for lower risk
and well-established devices.

In all cases, a justification for the frequency of

updates should be provided.

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CHAPTER FOUR

CLINICAL EVALUATION:
DOCUMENTATION

To plan and document the clinical evaluation and The risk class determines the level of control and
evidence, a well-designed and clearly written clinical scrutiny required to assure the safety and
evaluation plan (CEP) and clinical evaluation report performance of your device and define the
(CER) is key and required for all device classifications conformity assessment route to follow.
(Class I to III) including both new and legacy devices.
These two regulatory documents required to support Major requirements for the CEP content, as
credible clinical evidence for the safety and described in MEDDEV 2.7/1 Rev 4 and MDR Annex XIV
performance of your device are essential for device Part A, are the following:
development and approval and should comply with
strict regulatory guidelines (MDR 2017/745 and
MEDDEV 2.7/1 version 4). The CEP and CER, as part of Device description including, but not
the Technical Documentation, are two critical limited to, model, size, components,
documents reviewed by the Notified Body, an device group to which your device
independent organization accredited by a European belongs (for more details consult
Member State and responsible for conformity MEDDEV 2.7/1 Rev 4 – Appendix A3)
assessment and (re-)certification of most medical Intended purpose and medical
devices and in-vitro diagnostics, allowing products to indications
be placed on the European market. Both documents Intended target population with
should be dated, version-controlled, and signed by indications and contraindications
the regulatory writer, evaluators, and manufacturer. Equivalence information (if claimed –
refer to 4.2.2)

4.1 CEP - ROADMAP OF THE State-of-the-art in the corresponding

CLINICAL EVALUATION STRATEGY medical field (refer to 4.2.1)

Intended clinical benefits with
The CEP (MDR Article 61 and Annex XIV, Part A; justification for relevant and specified
MEDDEV 2.7/1 Rev 4) is key as the start and guide clinical outcome parameters
of the clinical evaluation of your medical device. Identification of general safety and
This primary document describes the scope of the performance requirements that require
clinical evaluation, how the clinical evaluation will be the support of clinical data
done, what data will be collected, when and how data Risk management documents e.g., the
will be assessed, presented, and reported. In the CEP, hazard identification list, clinical risks
it is important to establish the appropriate risk identified from the risk analysis·
class of your device (class I, IIa, IIb, or III).

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Methods to evaluate the clinical safety
and determine residual risks and side
effects
Parameters to determine the
acceptability of benefit-risk ratio for the
indication(s) and intended purpose of
the device, as per state-of-the-art
Benefit-risk issues relating to specific
device components such as the use of
pharmaceutical, non-viable animal or
human tissues
Data source(s) and type(s) of data to be
used in the clinical evaluation – clinical
investigations, PMS, pre-clinical studies,
literature (refer to 4.2.3, 4.2.4, and 4.2.5)
Clinical development plan with a clear
indication of milestones and description
of potential acceptance criteria for each
progression
For CE marked devices additional aspects need to
be considered in the CEP:
Any changes in device design, materials,
manufacturing, information (IFU,
brochures), claims, equivalence (if
claimed – refer to 4.2.2)
Any new concerns to be addressed
PMS updates, e.g., new data for device or
equivalent, new knowledge about
hazards, risks, performance, benefits, or
claims
Needs for planning PMS activities
The CEP and CER are two closely linked key regulatory
documents with very similar layouts. The CEP plans
and describes the clinical evaluation strategy, while
the CER presents the output of the clinical evaluation,
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CLINICAL EVALUATION FOR MEDICAL DEVICES UNDER MDR
i.e. the clinical data that demonstrate conformity
with general safety and performance
requirements when your device is used as
intended.
The CEP is often overlooked and a common gap in
the clinical evaluation of a medical device. It is
important to recognize that this document is the
driver of other essential documents being PMCF
plan as part of the PMS plan, and the CER which
in turn feeds the PMS report, the Periodic Safety
Update Report (PSUR), and the Summary of Safety
and Clinical Performance (SSCP). Needless to say,
that time and resource investment to the setup of
the CEP pays off in the long term!
4.2 CER - A MUST-HAVE FOR ALL
DEVICE CLASSIFICATIONS
To document the clinical evaluation of your device
and its output, a Clinical Evaluation Report or CER
(MDR Article 61 and Annexes IX Chapter II and XIV,
Part A; MEDDEV 2.7/1 Rev 4) has to be compiled.
The CER is a living document that outlines the clinical
background and scope, and identifies, appraises and
analyses pre- and post-market data pertaining to
your device to draw firm conclusions about its safety,
performance, and usability, and the acceptability of
the benefit-risk profile of your device. In the MDR, no
specifications on the CER table of contents are given,
however, guidance on the CER outline is provided in
Appendix A9 of MEDDEV 2.7/1 Rev 4.
The body of the CER consists of a description of the
state-of-the-art on the one hand and a
comprehensive analysis of preclinical data and
pre- and post-market clinical data relevant to your
device on the other hand. All data sets should be
documented, adequately analyzed, appraised,
summarised, and referenced in the CER.
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4.2.1 CER - State-of-the-art

The state-of-the-art provides the clinical background
and identifies the current knowledge in
respective medical field. This section of the CER also
aims to identify safety and performance endpoints
and potential clinical hazards and to justify the
validity of potential surrogate endpoints for the
device under evaluation.
In MDR 2017/745 and MEDDEV 2.7/1 rev. 4, state-of-
the-art is referred to frequently but not defined.
MDCG-2020-6 ‘Clinical Evidence for Legacy Devices’
uses the definition provided by the International
Medical Device Regulators Forum (IMDRF) as follows:
MEDDEV 2.7/1 rev. 4 appendix A9 also describes the
the available treatment options including currently
approved benchmark devices with their respective
safety and performance profile (advantages and
disadvantages), historical context, and unmet medical
needs.
The device under evaluation should be compared to
benchmark devices, and its risks and clinical
benefits are discussed in light of the existing
therapeutic options and/or available devices. State-
of-the-art assessment defines the safety and
performance, and benefit-risk acceptability criteria
for the device under evaluation. With the new MDR,
effective from May 2021, increased scrutiny towards

‘Developed stage of current technical capability alternative treatment methods for the same

and/or accepted clinical practice in regard to indication(s) is to be expected.

products, processes and patient management,

based on the relevant consolidated findings of To establish the state-of-the-art, safety and

science, technology and experience.' performance of benchmark/similar devices, an in-

MDCG-2020-6 further notes that
‘The state-of-the-art embodies what is currently
and generally accepted as good practice in
technology and medicine. The state-of-the-art
does not necessarily imply the most
technologically advanced solution’.
depth literature review has to be performed, which
needs to be documented in the literature search plan
and report, two essential documents inextricably
intertwined with the CER. Hereto, various sources can
be used among which (systematic) reviews,
professional society guidelines, metanalyses, and
clinical studies on benchmark devices are commonly
employed.
Comprehensive, objective and thorough literature
searches to identify all relevant favorable and
unfavorable data follow strict requirements as per
MDR and MEDDEV 2.7/1 Rev. 4.

MEDDEV 2.7/1 rev. 4 appendix A9 explains the

content of the state-of-the-art section in the CER. The literature review starts with the development of

State-of-the-art defines the medical condition or a literature review plan or protocol that specifies

disease, epidemiology, pathology, and patient the background and scope of the literature review as

population being treated. well as the methods for identification, selection, and
appraisal of the relevant publications to address the
literature review questions.

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The search strategy, as well as screening and Poor literature search strategies and methods are a
appraisal criteria, should be sufficiently detailed common ‘gap’ in CERs. Inappropriate database
and justified so that the literature search is selection, inadequate search terms, lack of
transparent and reproducible, particularly justification for in- and exclusion criteria, state-of-
important when updates are to be performed. the-art assessment, and weighing of clinical data
lead to non-compliance and jeopardize CE marking
To search for and screen relevant peer-reviewed of your medical device.
clinical data, at least 2 scientific literature
databases (e.g., MEDLINE and EMBASE) should be Keep in mind that a well-developed literature
applied. review protocol can be easily repeated and will
save you a lot of time when updating the CER.
Clinical safety and performance data extracted
from publications are subject to appraisal and
analysis and should be summarized, 4.2.2 CER - Equivalence
preferentially using in-text summary tables.
Theoretically, a clinical evaluation may be based
The output of the literature search and review is on clinical data relating to a device for which
described and summarized in the literature equivalence to the device in question can be
review report that contains a review of the demonstrated.
current knowledge/state-of-the-art and the
retrieved clinical safety and performance data on To this end, technical, biological, and clinical
benchmark devices and/or the equivalent device characteristics have to be similar to the extent
(if claimed). that there would be no clinically significant
difference in the safety and clinical performance
The ultimate intention of a literature review is to of the device (MDR Annex XIV Part A), with proper
draw firm conclusions on the safety, scientific justification for any differences between
performance, clinical benefit, and benefit-risk both devices.
profile as well as on the acceptability of
undesirable side-effects for your device. Historically, CE certification under the Medical
Device Directive 93/42 EEC (MDD) was often
Cross-check if the clinical literature supports the based on device equivalence. However, under
IFU as well as the output of any clinical MDR the requirements for equivalence
investigations and PMS. Last but not least, ensure justification are substantially tightened as
that the literature review plan is aligned to the manufacturers must have sufficient levels of
CEP and IFU to avoid inconsistency between these access to the technical documentation relating to
crucial documents and non-compliance with the devices with which they are claiming equivalence.
MDR.

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On top of that, the clinical evaluation of the For CE renewal, and thus continuous clinical
equivalent device must be performed in evaluation of your device, clinical data from
compliance with MDR requirements, thus
risk management activities and Post Market
certified under MDR, and, for class III and
Surveillance (PMS) such as Post-Market
implantable devices, a contract between the two
Clinical Follow-up (PMCF) studies (PMCF
manufacturers should be in place allowing full
access to the technical documentation on an clinical investigations, scientific literature on

ongoing basis. Obviously, the equivalence route the device under evaluation, registries,
to market is almost completely extinguished. cohort data, etc.), incident reports and
complaints are also considered for clinical
Nevertheless, for those rather exceptional cases
evaluation.
where the equivalence route is performed e.g., by
using the manufacturer’s own devices MDCG
Pre-market clinical investigations
2020-5 covers equivalence in clinical evaluation.

To assess conformity with the General Safety and

This document is a guide for the equivalence
Performance Requirements and benefit-risk
assessment of the device and further defines
acceptability criteria, as established in the state-
the process for demonstrating equivalence. A
of-the-art section of the CER, data from pre-
template table for the demonstration of
market clinical investigations should be analyzed,
equivalence is also provided.
appraised, and summarized in the CER. Typically,
pre-market investigations have prespecified
4.2.3 CER - Pre-clinical data safety and performance endpoints and
appropriate statistical analysis is employed.
Pre-clinical data of a medical device is held by the
manufacturer and generated from bench
As per MDR 2017/745 Annex XV Clinical
testing and animal studies. These studies are
Investigations and ISO 14155:2020, the design
detailed in a pre-clinical evaluation report as
and conduct of a clinical investigation is described
part of the technical file. In the CER, analysis and
in a clinical investigation plan (CIP) and results
appraisal of pre-clinical data are summarized.
are compiled in a clinical investigation report
(CIR).

4.2.4 CER - Clinical data

Clinical investigations, required to show that
your device is safe and performs as intended, are
For initial conformity assessment under MDR (to
planned and documented in the clinical
obtain the first CE mark), clinical data generated
development plan.
by the manufacturer typically covers pre-market
investigations.

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This document is closely tied with the CEP and
CER and sets forth the clinical development
strategy. To obtain a CE mark for your device,
carefully consider the type of
investigation, if any required, and appropriately
select relevant and feasible safety
performance endpoints.
Under MDR, clinical investigations
mandatory for class III medical devices, except
if equivalence can be claimed to the marketed
device, and required for all device classifications
when knowledge gaps can’t be filled by pre-
clinical, PMS, or literature data.
PMS and PMCF - clinical post-market data
A strong focus on the post-market phase is a
major change under MDR. A comprehensive PMS
system should be in place to proactively and
systematically collect and review post-market
data of your device, implemented in your quality
management system, and set out in a PMS plan.
PMCF activities, complaints, and device vigilance
are all part of PMS data. PMCF activities include a
scientific literature search on the device under
evaluation. After being placed on the market, and
thus for continuous post-market
evaluation of your device, a literature search
focussed on your device (and/or equivalent device
if equivalence is claimed) is required to identify,
analyze and appraise all published clinical safety,
performance and usability data pertaining to your
medical device. Other PMCF activities include
PMCF and/or extended clinical investigations,
registries, cohort studies, and feedback from
users. Clinical data on the device
evaluation retrieved from PMCF further support
the clinical evaluation of your device with the
ultimate goal to confirm its post-market safety
and performance.
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CLINICAL EVALUATION FOR MEDICAL DEVICES UNDER MDR
Results of the PMS evaluation, in particular of the
PMCF activities, are presented in a PMS Report for
Class I or PSUR for Class IIa, IIb, and III devices of
clinical which a summary is included in the PMS section
of the CER update.
and
4.2.5 CER- Risk Assessment
are Risk analysis of your device is part of the QMS
and documented in the risk management plan
and report. In the CER, identified clinical data
regarding safety and risks should be analyzed and
summarized, and compared to the existing risk
analysis documents of your device. If new risks
have been identified, these are to be fed into the
risk management process for analysis. It’s
important to discuss residual risks and any
undesirable side effects as well as how risks will
be mitigated (e.g., training, labeling, product
design). In addition, the clinical benefit(s) should
be set out clearly under MDR and be consistent
with product claims in the IFU.
Clinical benefits are objective and supported by
data presented in the clinical evaluation of your
device. The benefit-risk profile is an important
aspect of the conclusion of the CER documents.
Evaluation, quantification, and discussion of
clinical benefits and risks are key. To wrap up, the CER
aims to confirm that your medical device does not
compromise the clinical condition or the safety
and health when used as intended and that the
benefit-risk profile is acceptable according to
State-of-the-art for each of the indications
claimed.
under
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CHAPTER FIVE

CLINICAL EVALUATION:
WHO?

The evaluators' clinical evaluation documentation

must have appropriate qualifications and
knowledge - medical and regulatory knowledge,
knowledge of how to use the device, experience
in academic literature research. Specific
requirements for the expertise and experience of
CER authors and evaluators include a relevant
higher education degree and five years related
professional experience, or ten years’
professional experience if a degree is not
considered a prerequisite for the task. Deviations
from these requirements should be documented
and duly justified. All evaluators must provide a
declaration of interest.

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CHAPTER SIX
CER - COMMON GAPS
AND HURDLES TO TAKE
Increased scrutiny of the clinical data on your
medical device is a reality under the new MDR. To
help you managing the clinical evaluation of your
device, we highlight common pitfalls and hurdles
to take:
6.1 CEP - POOR LITERATURE
REVIEW
Under MDR and MEDDEV 2.7/1 Rev. 4, strict
obligations have been put in place, especially with
regards to literature reviews. Literature searches
and analyses often have major deficiencies to
these new requirements.
Robust and reproducible systematic literature
searches and search strategies are compulsory
which is challenging and requires professional
skills. An organized and highly skilled researcher
or evaluator proficient in medical writing and with
a medical and regulatory background in medical
devices is essential to execute a dedicated
strategy for literature screening, selection,
appraisal, and analysis.
6.2 MISSING CRITICAL
DOCUMENTS RELATED TO THE CER
Documents closely linked with the CER such as
the CEP, PMS, and PMCF plans as well as the
literature review plan and report are often
missing.
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CLINICAL EVALUATION FOR MEDICAL DEVICES UNDER MDR
Keep track of all required documents related to
the clinical evaluation of your device and make
sure that all are in place for initial CE submission.
6.3 INCONSISTENCY BETWEEN
ESSENTIAL DOCUMENTS
A common flaw is an inconsistency between
information materials (IFU, user manual) and the
clinical evaluation documentation, particularly
with regards to the device claims. Ensure that all
documents for CE submission are aligned with
respect to intended use, indication(s), and patient
population as well as to safety, performance, and
clinical benefit claims.
6.4 INPUT FROM DIVERSE EXPERT
TEAMS
Preparation and the actual writing of the CER is
often a dedicated task of a medical regulatory writer.
However, the input, feedback, advice, and oversight
of a multi-disciplinary team of experts with a diverse
set of skills and backgrounds is a prerequisite to
conduct and document the clinical evaluation of
your medical device according to the high standards
of the current regulations and requirements.
Although working with a cross-functional team can
be quite challenging, close collaboration with
different experts is central to getting the clinical
documentation ready at a fast pace.
PAGE 14
Take advantage of the multi-disciplinary expertise
of QbD and TRIUM to speed up and deliver an
MDR-compliant clinical evaluation in an efficient
way.

6.5 TEMPLATES COMPLIANT TO

MDR AND MEDDEV 2.7/1 REV 4

For start-up companies aiming to get their

medical device certified the preparation of the
CEP and CER and its associated clinical
documents might be a daunting task. To get CE
approval, essential documents should comply
with the applicable regulations, however,
templates for the documentation of the clinical
evaluation and systematic literature compliant to
MDR and MEDDEV 2.7/1 rev 4 are not readily
available from official EU sources.

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CHAPTER SEVEN

HOW CAN QBD ASSIST IN THE CLINICAL

EVALUATION OF YOUR MEDICAL DEVICE?

At QbD Clinical, we provide knowledge-based To speed up the preparation of the required

expertise to help you set out the clinical strategy documentation and ensure high-quality
and plan and document the clinical evaluation deliverables, a team of regulatory affairs
process throughout the journey of your medical specialists, literature review experts, medical
device – from start to finish. writers, medical advisors, and project managers
work closely together.

OUR SERVICES AT A GLANCE

Gap analysis of clinical evaluation documents

Systematic literature reviews – literature review plan and report
Regulatory Medical Writing – CEP, CER, PMS plan and report, PMCF plan and report, PSUR
Clinical medical writing – CIP and CIR
Advise in clinical strategy
Operational management of pre-and post-market clinical investigations

Interested to know more?

Get in touch!

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