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ENQUIRY TO
MEDICAL DEVICE COMPETENT AUTHORITIES
Helsinki Procedure 2013
Problem : Classification of embolization microspheres with the capacity of
loading and then eluting doxorubicin
Originating CA: MHRA United Kingdom and ASNM France
Contact Point: Clare Headley and Muriel Gaffiero
E-mail : clare.headley@mhra.gsi.gov.uk and
muriel.gaffiero@afssaps.sante.fr
Circulated : 3/5/2013
Deadline: 3/6/2013
Extended deadline: 14/6/2013 and 8/7/2013 and
19/8/2013
Date Summary issued: 1/11/2013
Updated 3/3/2014
SUMMARY
Description of the problem
Embololotherapy is a procedure used in the treatment of metastatic liver cancer. This
technique consists of the therapeutic introduction of microspheres (non absorbable with a
size from 200-900 µm) into the circulation to devitalize a tumour by occluding its blood
supply.
Several years ago, a new type of embolisation particle appeared on the market. We are
aware that the following products DC Bead, HepaSphere Microspheres and Embozene
TANDEM have been CE marked as medical devices and are indicated for the treatment of
HCC after loading with chemotherapeutic agents (i.e. doxorubicin and irinotecan). The
products have a dual action -embolisation and delivery of a local, controlled, sustained dose
of doxorubicin or irinotecan to the tumour although the manufacturers claim that the principal
intended action still remains as embolisation .
.
At the moment, such microspheres intended to be loaded with and release doxorubicin or
other chemotherapeutic agents are placed on the market as medical devices under the rule 8
of the Annex IX in class IIb (implantable medical device) or III (implantable medical device
intended to administer a chemotherapeutic agent). In the case of DC Bead this product has
recently been re-classified from Class 11b to Class III under rule 8.
The loading of the drug is either performed at the moment of administration or the loaded
microspheres may be prepared in advance and stored in a fridge for a specified time.
The IFU’s for all of these medical devices do not mention the names of individual licensed
medicinal products. However, they do mention that other chemotherapeutic agents such as
cisplatin, epirubicin, flurouracil, irinotecan and mitomycin could be loaded on microspheres.
Doxorubicin or other chemotherapeutic agents are medicinal products which are not provided
with the microspheres. The use of these medicinal products in combination with
microspheres is not covered by a medicines marketing authorisation because the route of
administration, dosage and even specific indications are not covered by the medicines
mailto:clare.headley@mhra.gsi.gov.uk
mailto:muriel.gaffiero@afssaps.sante.fr
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Summary of Product Characteristics. The medical device manufacturer is therefore
recommending a new use for the medicinal products. This is not clearly explained in the
most of the IFU’s. Thus physicians may not be aware that the use of these licensed
medicinal products is ‘off-label’ use and that they would be personally responsible for the
treatment they are administering.
MEDDEV 2.1. /3 rev 3 point B4 established that “a medical device incorporates a medicinal
substance as an integral part, within the meaning of Article 1 (4) if and only if the device and
the substance are physically or chemically combined at the time of administration (i.e. use,
implantation, application etc) to the patient. According to this interpretation, the microspheres
could be classified in class III under rule 13.
If this were to be the case an evaluation of the quality, safety and usefulness of the
chemotherapeutic agent incorporated in the microspheres would be verified by a medicines
competent authority. However, the manufacturer of the microspheres would face a difficulty
during the conformity assessment procedure since the information about the quality aspects
of the medicinal product are data that is not held by them but by the licence holder for the
medicinal product. None of the microsphere products of which we are currently aware are
supplied with the medicinal product (i.e. the microspheres are supplied on their own).
.
It is also possible that the microspheres are in class III under rule 8 last intent as implantable
devices intended to administer medicines. However, in this case, the release kinetics of the
medicine, its usefulness/efficacy and its safety by this means of administration will not have
been evaluated during the assessment process for the medicinal products marketing
authorisation (as the drug is not licensed for this indication) and in addition would not be
reviewed during the CE marking process either by a notified body or a medicines authority.
Consequently, we would like to know the Members States’ opinion on the classification that
should be applied to the microspheres when they are intended to deliver the
chemotherapeutic agent (the drug).
Enquiry result
17 CA’s responded to this enquiry, however no consensus was reached. Although nearly all
those who responded did not consider such a product would be Class IIb under rule 8,
approximately 50% of the CA’s considered such a product should be Class III under rule 8
and 50% considered that Class III under rule 13 would be applicable. Some of the
responses were, however contradictory (see summary).
This subject clearly needs additional discussion and therefore no suggested entry for the
manual of decisions has been provided.
No additional responses were received as a result of issuing the original summary. This
issue requires additional discussion.
Best regards,
Clare Headley
Version 1
Do you consider that
microspheres
intended to load and
release doxorubicin
or other
chemotherapeutic
agents are in class IIb
under rule 8?
Do you consider that
microspheres
intended to load and
release doxorubicin
or other
chemotherapeutic
agents are in class III
last indent under rule
8?
Do you consider that
microspheres
intended to load and
release doxorubicin
or other
chemotherapeutic
agent (which is not
provided for this use)
are in class III under
rule 13 ?
If you consider
that
microspheres
intended to load
and release
doxorubicin or
other
chemotherapeuti
c agents (which
is not provided
for this use) are
not in class III
under rule 13,
how do you think
that the
verification of the
quality, safety
and usefulness
for such
substances
should be carried
out?
If you consider
that
microspheres
intended to load
and release
doxorubicin or
other
chemotherapeuti
c agent (which is
not provided for
this use) are not
in class III under
rule 13, should
they be included
in the Recast
discussion to
cover the quality,
safety and
usefulness of the
medicinal
substance?
Additional rationale / remarks
Competent
Authority
14 = No 8 = yes 7 = No 8 = Yes 6 = No 12 = N/A 3 = Yes 1 = No
10 = N/A
1
No Yes Yes
Microspheres supplied
without a medicinal product
fall under rule 13 as well as
rule 8 if they may be
combined with a medicinal
product according to the
manufacturer’s specification.
According to MEDDEV 2.4/1
rev. 9, rule 13 may apply to
any device where device and
medicinal product are
physically or chemically
combined at the time of
administration to the patient,
N/A N/A If the manufacturer of a medical device
(microspheres) promotes the combination
of a medicinal product with his device, the
following conditions should be met for this
combination (by the manufacturer of the
medical device or the medicinal product):
Verification of the quality,
safety and usefulness of the
“substance/chemotherapeutic
agent/medicinal product” by
analogy with the methods
specified in Annex I to Directive
2001/83/EC
Evaluation of the release
kinetics and dosage of the
medicine, specific indications,
its usefulness/efficacy and its
safety by this means of
administration
If above mentioned conditions are not
met, the medicinal product in combination
with the medical device (microspheres) is
being used off-label.
In our opinion the IFU of the medical
device should include precise information
on this specific subject.
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2
No Yes
We consider that the
appropriate classification is
class III under rule 8 last
intend (implantable medical
device intended to administer
a chemotherapeutic agent).
See additional rationale and
remarks
No N/A N/A The manufacturer has to provide clinical
evidence that clearly demonstrate the
main role of the microspheres and the
main mechanism of achievement of their
intended purpose.
3
Yes
4
No
Rule 8
All implantable devices
intended to administer
medicines are in Class III.
Yes
In our opinion, the
embolization miscrospheres
has two purposes:
as an embolic
agents, and
for the
administration of
cytotoxic drugs.
For instance, preclinical and
clinical studies have shown
that drug eluting beads is a
drug delivery embolization
system that has been design
to deliver higher chemo dose
into the tumour with minimal
systemic effects. Therefore, is
an implantable device
intended to administer
medicinal products.
Lammer J, Malagari K, Vogl
T, et. al. Prospective
randomized study of
Doxorubicin-Eluting-Bead
embolization in the treatment
of Hepatocellular carcinoma.
Results of the PRECISION V
Study. Cardiovasc Intervent
Radiol. 2010:33(1): 41-52
Lewis AL, Gonzalez MV,
Leppard SW, et al.
Doxorubicin eluting beads.
Effects of drug loading on
bead characteristics and drug
distribution. J Mater Sci Mater
Med. 2007;18:1691–1699.
Lewis AL, Taylor RR, Hall B,
et al. Pharmacokinetic and
safety study of doxorubicin-
eluting beads in a porcine
model of hepatic arterial
No
The medicinal drug is not an
integral part of the device
N/A
Directive 93/42/EEC,
Annex I, point 7.3
A device intended to
administer medicinal
products must be
design and
manufactured so to be
used safely, to be
compatible with the
medicinal products and
medicine’s performance
must be maintained in
accordance with the
intended use
N/A
In our opinion
microspheres intended
to load and release
Doxirubicin are in class
III under rule 13
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embolisation. J Vasc Interv
Radiol. 2006;17:1335–1343.
5
NO NO YES
At the time of administration
the medical device
incorporates a medicinal
substance as an integral part;
therefore the rule 13 should
be applied.
N/A N/A
6
NO
The device has a dual
intended purpose of which
the highest classification
applies.
YES NO
The devices are not placed
on
the market in such a way that
the device and the medicinal
product form a single integral
unit with the medicinal
product.
This should be included
in the assessment of
the medicinal product.
The medicinal product’s
SmPC must allow the
product to be
administered in this
manner.
Adequate information
regarding the medicinal
product or products
which the device is
designed to administer,
including
any limitations in the
choice of substances to
be delivered must be
provided in the device’s
instructions for use.
NO
7
No Yes
Since the highest
classification applies, the
microspheres are a Class III
device
No N/A Yes
8
NO
No, the device has 2 intended
purposes, one of which is to
deliver medicines, which
makes the device Class III
under Rule 8.
YES
The device has two intended
purposes:
the primary being
embolisation,
the secondary being
drug delivery.
Under rule 8, the device is
Class IIb based on its
intended embolisation
purpose and Class III based
on its intended purpose of
administering medicine.
Since the highest
classification applies, the
microspheres are a Class III
device
NO
The devices are not supplied
with the medicinal product.
In an analogous manner, a
syringe is not Class III under
rule 13 just because its
intended to administer a
medicinal product.
N/A
Essential Requirement
7.3 requires the device
to be designed and
manufactured so that
it’s safe for use
with all substances
it contacts during
use
it’s compatible with
the medicinal
products being
administered and
the medicine’s
performance is
maintained according to
its intended purpose i.e.
the medicinal product’s
SmPC must allow the
product to be used in
this manner.
YES
In addition, if the SmPC
does not facilitate use
of the medicinal product
with the microspheres,
it is being used off-label
and the IFU should
clearly state this. The
IFU should direct the
user to check the
relevant SmPC.
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9
No Yes
The device has two intended
purposes:
embolisation,
drug delivery.
Based on rule 8, the highest
classification applies: the
device could be Class IIb if its
intended use was
embolisation only and class
III if its intended also to
administer medicines.
Although the device is not
supplied with the medicinal
product and since the
chemoterapic has not an
ancillary action, the
responsibility for the
combination should be
divided between the
manufacturer of the medical
device taking responsibility
for the microspheres, and the
marketing authorization
holder of the medicinal
products taking responsibility
for that the chemotherapeutic
agent(s) administered by the
microspheres.
For this reason the device
should be evaluated as class
III according to rule 13 in
order to follow the
consultation procedure for the
medicinal product.
For the medical device
essential Requirement
7.3
For the medicinal
product Notice to
Applicant
Yes
The medicinal product
SPC should provide
complete information
concerning its use with
the microspheres
otherwise an off-label
use occurs. On the
other hand the device
IFU should provide
information concerning
which medicinal
products could be use
in combination with
microspheres and
direct the user to check
the relevant SPC.
10
No No Yes N/A N/A
11
Yes See directive why not medicinal product :
article 1 – point 3 – second
paragraph ?
12
No No Yes
If chemotherapeutic agent
has an ancillary action to
microspheres, microspheres
intended to load and release
any chemotherapeutic agent
should be classified as class
III under rule 13.
Furthermore, if manufacturer
of microspheres declares that
they are suitable for loading
chemotherapeutic agents but
it was not predicted by
manufacturers of these
agents, he should provide
documentation concerning
safety, usefulness and
effectiveness of these
chemotherapeutic agents
complemented with a new
indication.
It is also worth considering
what, chemotherapeutic
agents or microspheres, have
an ancillary action. The
manufacturers of
N/A N/A
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microspheres say that
embolisation is the main
principal intended action.
However it is also possible
that embolisation is
equivalent or even ancillary to
action of used medicinal
product.
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13
No No `Yes
Considering all of the points
indicated by our colleagues,
the most appropriate class,
and classification rule for
these products would be
class III according to rule 13.
As stated, the products have
a dual action - embolisation
and delivery of a local,
controlled, sustained dose of
chemotherapeutic agents
(medicinal products), and
according to point B4. of
MEDDEV 2.1/3 rev 3.: “This
case relates to a device that
incorporates, as an integral
part, a substance which, if
used separately, may be
considered to be a medicinal
product within the meaning of
Article 1 of MPD and which is
liable to act upon the body
with action that is ancillary to
that of the device (…) a
medical device incorporates a
medicinal substance as an
integral part, within the
meaning of Article 1 (4) MDD
and Article 1 (4) AIMDD, if
and only if the device and the
substance are physically or
chemically combined at the
time of administration (i.e.
use, implantation, application
etc) to the patient.
.
N/A N/A We share the concern expressed
regarding the need for proper
evaluation of the combination of
medicinal products +
microspheres. Classification
rules should serve the purpose of
ensuring that products are
assessed according to the most
adequate conformity assessment
procedure, and this seems to be
the most appropriate solution
14
Microspheres intended to load
medicinal product is a medical
device, class III under rule 8 or
13.
15
No No
Microspheres are not
intended to administer
medicines (1. the use of
these medicinal products in
combination with
microspheres is not covered
by a medicines marketing
authorisation, 2.
microspheres are intended to
occlude tumour’s blood
supply)
Yes N/A N/A
16
No No Yes
It is important that this route
of exposure is evaluated.
N/A N/A
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Since the manufacturer of the
medical device take
responsibility for the
combination of the
microspheres and the
chemotherapeutic agent(s),
this combination has to be in
class III according to rule 13.
However, in the best of
worlds, the responsibility for
the combination should be
divided between the
manufacturer of the medical
device taking responsibility
for the microspheres, and the
producer of the medicinal
products taking responsibility
for that the chemotherapeutic
agent(s) could be delivered
by microspheres. If that would
be the case, we think that rule
6 would be applicable for the
medical device as administer
of the chemotherapeutic
agent(s), whereas the
microsphere could be
classified according to rule 8
for its embolisation effect.
Both rule 6 and 8 leading to
class IIb.
17
No No
The microspheres are not
only intended to deliver the
drug.
No
If the microspheres are only
intended to be loaded with a
drug, then they are
considered as semi-finished
products.
If the microspheres are also
placed on the market as such
(without any drug) then they
could be considered as class
IIb under rule 8.
The loaded microspheres
could be classified as class III
medical devices provided that
the manufacturer can prove
that the main effect of the
loaded microspheres is
physical (embolisation).
N/A N/A
31.07.2014
Datei
PD
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ENQUIRY TO
MEDICAL DEVICE COMPETENT AUTHORITIES
Helsinki Procedure 2013
Confidential between Member States
Problem : Classification of wound gel as Class III Rule 13
Originating CA: MHRA
Contact Point: Clare Headley
E-mail : clare.headley@mhra.gsi.gov.uk
Circulated : 28.06.2013
Deadline: 28.7.2013
Extended deadline: 12/8/2013
Date Summary issued: 3/3/2014
SUMMARY
Description of the problem
The MHRA has received a request for consultation wound healing product that contains an soluble beta-glucan
(SBG) as an ancillary medicinal substance.
The product as proposed for market contains carboxymethylcellulose (CMC) and glycerol which are both
established components of wound healing dressings presented as gels.
The primary function of the product is claimed as a hydrogel wound dressing with moistening and assisting
debriding effect in the wound bed. This is achieved by the functionality of glycerol and CMC being able to bind
excessive amounts of water (i.e., having a high viscosity event at 1 to 2% concentration). The SBG
polysaccharide component also contributes to this function as it forms a weak gel at a 2% concentration in water.
The SBG is claimed to have a dual action. The ancillary or medicinal substance effect, is claimed to stimulate
the wound healing process by modulating phagocytic cells in the wound bed, especially macrophage functions.
SBG may also contribute to reducing the risk for secondary wound infection by modulating the functions of cells
belonging to the innate immunological system and by recruiting phagocytic cells into the wound area (although
no claims are made for this).
The manufacturer and Notified Body have agreed on classification of the product as a medical device
incorporating ancillary medicinal substance, i.e. Class III medical device according to Rule 13.
However, this particular case is complicated because
1) the ‘ancillary medicinal substance’ SBG is not a recognised, authorised medicinal substance. It is a natural
substance obtained from baker’s yeast and utilised in a number of different applications in foods, cosmetics and
other industries. Indeed it is a component of another medical device with similar formulation. It is currently
marketed as a wound healing medical device, where no specific claims for medicinal action are made. This is
believed to be a Class IIb device.
2) however, there is a great deal of research into the immuno-modulatory effects of SBG. The possibility of
presenting a 2% formulation of SBG in water as a new medicinal substance was discussed at a Scientific Advice
meeting at EMA in May 2007. The manufacturer was advised about requirements for pre-clinical and clinical
studies required should the product be the subject of a medicinal product Marketing Authorisation Application
(MAA). There is also a reference to the clinical trial of SBG as a drug for use as treatment for diabetic foot
ulcers on the US ClinicalTrials.gov website.
mailto:clare.headley@mhra.gsi.gov.uk
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The initial 2% formulation of the SBG in water used in these clinical trials showed mixed results – in
approximately 50% of cases, the gel structure degraded but in the remainder, where gel viscosity was
maintained, a positive effect was seen. Further investigative work and research resulted in the formulation being
changed to incorporate the wound healing properties of typical wound gel components (carboxymethylcellulose
(CMC) and glycerol).
Formulation of gels used in clinical, animal and in vitro studies to demonstrate effect on wound healing:
Product name
Water % SBG % CMC or MC % Glycerol %
2% SBG gel 98 2
Product X 76 2 2 (CMC) 20
”Product X” without
SBG
78 2 (CMC) 20
The product is now presented as a medical device with ancillary medicinal substance function, on the basis of the
principal mode of action being due to maintaining a moist wound healing environment, with ancillary immuno-
modulatory effects of the SBG.
The rationale for such classification is plausible. However there is currently debate within Europe about both
dual action products and the requirement to demonstrate ancillary rather than principal medicinal mode of action.
MHRA seek to obtain the opinion of other Members States as to the appropriate classification of this product
based on the data provided.
Background
The product, Product X, is a sterile, non-preserved amorphous and thixotropic wound filling gel containing
Water (76%), Glycerol (20%), Carboxymethylcellulose (~2%) and Soluble Beta-Glucan (2%). The product
formulation is heat sterilized in bulk and then aseptically filled into gamma sterilized laminated and tamper
evident PE/Al/PE- tubes. Each tube contains 4 gram of the gel. It is to be administered to the wound surface as a
primary wound dressing, which then will be covered with a conventional secondary dressing. The medical
device is intended for single use and single patient use.
Soluble beta-glucan (SBG) is an aqueous soluble -1,3/1,6-glucan produced from baker's yeast; it is a polymer
containing glucose as the only monomer. A 2% formulation in water presents as an adhesive gel-like solution.
SBG has been found to be an inducer of innate immune responses through its action on phagocytic cells at the
beta-glucan receptor Dectin-1, which stimulates macrophage migration into wounds.
The general structural formula is shown below.
OR
1
CH
2
O
OH
O
OH
CH
2 O
OH
OH
OH
n
O OH
CH
2 O
OH
OH
OR
3
OR
2
R= H or (C6H9-10O5)1-50; n= 35-1600
The gel product as proposed for market contains carboxymethylcellulose (CMC) and glycerol which are both
established components of wound healing dressings presented as gels.
The device is claimed to have as its primary function a hydrogel wound dressing with moistening and assisting
debriding effect in the wound bed. This is achieved by the functionality of glycerol and CMC being able to bind
excessive amounts of water (i.e., having a high viscosity event at 1 to 2% concentration), but also by the SBG
polysaccharide component which forms a weak gel at a 2% concentration in water.
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The purpose of the ancillary medicinal substance, SBG, is to stimulate the wound healing process by modulating
phagocytic cells in the wound bed, especially macrophage functions.
The manufacturer has performed a number of studies to elucidate the immuno-modulatory, wound healing mode
of action of the soluble beta-glucan and has found that the mode of action includes effects on cell proliferation,
angiogenesis and tissue factor (TF) activity (see summary data below):
Supporting data
Data for the following studies were provided:
Wound bed cell proliferation and blood vessel formation to demonstrate that in the centre and intermediate
areas of the wound model, the effects of Product X were significant when compared to the innate effects of water
or other components without SBG, but at the margins of the wound the effect was less pronounced and therefore
may be considered ancillary. This study also showed that the water and other components of the wound healing
gel have a major contributory effect on cell proliferation and blood vessel formation, indicating that the effect of
the SBG may be considered to be ancillary.
Effects of SBG on Tissue Factor activity demonstrated that the stimulatory effects of Product X on Tissue
Factor activity are due to the SBG component and similar to the positive control of lipopolysaccharide (LPS).
These data supported the claim of SBG having an immuno-modulatory effect due to pharmacological,
immunological and/or metabolic mode of action in the wound healing gel.
Demonstration of ancillary effect of SBG: In order to demonstrate that the immuno-modulatory effects on
wound healing are only ancillary to the principal mode of action due to the physical/ mechanical effects of
maintaining a moist wound environment, a transgenic mouse model of diabetic ulcers was used to compare
wound contraction compared to water alone or components of Product X.
Taken together, it may be concluded that the SBG component has a significant effect on wound healing. It is
difficult to state conclusively that the effect of the SBG is ancillary to the device component. However the data
provided indicate that the effect is in addition to, and not greater than, the effect of the other components alone.
Indeed the occlusive dressing and water controls used demonstrated the positive effects of maintaining moisture
on the wound healing process as well as the contribution of gel structure to wound healing.
Product claims and presentation
The claims made are as follows (see IFU attached as Annex 2 (Not provided for circulation to full Borderline
and Classification Working Group. Instead, the sections on claimed mode of action and incorporated medicinal
substance are provided below):
Product X provides a moist environment that assists wound healing by promoting the debridement of the wound
through natural autolysis. It also rehydrates necrotic tissue, prevents desiccation, and absorbs slough. Product X
contains Soluble Beta Glucan (SBG) from S. cerevisiae. SBG modulates macrophage functions and attracts
phagocytic cells to the wound bed, thereby facilitating wound healing and wound contraction.
The product is presented as a gel in a tube. This is not unlike a number of other CE marked wound healing gel
products currently marketed. However, the labelling should be amended to remove reference to ‘medicinal
substance’ and clarify that the SBG is an ancillary component. Currently the packaging is presented as for a
medicinal substance.
(i.e. active ingredient and strength underneath the product name)
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Reference to MEDDEV, Manual of Decisions and precedent
MEDDEV 2.1/3 rev 3 section A.2.1.2 refers to examples of wound dressings in the form of liquids, gels or
pastes, where the principal intended action is as a medical device but they may be assisted by ancillary medicinal
substances
Manual of Decisions March 2013 4.2. Elastoviscous fluids may be considered relevant since additional
pharmacological benefits claimed which are ancillary to the mechanical action are stated not to alter the medical
device status; whereas if the predominant claims are pharmacological they should be classed as medicinal
products.
Therefore it is appropriate to follow a case by case approach, taking into account all product characteristics and
in particular:
Precedent: It is now well established that maintaining a moist wound bed environment improves the healing
process and accelerates closure of the wound (2). A number of different liquid bandages or gels are employed in
wound management, typically falling into three categories: alginates, hydrocolloids and hydrogels. All of which
would have a moistening effect on the wound promoting natural autolytic debridement, reducing wound pain and
to a certain extent absorbing excess wound exudates. Some of these products may be unclassified or marketed as
Class IIb medical devices. A product containing beta-glucans from oat combined with carboxymethylcellulose
and glycerol (MacroPro Gel) is understood to be currently marketed as a Class IIb CE labelled product with no
claimed biological properties.
Opinion of MHRA
The opinion of MHRA is that the experimental data and justification provided for classification as a Class III
medical device with ancillary medicinal (immuno-modulatory) action is considered acceptable, taking into
account the product characteristics, i.e. presentation, intended use and claims.
However, due to ongoing discussions at European level around borderline medicine/medical device products,
acceptable demonstration of ancillary activity and the fact that the opinion of EMA was initially sought as a
medicinal product, we would like to confirm that this opinion is supported by colleagues in other Member States.
Additional remark
The original clinical studies were performed on 2% SBG in water. No clinical studies have yet been performed
with Product X, however this has been justified by bridging studies. The manufacturer argues that the studies in
transgenic mice, preliminary clinical and animal work on the initial formulation of SBG alone and use of known
ingredients are sufficient to address usefulness and safety concerns prior to marketing. A Post Marketing Clinical
Follow-up study is proposed to confirm the effects in humans.
References
1 Wound-healing studies in transgenic and knockout mice Grose R, Werner S., Mol Biotechnol. 2004
Oct;28(2):147-66.
2 Overview of wound healing in a moist environment Charles K. Field,, Morris D. Kerstein, American J
Surgery Volume 167, Issue 1, Supplement, January 1994, Pages S2–S6
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ANNEX 1 SUPPORTING DATA
Figure 1 demonstrates the medicinal mode of action on cell proliferation and angiogenesis in the wound bed. In
the centre and intermediate areas of the wound, the effects of Product X were significant when compared to the
innate effects of water or other components without SBG, but at the margins of the wound the effect was less
pronounced and therefore may be considered ancillary.
Figure 1: Wound bed cell proliferation and blood vessel formation
In Figure 2 the stimulatory effects of Product X on Tissue Factor activity are shown to be due to the SBG
component and similar to the positive control of lipopolysaccharide (LPS).
Figure 2 Effects of SBG on Tissue Factor activity
Version 1
These graphs clearly show that the SBG component will have some medicinal effect on wound healing that can
be considered as due to pharmacological, immunological and/or metabolic mode of action. These data support
the claim of SBG having an immuno-modulatory effect in the wound healing gel.
However, Figure 1 shows that the water and other components of the wound healing gel have a major
contributory effect on cell proliferation and blood vessel formation, indicating that the effect of the SBG may be
considered to be ancillary.
In order to demonstrate that the immuno-modulatory effects on wound healing are only ancillary to the principal
mode of action due to the physical/ mechanical effects of maintaining a moist wound environment, a model of
diabetic ulcers was used to compare wound contraction compared to water alone or components of Product X.
The transgenic mouse model is considered to be a useful model in studying the molecular mechanisms involved
in wound healing (1).
Figure 3a: Demonstration of ancillary effect of SBG on wound contraction
Figure 3b: Demonstration of ancillary effect of SBG on wound healing
Version 1
Figure 3c: Demonstration of ancillary effect of SBG on wound healing – effect of gel structure
Water and gel effect on wound healing in db/db mice
(Report CICA-BIOT-1)
1
Dressing only
Water control
Non-gel SBG
Gel SBG
Applying water under occlusive dressing improved healing performance. SBG as gel performed better
than SBG where gel characteristic was lost.
0
20
40
60
80
100
120
0 4 8 12 16
Days Post-wounding
Non-gel SBG
Gel SBG
Water control
Dressing only
%
w
o
u
n
d
a
re
a
r
e
m
a
in
in
g
Figure 3c compares the effect of the 2% SBG formulations where gel structure was intact and after gel structure
was lost.
Taken together, it may be concluded that the SBG component has a significant effect on wound healing. It is
difficult to state conclusively that the effect of the SBG is ancillary to the device component. However the data
provided indicate that the effect is in addition to, and not greater than, the effect of the other components alone.
Indeed the occlusive dressing and water controls in Figure 3c demonstrate the positive effects of maintaining
moisture on the wound healing process as well as the contribution of gel structure to wound healing.
Version 1
ANNEX 2 Instructions for Use
The information available on the manufacturer’s website is consistent with presentation as a medical device with
ancillary medicinal action and claims made in the IFU.
Version 1
ANNEX 3 Product packaging
Version 1
Enquiry result
Only 13 CA’s responded to this enquiry, however of these 12 considered that the product would be
acceptable as a medical device (92%). 9 considered that the experimental data provided was
sufficient to support ancillary medicinal action of the SBG (69%). 11 considered that the product
would be acceptable as a Class III rule 13 medical device (84%), with one CA advising ‘no’ on the
basis that the data would need to be more robust to support ancillary action and one CA considering
the product to be a Class IIb device under rule 4 as SBG is not a recognised, authorised medicinal
substance.
The majority view is therefore that there is sufficient evidence to support the qualification of the
product as a Class III rule 13 medical device, since question 2 related specifically to the data
supplied.
This enquiry contained a large amount of information which it would be inappropriate to place in the
manual of decisions. However the issue is complex and therefore the text of what could be included
in the manual of decisions needs to be carefully considered. It will be necessary to ensure that the
entry is clear and does not cause confusion on the regulatory route for other products in future. It is
suggested therefore that the entry makes it clear that this determination was on one very specific
product and does not necessarily indicate that similar products would be acceptable as medical
devices without a thorough review.
Qualification and classification of a wound gel containing soluble beta glucan
Background
The product is a sterile, non-preserved amorphous and thixotropic wound filling gel containing water,
glycerol, carboxymethylcellulose, and soluble beta-glucan (SBG, 2%). It is to be administered to the
wound surface as a primary wound dressing, which then will be covered with a conventional
secondary dressing.
The question was whether such a product would be acceptable as a class III medical device with
ancillary medicinal action under classification rule 13.
The soluble beta-glucan utilised is an aqueous soluble -1,3/1,6-glucan produced from baker's yeast;
it is a polymer containing glucose as the only monomer. A 2% formulation in water presents as an
adhesive gel-like solution. SBG has been found to be an inducer of innate immune responses
through its action on phagocytic cells at the beta-glucan receptor Dectin-1, which stimulates
macrophage migration into wounds.
The gel product contains carboxymethylcellulose (CMC) and glycerol which are both established
components of wound healing dressings presented as gels.
The product claimed to have as its primary function a hydrogel wound dressing with moistening and
assisting debriding effect in the wound bed. This is achieved by the functionality of glycerol and
CMC being able to bind excessive amounts of water (i.e., having a high viscosity event at 1 to 2%
concentration), but also by the soluble beta-glucan polysaccharide component which forms a weak
gel at a 2% concentration in water.
The soluble beta-glucan was claimed to have a dual action. The ancillary or medicinal substance
effect, is claimed to stimulate the wound healing process by modulating phagocytic cells in the
wound bed, especially macrophage functions. Soluble beta-glucan may also contribute to reducing
the risk for secondary wound infection by modulating the functions of cells belonging to the innate
immunological system and by recruiting phagocytic cells into the wound area.
A large amount of data was submitted to the Competent Authorities to support the contention that the
pharmacological/immunological/metabolic (medicinal) mode of action is ancillary to the moist wound
healing effect.
Outcome
For this specific product only, the experimental data provided sufficient evidence to support ancillary
medicinal action for the soluble beta-glucan and therefore to support the qualification of this specific
Version 1
product as a Class III medical device under classification rule 13. This should not be taken to mean,
however, that other products containing soluble beta-glucans or other ‘dual action’ products will be
acceptable as medical devices.
Best regards,
Clare Headley
Version 1
Do you consider that
the proposed
formulation of the
product is acceptable
as a medical device?
If not, please provide
an explanation.
Do you consider that
the experimental data
provided are
satisfactory to
support ancillary
immuno-modulatory
medicinal action of
the SBG?
If not, please provide
an explanation.
Do you support classification as a
Class III medical device incorporating
ancillary medicinal substance (Rule 13)
on the basis of the justificaton
provided?
Competent
Authority
12 = yes 1 = no 9= yes 3 = no 11 = yes 2 = no
1
Yes No There is not enough
data supporting
ancillary action of the
SBG.
No
Class IIb
Rule 4
We consider the classification as a Class
IIb device is more appropriate in this case,
moreover the SBG is not a recognised,
authorised medicinal substance.
2
Yes
We agree with the
opinion of MHRA
N/A Yes N/A Yes
3
Yes
We agree with the
opinion of MHRA.
N/A Yes N/A Yes
4
Yes Yes Yes
5
Yes
Taking into account the
information provided
N/A Yes
It could be satisfactory
Yes
The demonstration of the pharmacological,
immunolugic, metabolic mean of action
should be coherent with the state of art for
the substance SBG to conclude. The
explanation that SBG modulates
macrophages function and attracts
phagocytes cells to the wound bed, allows
to consider that the action is
pharmacologic. However, the finalisation
and publication of the Meddev 2.1/3
concerning the pharmacological,
immunological and metabolic mean of
action is very necessary to determine the
status and class of this kind of product.
6
YES N/A YES N/A We previously reviewed the classification
of a similar soluble beta-glucan wound gel
which was in development circa 2010.
Version 1
During this original review in 2010,
discussion focused on beta-glucan which
appears to act as a macrophage stimulant
via the binding of glucan to the hDectin-1
receptors of macrophages resulting in the
activation and up regulation of
macrophage cell activity. However, the
manufacturer presented research which
indicated glucan’s ability to have an
immunological effect through interaction
with macrophages was significantly
dependent upon their physical nature. The
most active products were found to be
insoluble beta-1,3-glucans, whereas a
soluble beta-1,3-linked glucan did not
induce any macrophage activation but was
shown on the contrary to inhibit
macrophage activation. The rationale for
the inclusion of soluble beta-glucan was
related to its water holding capacity and
gel formation characteristics which facilities
adhesion to the wound bed and barrier
formation. Where this is the case, and is
scientifically demonstrable, a classification
of Class IIb may be appropriate for soluble
beta-gluan wound gels.
However, the additional data presented in
the Annex I, would indicate an ancillary
immuno-modulatory action by the beta-
glucan; its classification as a Class III
medical device with an ancillary medicinal
action may be considered acceptable.
Version 1
7
Yes N/A Yes N/A Yes
Data provided in Annex 1 allow to
conclude that the product can be qualified
as medical device and classified in class III
based on rule 13.
8
Yes N/A Yes N/A Yes
9
Yes N/A Yes
Figure 1 and 2 clearly
stated that soluble
beta-glucan exerts
significant effect on cell
proliferation,
angiogenesis and
tissue factor activity.
Figures 3a, 3b and 3c
show that the immuno-
modulatory effect of the
SBG on wound-healing
is ancillary to the
principal mode of action
due to the
physical/mechanical
effects of maintaining a
moist wound
environment.
N/A Yes
According to the applied information SBG
has immunological action – modulates
macrophage functions and attract
phagocytic cells to the wound bed. So
SBG acts as a medicinal product. On the
basis of supporting data and information
contained in the Instruction for Use SBG
exerts ancillary action to the product.
Primary function of the product is achieved
by functionality of glycerol and CMC being
able to bind excessive amount of water
provides a mist environment that assists
wound healing by promoting the
debridement of the wound through natural
autolysis.
10
Yes
Considering the
information presented
we agree with the
presented opinion:
“The opinion of MHRA
is that the experimental
data and justification
provided for
classification as a Class
III medical device with
ancillary medicinal
(immuno-modulatory)
N/A The data presented
seems to fundament
the ancillary action of
the SBG.
However, we consider
that it would be useful
to present this
information to our
colleagues of the
medical products area.
We will take this
approach and present
N/A Yes
Version 1
action is considered
acceptable, taking into
account the product
characteristics, i.e.
presentation, intended
use and claims.”
Considering as ancillary
the action of SBG, the
product should be
classified as a class III
MD.
their feedback, as soon
as possible.
Unfortunately, we will
not be able to present it
before August (being
the deadline of this
enquiry the 28th of july).
Version 1
11
Yes
Taking into account
provided information.
N/A Yes N/A Yes
12
Probably not
The supporting data in
Annex 1 clearly shows
that Product X has a
greater effect on would
healing/contraction
compared to Product X
without SBG and that
SBG alone has a
pharmacologic effect
(Figure 2). However we
believe that Figure 1, 2,
3a and 3b do not
provide enough data to
demonstrate an
ancillary (and not
major) effect of SBG –
rather it seems that
SBG is responsible for
the main effect of
Product X.
Only Figure 3c gives an
idea that the
pharmacologic/immunol
ogic effect of SBG is
only ancillary, since the
gel-structured SBG
(which is supposed to
bind excessive water
and therefore act in the
same way as CMC and
glycerol) gives an
increased effect
compared to non-gel
SBG. Moreover, the
manufacturer itself
states that “It is difficult
to state conclusively
that the effect of the
SBG is ancillary to the
device component.”.
Given also the fact the
SBG is being
The supporting data in
Annex 1 clearly shows
that Product X has a
greater effect on would
healing/contraction
compared to Product X
without SBG and that
SBG alone has a
pharmacologic effect
(Figure 2). However we
believe that Figure 1, 2,
3a and 3b do not
provide enough data to
demonstrate an
ancillary (and not
major) effect of SBG –
rather it seems that
SBG is responsible for
the main effect of
Product X.
Only Figure 3c gives an
idea that the
pharmacologic/immunol
ogic effect of SBG is
only ancillary, since the
gel-structured SBG
(which is supposed to
bind excessive water
and therefore act in the
same way as CMC and
glycerol) gives an
increased effect
compared to non-gel
SBG. Moreover, the
manufacturer itself
states that “It is difficult
to state conclusively
that the effect of the
SBG is ancillary to the
device component.”.
Given also the fact the
SBG is being
investigated as a drug
No The supporting data in
Annex 1 clearly shows
that Product X has a
greater effect on would
healing/contraction
compared to Product X
without SBG and that
SBG alone has a
pharmacologic effect
(Figure 2). However we
believe that Figure 1, 2,
3a and 3b do not
provide enough data to
demonstrate an
ancillary (and not
major) effect of SBG –
rather it seems that
SBG is responsible for
the main effect of
Product X.
Only Figure 3c gives an
idea that the
pharmacologic/immunol
ogic effect of SBG is
only ancillary, since the
gel-structured SBG
(which is supposed to
bind excessive water
and therefore act in the
same way as CMC and
glycerol) gives an
increased effect
compared to non-gel
SBG. Moreover, the
manufacturer itself
states that “It is difficult
to state conclusively
that the effect of the
SBG is ancillary to the
device component.”.
Given also the fact the
SBG is being
investigated as a drug
No
If the supporting data would more strongly
support an ancillary effect of SBG the
product could be classified as a MD and
Rule 13 would be applicable in this case.
Version 1
investigated as a drug
in a clinical trial for the
treatment of diabetic
foot ulcer, we do not
think that enough
experimental data is
given to support
ancillary (and not
principal) immune-
modulatory action of
SBG.
in a clinical trial for the
treatment of diabetic
foot ulcer, we do not
think that enough
experimental data is
given to support
ancillary (and not
principal) immune-
modulatory action of
SBG.
in a clinical trial for the
treatment of diabetic
foot ulcer, we do not
think that enough
experimental data is
given to support
ancillary (and not
principal) immune-
modulatory action of
SBG.
13
Yes N/A No
Only parts of studies
have been included and
no clinical studies (on
humans) have been
provided.
Furthermore,
requirements of
documentation
concerning the ancillary
substance should meet
the criteria described in
MEDDEV 2.1/3 rev 3,
C3.
We do not think that
safety or efficacy has
been proven when no
clinical data has been
provided.
Yes
31.07.2014
Datei
PD
page 1 of 46
EUROPEAN COMMISSION
ENTERPRISE AND INDUSTRY DIRECTORATE GENERAL
Consumer Goods
Cosmetics and Medical Devices
MEDDEV. 2.7.1 Rev.3
December 2009
GUIDELINES ON MEDICAL DEVICES
CLINICAL EVALUATION:
A GUIDE FOR MANUFACTURERS AND NOTIFIED
BODIES
The present guidelines are part of a set of guidelines relating to questions of application of EU-Directives
on MEDICAL DEVICEs. They are legally not binding. The guidelines have been carefully drafted through
a process of intensive consultation of the various interested parties (competent authorities, Commission
services, industries, other interested parties) during which intermediate drafts were circulated and
comments were taken up in the document. Therefore, this document reflects positions taken by
representatives of interested parties in the MEDICAL DEVICEs sector.
These guidelines incorporate changes introduced by Directive 2007/47/EC amending Council Directive
90/385/EEC and Council Directive 93/42/EEC and will be applicable as of 21st March 2010. The
transitional period allowing a gradual implementation of the guidelines will therefore end on 20 March
2010.
Note:
This document is a revision of an earlier document published in April 2003 as MEDDEV 2.7.1
This document has been drafted on the basis of GHTF Guideline SG5/N2R8:2007 Clinical Evaluation of 29
June 2007 published at www.ghtf.org
page 2 of 46
Contents
Preface............................................................................................................................……4
1.0 Introduction...................................................................................................................... 5
2.0 Scope................................................................................................................................ 6
3.0 References........................................................................................................................ 7
4.0 Definitions........................................................................................................................7
5.0 General principles of clinical evaluation ......................................................................... 9
6.0 Sources of data/documentation used in a clinical evaluation (Stage 1).......................... 12
6.1 Data generated through literature search 12
6.2 Data generated through clinical experience 13
6.3 Data from clinical investigations 14
7.0 Appraisal of clinical data (Stage 2)................................................................................. 16
8.0 Analysis of the clinical data (Stage 3) ............................................................................ 17
9.0 The Clinical Evaluation Report....................................................................................... 18
10 The role of the notified body in the assessment of clinical evaluation data………… 19
10.1 Examination of design dossier 20
10.2 Evaluation as part of the quality system procedure 23
10.3 Notified body specific procedure and expertise 24
Appendices....................................................................................................................…… 27
A: A possible format for the literature search report 28
B: A possible methodology for documenting the screening and selection of literature 29
within a literature search report
C: Some examples to assist with the formulation of criteria 30
D: A possible method of appraisal 32
E: A possible format for a clinical evaluation report 34
F: Clinical evaluation checklist for Notified Bodies 37
page 3 of 46
Preface
These guidelines on Clinical Evaluation are part of a set of Medical Device Guidelines that
promote a common approach by Manufacturers and Notified Bodies involved in clinical
evaluation procedures according to the relevant annexes of the Medical Devices Directives
and by the National Competent Authorities charged with safeguarding public health.
They have been carefully drafted through a process of consultation with various interested
parties during which comments were taken up in the documents. Therefore, it reflects
positions taken in particular by representatives of National Competent Authorities and
Commission Services, Notified Bodies, industry and other interested parties in the MEDICAL
DEVICEs sector.
The guidelines are regularly updated accordingly with regulatory developments. The latest
version of the guidelines should always be used. This revision of these guidelines has:
• amended the document according to the most recent amendment to the Medical
Device Directives (Directive 2007/47/EC) and in the light of experience
• and has carefully considered and transposed into the European context the Global
Harmonisation Task Force (GHTF) international regulatory guidance document on
clinical evaluation (SG5/N2R8:2007).
These guidelines are not legally binding. It is recognised that under given circumstances, for
example, as a result of scientific developments, an alternative approach may be possible or
appropriate to comply with the legal requirements.
Nevertheless, due to the participation of the aforementioned interested parties and of experts
from National Competent Authorities, it is anticipated that the guidelines will be followed
within the Member States and, therefore, work towards uniform application of relevant EU
Directive provisions and common practices within Member States.
However, only the text of the Directives is authentic in law. On certain issues not addressed in
the Directives, national legislation may be different from these guidelines.
page 4 of 46
1. Introduction
What is clinical evaluation?
Clinical evaluation is the assessment and analysis of clinical data pertaining to a medical
device in order to verify the clinical safety and performance of the device.
When is clinical evaluation undertaken?
Clinical evaluation is an ongoing process conducted throughout the life cycle of a medical
device. It is first performed during the conformity assessment process leading to the
marketing of a medical device and then repeated periodically as new clinical safety and
performance information about the device is obtained during its use. This information is fed
into the ongoing risk analysis and may result in changes to the Instructions for Use.
Why is clinical evaluation important?
When placing a medical device on the market the manufacturer must have demonstrated
through the use of appropriate conformity assessment procedures that the device complies
with the relevant Essential Requirements covering safety and performance. Generally, from a
clinical perspective, it is expected that the manufacturer has demonstrated the device achieves
its intended performance during normal conditions of use and that the known and foreseeable
risks, and any adverse events, are minimised and acceptable when weighed against the
benefits of the intended performance, and that any claims made about the device’s
performance and safety (e.g. product labelling and instructions for use) are supported by
suitable evidence.
With regard to post market activities, manufacturers are expected to implement and maintain
surveillance programs that routinely monitor the clinical performance and safety of the device
as part of their Quality Management System. The scope and nature of such post market
surveillance should be appropriate to the device and its intended use. Using data generated
from such programs (e.g. safety reports, including adverse event reports; results from
published literature, any further clinical investigations and formal post market surveillance
studies; etc), a manufacturer should periodically review performance, safety and the benefit-
risk assessment for the device through a clinical evaluation, and update the clinical evidence
accordingly. This ongoing clinical evaluation process should allow manufacturers to
communicate with conformity assessment bodies and Regulatory Authorities in accordance
with local reporting requirements, any information that has an important bearing on the
benefit-risk assessment of the device or that would indicate a need for labelling changes
regarding contraindications, warnings, precautions or instructions for use etc.
What is the process?
To conduct a clinical evaluation, a manufacturer needs to:
• identify the Essential Requirements that require support from relevant clinical data;
• identify available clinical data relevant to the device and its intended use;
• evaluate data in terms of its suitability for establishing the safety and performance of
the device;
• generate any clinical data needed to address outstanding issues;
page 5 of 46
• bring all the clinical data together to reach conclusions about the clinical safety and
performance of the device.
The results of this process are documented in a clinical evaluation report. The clinical
evaluation report and the clinical data on which it is based serve as the clinical evidence that
supports the marketing of the device.
The clinical evidence, along with other design verification and validation documentation,
device description, labelling, risk analysis and manufacturing information, is needed to allow
a manufacturer to demonstrate conformity with the Essential Requirements and is part of the
technical documentation of a medical device.
How detailed should the clinical evaluation be?
A clinical evaluation should be thorough and objective (i.e. it should consider both favourable
and unfavourable data), with the intention of demonstrating valid clinical evidence of the
safety and performance of the device. However, it is important to recognise that there is
considerable diversity in the types and history of technologies used in medical devices and the
risks posed by them. Many devices are developed or modified by incremental innovation, so
they are not completely novel. Thus, it is often possible to draw on the clinical experience and
literature reports of the safety and performance of equivalent devices to establish the clinical
evidence, thereby reducing the need for clinical data generated through clinical investigation
of the device in question. Similarly, it may be possible to use compliance with recognised
standards to satisfy the clinical evidence requirements for devices based on technologies with
well established safety and performance characteristics.
The depth and extent of clinical evaluations should be flexible, not unduly burdensome, and
appropriate to the nature, classification, intended use, manufacturer’s claims and risks of the
device in question. Therefore, this guidance is not intended to impose specific requirements.
2. Scope
The primary purpose of this document is to provide manufacturers and notified bodies with
guidance on how to conduct and document the clinical evaluation of a medical device as part
of the conformity assessment procedure prior to placing a medical device on the market as
well as to support its ongoing marketing. It is also intended to provide guidance to regulators
and other stakeholders when assessing clinical evidence provided by manufacturers.
This document provides the following guidance:
• general principles of clinical evaluation;
• how to identify relevant clinical data to be used in a clinical evaluation;
• how to appraise and integrate clinical data into a summary; and
• how to document a clinical evaluation in a clinical evaluation report.
The guidance contained within this document is intended to apply to medical devices
generally and the device component of combination products. It is not intended to cover in
vitro diagnostics.
page 6 of 46
3. References
European Legislation
Council Directive 90/385/EEC of 20 June 1990 concerning active implantable medical
devices
Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
GHTF final documents
SG1/N011:2008 Summary Technical Documentation for Demonstrating Conformity to
the Essential Principles of Safety and Performance of Medical Devices
(STED)
SG1-N44:2008 Role of Standards in the Assessment of Medical Devices
SG1/N029:2005 Information Document Concerning the Definition of the Term
“Medical Device”
SG1/N040:2006 Principles of Conformity Assessment for Medical Devices
SG1-N41R9:2005 Essential Principles of Safety and Performance of Medical Devices
SG5/N1R8:2007 Clinical Evidence – Key definitions and Concepts
SG5/N2R8:2007 Clinical Evaluation
International standards
ISO 14155-1: 2003 Clinical investigation of medical devices for human subjects – Part 1
General requirements
ISO 14155-2: 2003 Clinical investigation of medical devices for human subjects – Part 2
Clinical investigation plan
ISO14971: 2007 Medical devices – application of risk management to medical devices.
European guidance documents
MEDDEV 2.10/2 Designation and monitoring of Notified Bodies within the framework of EC
Directives on medical devices
MEDDEV 2.12/2 Guidelines on post-market clinical follow up
NBOG BPG 2009-1 Guidance on design dossier examination and report content
http://www.nbog.eu/resources/NBOG_BPG_2009_1.pdf
NBOG BPG 2009-4 Guidance on NB‘s Tasks of Technical Documentation Assessment on a
Representative Basis
http://www.nbog.eu/resources/NBOG_BPG_2009_4_EN.pdf
4. Definitions
Adverse Event: Any untoward medical occurrence in a subject.
Note: For the purposes of this document, this is intended to include any
adverse event whether device related or not
Clinical Data: Safety and/or performance information that are generated from the use of a
medical device. (This term is further explained in GHTF document
SG5/N1R8:2007)
page 7 of 46
Clinical Evaluation: The assessment and analysis of clinical data pertaining to a medical
device to verify the clinical safety and performance of the device when used
as intended by the manufacturer. (This term is further explained in GHTF
document SG5/N1R8:2007)
Clinical Evidence: The clinical data and the clinical evaluation report pertaining to a medical
device. (This term is further explained in GHTF document SG5/N1R8:2007)
Clinical Investigation: Any systematic investigation or study in or on one or more human
subjects, undertaken to assess the safety and/or performance of a medical
device. (This term is further explained in GHTF document SG5/N1R8:2007)
Clinical Investigation Plan: Document that states the rationale, objectives, design and
proposed analysis, methodology, monitoring, conduct and record-keeping of
the clinical investigation.
Clinical Investigator: The individual responsible for the conduct of a clinical investigation
who takes the clinical responsibility for the well-being of the subjects
involved.
Clinical Performance: The ability of a medical device to achieve its intended purpose as
claimed by the manufacturer.
Clinical Safety: The absence of unacceptable clinical risks, when using the device according
to the manufacturer’s Instructions for Use.
Conformity Assessment: The systematic examination of evidence generated and procedures
undertaken by the manufacturer, under requirements established by the
Regulatory Authority, to determine that a medical device is safe and
performs
as intended by the manufacturer and, therefore, conforms to the Essential
Requirements.
Serious Adverse Event: An adverse event that
1 led to a death;
2 led to a serious deterioration in health of a patient, user, or others that:
(a) results in a life threatening illness or injury;
(b) results in a permanent impairment of a body structure or body
function;
(c) requires in patient hospitalisation or prolongation of existing
hospitalisation
(d) results in medical or surgical intervention to prevent permanent
impairment to body structure or a body function;
(e) led to foetal distress, foetal death or a congenital abnormality/
birth defect.
Harmonised Standards: Standards deemed to offer the presumption of conformity to the
Essential Requirements of the Directives.
Technical Documentation: The documented evidence, normally an output of the quality
management system that demonstrates compliance of a device to the
Essential Requirements.
page 8 of 46
5. General principles of clinical evaluation
5.1 What is the scope of a clinical evaluation?
The clinical evaluation is based on a comprehensive analysis of available pre- and post market
clinical data relevant to the intended use of the device in question, including clinical
performance data and safety data. This includes data specific to the device in question as well
as any data relating to devices claimed as equivalent by the manufacturer.
The evaluation must also address any clinical claims made about the device, the adequacy of
product labelling and product information (particularly claims, contraindications,
precautions/warnings), and the suitability of instructions for use.
Before a clinical evaluation is undertaken the manufacturer should define its scope, based on
the Essential Requirements that need to be addressed from a clinical perspective.
Considerations should include:
(a) whether there are any design features of the device or target treatment populations that
require specific attention.
The clinical evaluation should cover any design features that pose special performance or
safety concerns (e.g. presence of medicinal, human or animal components), the intended
purpose and application of the device (e.g. target treatment group and disease, proposed
warnings, contraindications and method of application) and the specific claims made by the
manufacturer about the clinical performance and safety of the device. The scope of the
clinical evaluation will need to be informed by and cross referenced to the manufacturer’s risk
management documents. The risk management documents are expected to identify the risks
associated with the device and how such risks have been addressed. The clinical evaluation is
expected to address the significance of any risks that remain after design risk mitigation
strategies have been employed by the manufacturer;
(b) whether data from equivalent devices can be used to support the safety and/or
performance of the device in question.
The devices should have the same intended use and will need to be compared with
respect to their technical and biological characteristics. These characteristics should be
similar to such an extent that there would be no clinically significant difference in the
performance and safety of the device. The intended use relates to the clinical condition
being treated, the severity and stage of disease, the site of application to/in the body and
the patient population; the technical characteristics relate to the design, specifications,
physiochemical properties including energy intensity, deployment methods, critical
performance requirements, principles of operation and conditions of use; and biological
characteristics relate to biocompatibility of materials in contact with the same body
fluids/tissues. In such cases the manufacturer is expected to include the supporting non
clinical information within the technical documentation for the device and cite its
location within the clinical evaluation report. (Note: the clinical evaluation is not
intended to assess the technical and biological characteristics per se); and
(c) the data source(s) and type(s) of data to be used in the clinical evaluation.
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Manufacturers are able to draw on any one or combination of data sources set out in
Section 6.0. Factors that should be considered when choosing the type of data to be used
in the clinical evaluation include the design, intended use and risks of the device; the
developmental context of the technology on which the device is based (new vs.
established technology); and, for established technology, the proposed clinical
application of that technology. Clinical evaluation of medical devices that are based on
existing, well established technologies and intended for an established use of the
technology is most likely to rely on compliance with recognised standards and/or
literature review and/or clinical experience of equivalent devices.
High risk devices, those based on technologies where there is little or no experience, and
those that extend the intended purpose of an existing technology (i.e. a new clinical use)
are most likely to require clinical investigation data. Therefore for implantable or class
III devices, clinical investigations are required unless it can be duly justified to rely on
existing clinical data alone, as stated in the annex X of Directives 93/42/EEC and annex
7 of 90/385/EEC as amended. The manufacturer will need to give consideration to the
advantages and limitations of each data type.
5.2 How is a clinical evaluation performed?
Once the scope has been defined, there are three distinct stages in performing a clinical
evaluation (Figure 1):
• identification of pertinent standards and clinical data;
• appraisal of each individual data set, in terms of its relevance, applicability, quality and
clinical significance; and
• analysis of the individual data sets, whereby conclusions are reached about the
performance, safety and presentational aspects (labelling, patient information and
instructions for use) of the device.
Each of these stages is covered in separate sections later in this document.
At the end of the clinical evaluation a report is prepared and combined with the relevant
clinical data to form the clinical evidence for the device. If the manufacturer concludes there
is insufficient clinical evidence to be able to declare conformity with the Essential
Requirements, the manufacturer will need to generate additional data (e.g. conduct a clinical
investigation, broaden the scope of literature searching) to address the deficiency. In this
respect clinical evaluation can be an iterative process.
5.3 Who should perform the clinical evaluation?
The clinical evaluation should be conducted by a suitably qualified individual or individuals.
A manufacturer must be able to justify the choice of the evaluator(s) through reference to
qualifications and documented experience.
As a general principle, evaluators should possess knowledge of the following:
• the device technology and its application;
• research methodology (clinical investigation design and biostatistics); and
• diagnosis and management of the conditions intended to be treated or diagnosed by
the device.
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Figure 1: Stages of clinical evaluation
*Conformity to harmonized performance standards may be sufficient to demonstrate
compliance to relevant Essential Requirements (ERs)
6. Sources of data/documentation used in a clinical evaluation (Stage 1)
Data relevant to the clinical evaluation may be held by the manufacturer (e.g. manufacturer
sponsored pre and post market investigation reports and adverse event reports for the device
in question) or in the scientific literature (e.g. published articles of clinical investigations and
adverse event reports for the device in question or for equivalent devices).
Stage 2
Appraisal of individual data sets
• Suitability
• Contribution of results to
demonstration of performance
and safety
Stage 3
Analysis of relevant data
• Strength of overall evidence
• Conclusions about performance
and safety
Is clinical evidence
sufficient to be
able to declare
conformity with
relevant ERs?
Y
E
S
Generate new or additional clinical
data
N
O
Stage 1*
Identify clinical data from
• Literature searching &/or
• Clinical experience &/or
• Clinical investigation
Produce clinical evaluation report
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The manufacturer is responsible for identifying data relevant to the device and determining
the types and amount of data needed for the clinical evaluation.
Where data are used from a combination of sources, the principles applicable to each source
apply to that data component within the clinical evaluation.
6.1 Data generated through literature search
Literature searching can be used to identify published clinical data that is not in the
possession of the manufacturer that may assist the manufacturer to establish acceptable
performance and safety of a medical device. The data generated through literature searching
may relate directly to the device in question (e.g. reports of clinical investigations of the
device in question that have been performed by third parties, adverse event reports) or to
equivalent devices.
For some devices, clinical data generated through literature searching will represent the
greater part (if not all) of the clinical evidence. Thus, when conducting a literature review
reasonable efforts should be made to conduct a comprehensive search.
Published data will need to be assessed with respect to its possible contribution and weighting
in establishing both the performance of the device in question and its safety. Papers
considered unsuitable for demonstration of performance because of poor study design or
inadequate analysis may still contain data suitable for assessing the safety of the device.
The key elements of literature search
The search strategy should be based on carefully constructed review questions. A protocol
should be developed to identify, select and collate relevant publications to address these
questions. This should be developed and executed by persons with expertise in information
retrieval, having due regard to the scope of the clinical evaluation set out by the manufacturer.
The involvement of information retrieval experts will help to maximise data retrieval.
The literature search protocol should include:
• the sources of data that will be used and a justification for their choice;
• the extent of any searches of scientific literature databases (the database search strategy);
• the selection/criteria to be applied to published literature and justification for their
choice; and
• strategies for addressing the potential for duplication of data across multiple
publications;
Once the literature search has been executed, a report should be compiled to present the
results of the search. A copy of the protocol should be included and any deviations noted. A
possible format for the literature search report is located at Appendix A.
It is important that the literature search is documented to such a degree that the methods can
be appraised critically, the results can be verified, and the search reproduced if necessary. A
possible methodology is presented in Appendix B.
Which data/documentation from the literature search should be included in the clinical
evaluation?
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The following documentation should be used in the clinical evaluation by the clinical
evaluator:
• the literature search protocol;
• the literature search report; and
• published articles and other references identified as being relevant to the device in
question and suitable for evaluation.
The literature search protocol, the literature search report and copies of relevant references
become part of the clinical evidence and, in turn, the technical documentation for the medical
device. With respect to the clinical evaluation, it is important that the clinical evaluator be
able to assess the degree to which the selected papers reflect the intended application/use of
the device, etc.
Copies of the actual papers and references are necessary to allow the evaluator to review the
methodology employed (potential sources of bias in the data), the reporting of results and the
validity of conclusions drawn from the investigation or report. Abstracts may lack sufficient
detail to allow these issues to be assessed thoroughly and independently.
6.2 Data generated through clinical experience
These types of clinical data are generated through clinical use that is outside the conduct of
clinical investigations and may relate to either the device in question or equivalent devices.
Such types of data may include:
• manufacturer-generated post market surveillance reports, registries or cohort studies
(which may contain unpublished long term safety and performance data);
• adverse events databases (held by either the manufacturer or Regulatory Authorities);
• data for the device in question generated from individual patients under compassionate
usage programs prior to marketing of the device;
• details of clinically relevant field corrective actions (e.g. recalls, notifications, hazard
alerts)
The value of clinical experience data is that it provides real world experience obtained in
larger, heterogeneous and more complex populations, with a broader (and potentially less
experienced) range of end-users than is usually the case with clinical investigations
1
.
The data are most useful for identifying less common but serious device-related adverse
events; providing long term information about safety and performance, including durability
data and information about failure modes and elucidating the end-user “learning curve”. It is
also a particularly useful source of clinical data for low risk devices that are based on long
standing, well-characterised technology and, therefore, unlikely to be the subject of either
reporting in the scientific literature or clinical investigation.
1
In contrast, clinical investigations involve the use of specific inclusion criteria to create a homogenous
population to reduce sources of variation and, therefore, increase confidence that the outcomes observed in the
investigation are due to intervention with the device in question. Also, investigators participating in the
investigation are chosen on the basis of their expertise and competence and often undergo training over and
above that available to other end-users of the device.
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How may clinical experience data/documentation be used in the clinical evaluation?
If a manufacturer chooses to use clinical experience data it is important that any reports or
collations of data contain sufficient information to be able to undertake a rational and
objective assessment of the information and make a conclusion about its significance with
respect to the performance and safety of the device in question. Reports of clinical experience
that are not adequately supported by data, such as anecdotal reports or opinion, should not be
used.
Post market surveillance reports are compiled by the manufacturer and often include details of
the device’s regulatory status (countries in which the device is marketed and date of
commencement of supply), regulatory actions undertaken during the reporting period (e.g.
recalls, notifications), a tabulation of adverse events (particularly serious events and deaths,
stratified into whether the manufacturer considers them to be device-related or not) and
estimates of the incidence of adverse events. Post-marketing data about adverse events are
generally more meaningful when related to usage but caution is needed because the extent of
reporting may vary considerably between countries. The analyses of data within these reports
may, for some devices, provide reasonable assurance of both clinical safety and performance.
It may be helpful to provide a table summarising device-related adverse events, paying
particular attention to serious adverse events, with comments on whether observed device-
related adverse events are predictable on the basis of the mode of action of the device.
Manufacturers should comment specifically on any clinical data that identifies hazards not
previously considered in the risk management documentation, outlining any additional
mitigation required (e.g. design modification, amendment of product literature such as
inclusion of contraindications etc).
6.3 Data from clinical investigations
The guidance included within this section applies to clinical investigations carried out by or
on behalf of a manufacturer specifically for the purposes of conformity assessment in
accordance with applicable regulations. Such clinical investigations are generally expected to
be designed, conducted and reported in accordance with EN ISO 14155, Parts 1 and 2,
Clinical Investigations of Medical Devices for Human Subjects, or to a comparable standard,
and in compliance with local regulations.
It is recognised that where manufacturers source clinical investigation data reported in the
scientific literature (i.e. investigations of either the device in question or equivalent devices
that are undertaken by a third party), the documentation readily available to the manufacturer
for inclusion in the clinical evaluation is likely to be no more than the published paper itself.
What clinical investigation documentation/data should be used in the clinical evaluation?
Where a clinical investigation has been carried out by or on behalf of a manufacturer, it is
expected that documentation relating to the design, ethical and regulatory approvals, conduct,
results and conclusions of the investigation needed for the clinical evaluation will be available
for consideration, as appropriate. These may include:
• the clinical investigation plan;
• clinical investigation plan amendments and the rationale for these changes;
• the relevant Ethics Committee(s)’ documentation, opinion(s) and comments for each;
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• investigation site, including a copy of the approved informed consent form(s) and
patient information documents;
• case report forms, monitoring and audit records;
• Regulatory Authority approvals and associated correspondence as required by
applicable regulations; and
• the signed and dated final report.
The clinical investigation plan sets out how the study was intended to be conducted. It
contains important information about the study design such as the selection and assignment of
participants to treatment, masking (blinding of participants and investigators) and
measurement of responses to treatment, which may be important sources of bias that can be
assessed and discounted when trying to determine the actual performance of the device. In
addition the clinical investigation plan sets out the intended participant follow-up, approaches
to statistical analyses and methods for recording outcomes, which may impact on the quality,
completeness and significance of results obtained for performance and safety outcomes.
Also, by having the clinical investigation plan, its amendments and the final report available,
the evaluator will be able to assess the extent to which the investigation was conducted as
planned and, where deviations of from the original plan have occurred, the impact those
deviations had on the veracity of the data generated and the inferences that can be drawn
about the performance and safety of the device from the investigation.
The final report should be signed by its author and appropriate reviewers to provide assurance
that the final report is an accurate reflection of the conduct and results of the clinical
investigation.
Another important consideration of the evaluation will be to assess whether the conduct of the
investigation was in accordance with the current applicable ethical standards that have their
origin in the Declaration of Helsinki and in accordance with applicable regulations. Clinical
investigations not in compliance with applicable ethical standards or regulations should be
rejected. The reasons for rejection of the investigation should be noted in the report.
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7. Appraisal of clinical data (Stage 2)
The purpose of undertaking appraisal of the data is to understand the merits and limitations of
the clinical data. Each piece of data is appraised to determine its suitability to address
questions about the device, and its contribution to demonstrating the safety and performance
of the device (including any specific claims about safety or performance).
What should be covered by the appraisal?
The data needs to be suitable for appraisal. It should be assessed for its quality and for its
relevance to the device in question (i.e. the data must be either generated for the device in
question or for an equivalent device) and its intended use. In addition, any reports or
collations of data should contain sufficient information for the evaluator to be able to
undertake a rational and objective assessment of the information and make a conclusion about
its significance with respect to the performance and/or safety of the device in question.
Further appraisal needs to be undertaken to determine the contribution of each data subset to
establishing the safety and performance of the device. The evaluator should examine the
methods used to generate/collect the data and assess the extent to which the observed effect
(performance or safety outcome(s)) can be considered to be due to intervention with the
device or due to confounding influences (e.g. natural course of the underlying medical
condition, concomitant treatment(s)) or bias.
2
There is no single, well established method for appraising clinical data. Therefore, the
evaluator should identify, in advance, the appropriate criteria to be applied for a specific
circumstance
These criteria should be applied consistently. Some examples to assist with the formulation of
criteria are given in Appendix C.
For many lower risk devices and devices based on long standing technology, the available
data may be qualitative rather than quantitative in nature, so the evaluation criteria should be
adjusted accordingly. The criteria adopted for the appraisal should be justified by the
evaluator.
Although there will be some overlap of safety and performance data, the data should be
categorised to allow for separate analysis. Additional categories may also be needed,
depending on the nature and intended use of the device to address additional claims. The data
should also be weighted according to its relative contribution. An example of a method of
data appraisal is shown in Appendix D.
2
Bias is a systematic deviation of an outcome measure from its true value, leading to either an overestimation or
underestimation of a treatment’s effect. It can originate from, for example, the way patients are allocated to
treatment, the way treatment outcomes are measured and interpreted, and the recording and reporting of data.
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8. Analysis of the clinical data (Stage 3)
The goal of the analysis stage is to determine if the appraised data sets available for a medical
device collectively demonstrate the clinical performance and safety of the device in relation to
its intended use.
The methods available for analysis of clinical data generally are either quantitative or
qualitative. Given the context within which most medical devices are developed (i.e. limited
need for clinical investigations because of incremental changes in device design and therefore
high use of literature and experience data), often qualitative (i.e. descriptive) methods will
need to be used primarily to address such incremental changes, if justified.
Any evaluation criteria developed and assigned during the appraisal stage can be used to
identify those sets of data which may be considered to be “pivotal” to the demonstration of
the performance and safety of the device, respectively. It may be useful to explore the results
of the pivotal datasets, looking for consistency of results across particular device performance
characteristics and identified risks. If the different datasets report similar outcomes, certainty
about the performance increases. If different results are observed across the datasets, it will be
helpful to determine the reason for such differences. Regardless, all data sets should be
included.
As a final step the evaluator should consider the basis on which it can be demonstrated that
the combined data show:
• the device performs as intended by the manufacturer;
• the device does not pose any undue safety concerns to either the recipient or end-user;
and
• any risks associated with the use of the device are acceptable when weighed against
the benefits to the patient.
Such considerations should take into account the number of patients exposed to the device,
the type and adequacy of patient monitoring, the number and severity of adverse events, the
adequacy of the estimation of associated risk for each identified hazard, the severity and
natural history of the condition being diagnosed or treated. The availability of alternative
diagnostic modalities or treatments and current standard of care should also be taken into
consideration.
The product literature and instructions for use should be reviewed to ensure they are
consistent with the data and that all the hazards and other clinically relevant information have
been identified appropriately.
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9. The Clinical Evaluation Report
At the completion of the clinical evaluation process a report should be compiled that outlines
the scope and context of the evaluation; the inputs (clinical data); the appraisal and analysis
stages; and conclusions about the safety and performance of the device in question.
The clinical evaluation report should contain sufficient information to be read as a stand alone
document by an independent party (e.g. Regulatory Authority or Notified Body). It is
important that the report outline:
• the technology on which the medical device is based, the intended use of the device
and any claims made about the device’s clinical performance or safety;
• the nature and extent of the clinical data that has been evaluated; and
• how the referenced information (recognised standards and/or clinical data)
demonstrate the clinical performance and safety of the device in question.
The clinical evaluation report should be signed and dated by the evaluator(s) and
accompanied by the manufacturer’s justification of the choice of evaluator.
A suggested format for the clinical evaluation report is located at Appendix E. Again, it
should be noted that the level of detail in the report content can vary according to the scope of
the clinical evaluation. For example, where a manufacturer relies on clinical data for an
equivalent device which has been the subject of an earlier clinical evaluation (for which the
manufacturer holds the evaluation report), it may be possible to cross-reference the data
summary and analysis sections to the earlier clinical evaluation report, which also becomes
part of the clinical evidence for the device in question.
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10. The role of the Notified Body in the assessment of clinical evaluation
data
The Notified Body plays a key role in the assessment and verification of clinical evaluations
provided by medical device manufacturers to support demonstration of conformity of a device
with the essential requirements of the relevant Directive.
This section of the document is intended to act as guidance to a Notified Body on the
assessment of clinical evaluations provided by medical device manufacturers as part of
technical documentation/design dossiers and as a part of their procedures for medical devices.
It might also be useful as best practice guidance for national Competent Authorities in their
market surveillance activities.
Pursuant to section 6a of Annex I to Directive 93/42/EEC and to section 5a of Annex 1 to
Directive 90/385/EEC), the demonstration of conformity with Essential Requirements must
include a clinical evaluation conducted in accordance with Annex X to Directive 93/42/EEC
or with Annex 7 to Directive 90/385/EEC. This is applicable for all classes of medical devices.
Demonstration of conformity without clinical data in accordance with section 1.5 of Annex 7
to Directive 90/385/EEC and section 1.1d of Annex X to Directive 93/42/EEC must be
adequately justified and based on the output of the risk management process. The device-body
interaction, the intended use and the claims of the manufacturer have to be specifically
considered. Adequacy of demonstration of conformity based on performance evaluation,
bench testing and pre-clinical evaluation in the absence of clinical evaluation must be duly
substantiated. The Notified Body must review the manufacturer’s justification, the adequacy
of data presented and whether or not conformity is demonstrated.
Notified Body Assessment of Clinical Evaluation by Conformity Assessment Route
With regard to the review of clinical evaluations the Notified Body has different roles
depending on the classification of the device and the conformity assessment procedure
followed.
This includes for medical devices in accordance with Directive 93/42/EEC:
• An audit as part of a quality system approval procedure (Annex II, section 3):
- The notified body assesses the manufacturer’s procedure for clinical evaluation.
- As part of the representative sampling of devices for review of their technical
documentation the notified body verifies the clinical evaluation data presented for
class IIa and IIb devices in accordance with the criteria outlined in this section.
• A design dossier (Annex II, section 4) or type examination dossier (Annex III) assessment:
- the notified body assesses the data presented in the clinical evaluation, verifies the
manufacturer’s assessment of that data and assesses the validity of the conclusions
drawn by the manufacturer.
For active implantable medical devices in accordance with Directive 90/385/EEC:
• A design dossier (Annex 2, section 4) or type examination dossier (Annex 3) assessment:
- the notified body assesses the data presented in the clinical evaluation, verifies the
manufacturer’s assessment of that data and assesses the validity of the clinical
evaluation report and the conclusions drawn by the manufacturer.
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The Notified Body should also have documented procedures to cover review of updates to
clinical evaluation data during their scheduled surveillance activities and at the time of
changes to or extensions of EC design-examination/EC type-examination certificates. This
arises from the obligation placed on the manufacturer to actively update the clinical
evaluation with data obtained from post-market surveillance e.g. post-market clinical follow-
up and ongoing literature reviews/surveys.
10.1. EXAMINATION OF A DESIGN DOSSIER (ANNEX II.4; ANNEX 2.4) OR OF A TYPE
EXAMINATION DOSSIER (ANNEX III; ANNEX 3)
The Notified Body examines the clinical evaluation documentation submitted (relevant
documentation referenced in sections 5 to 9 of this MEDDEV), verifies the manufacturer’s
identification, appraisal, analysis and assessment of that data and validates the conclusions
drawn by the manufacturer. In order to do so, the Notified Body should possess enough
knowledge and experience in clinical evaluation as stated in section 10.3 of this document.
In Appendix F of this document a checklist is provided for use by a Notified Body during the
assessment of clinical evaluation data. This checklist should be used as a supplementary tool
but should not replace the Notified Body Report outlined below.
10.1.1 Decision-making by the Notified Body
In reviewing the evaluation of clinical data submitted by the manufacturer, the Notified Body
verifies and decides whether or not the manufacturer has adequately:
- supplied clinical evaluation documentation (as referenced in sections 5 to 9);
- followed relevant procedures (as addressed by sections 5 to 9);
- described and verified the intended characteristics and performances related to clinical
aspects;
- performed an appropriate risk analysis and estimated the undesirable side effects;
- involved appropriate clinical expertise in the compilation of the risk analysis to ensure
risks and benefits associated with real clinical use are adequately defined;
- justified the chosen route(s) of clinical data retrieval (according to sections 5 and 6);
- identified, appraised, analysed and assessed the clinical data (according to sections 5
to 9) and demonstrated the relevance and any limitations of the clinical data identified
in demonstrating compliance with particular requirements of the Directive or cited in
particular aspects of the risk analysis;
- provided sufficient clinical data relating to the safety, performance, design
characteristics and intended purpose of the device in order to demonstrate conformity
with each of the relevant essential requirements;
- if a critical evaluation of relevant scientific literature is provided, the notified body
verifies that this data relates to the safety, performance, design characteristics and
intended purpose of the device;
- if a critical evaluation of relevant scientific literature is provided the notified body
verifies that the device under assessment is demonstrated as equivalent to the device to
which the data relates in all necessary areas (i.e. clinical, design, biological etc.);
- if a critical evaluation of relevant scientific literature is provided the notified body
verifies that the data presented for equivalent devices adequately addresses each of the
relevant essential requirements;
- provided specific justification if a specific clinical investigation was not performed for
class III or implantable devices.
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Note: A clinical evaluation is required for all classes of medical devices, the relevance
of the data or the need for clinical investigation data should always be assessed and
documented by the notified body;
- provided evidence that clinical investigations presented are in compliance with
applicable regulatory and ethical requirements e.g. ethics committee approval,
competent authority approval;
- justified the appropriateness of the planned post-market clinical follow up;
- justified and documented if post-market clinical follow-up is not planned as part of the
post-market surveillance plan for the device;
- concluded on the basis of documented justification that the risks are acceptable when
weighed against the intended benefits and the relevant Essential Requirements are met.
The assessment carried out by the Notified Body will typically cover the following aspects of
the manufacturer’s clinical evaluation:
- appraisal to determine suitability and any limitations of the data presented to address
the essential requirements in particular relating to the safety and performance of the
device as outlined in section 7;
- complete and adequate documentation (according to sections 5 to 9);
- adequate procedures (according to sections 5 to 9)
- the validity of any justification given;
- the listing, characterisation and proof of the clinical performance of the device
intended by the manufacturer and the expected benefits for the defined patient
group(s);
- the use of harmonised standards
- the use of the list of identified hazards to be addressed through evaluation of clinical
data as described in section 8;
- the adequate estimation of the associated risks for each identified hazard by:
a) characterising the severity of the hazard;
b) estimating and characterising the probability of occurrence of harm, health
impairment or loss of benefit of the treatment (document with rationale).
The decision on the acceptability of risks
3
in relation to each identified hazard, and
characterisation of the corresponding risk/benefit ratio as:
- unacceptable; or
- broadly acceptable; or
- acceptable under specified conditions.
For drug-device combination products where a scientific opinion from a medicinal competent
authority or from the EMEA has been sought, the notified body should consider any
comments or considerations raised in the medicinal clinical assessment when making its final
decision on the device. In the case of devices with a human blood derivative the notified body
may not deliver a positive decision to issue a certificate if the EMEA's scientific opinion is
unfavourable.
10.1.2 The report of the Notified Body
3
Valid decision making criteria from applicable guidance and standards may be employed e.g. ISO 14971.
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The Notified Body writes a report on its assessment of the submitted clinical evaluation
documentation.
If a design dossier report is applicable the clinical report should be incorporated into this
report. The report should clearly identify the Notified Body’s assessment, verification on each
of the critical elements and overall conclusions.
NBOG BPG 2009-1 defines the minimum content for a design dossier review report in the
following sections:
- Manufacturer details
- Details relating to the application and NB review (including staff and experts involved
in the review and the aspects assessed by each, signatures of responsible reviewers etc.)
- Device description and product specification
- Classification
- Requirements regarding manufacturing
- Requirements regarding design and construction
- Pre-clinical evaluation
- Clinical evaluation/performance evaluation
- Other applicable Directives
- Risk analysis and risk management
- Review of declaration of conformity
- Post-market surveillance
- Summary of review
The Notified Body should justify and document each step of the decision making process
referred in 10.1.1.above. One single “unacceptable risk/benefit ratio” leads to a negative
conclusion
4
;
The clinical evaluation assessment report should:
- Record whether the clinical evaluation documentation was complete and adequate
- Record the Notified Bodies verification of each step of the clinical evaluation process,
from scoping, choice of route(s), identification, appraisal, analysis and overall
assessment of the clinical data, to concluding and reporting
- Record the completeness of the clinical evaluation conducted and its accordance with
this document
- Record the Notified Body’s assessment of the clinical investigation data and/or
literature review assembled, relevant procedures and compliance to relevant standards
- Verify that the device has met the claimed performance/intended use and side-effects
and risks have been properly evaluated
- Record the Notified Body’s assessment of the clinical safety, performance and
benefit/risk ratio
- Record the Notified Body’s assessment of the conclusions drawn by the manufacturer
from the clinical data presented
- Record the Notified Body’s assessment of the validity of the clinical evaluation and its
steps
- Record the Notified Body’s conclusions on the clinical evaluation, documenting each
step in the decision making process as per section 10.1.1.
4
In some cases, the combination of the conditions specified in order to characterise different individual
risk/benefit ratios as acceptable may be contradictory or impracticable, and so also leads to an overall negative
conclusion. Positive benefit/risk ratios for specific aspects do not compel an overall positive benefit/risk ratio for
the device.
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10.2. EVALUATION AS PART OF QUALITY SYSTEM RELATED PROCEDURES (Annex II.3 of
Directive 1993/42/EEC)
10.2.1. Review of the manufacturer’s procedures
The Notified Body shall, as part of the review of the manufacturer’s quality system, assess the
establishment, maintenance and application of the manufacturer’s documented procedures for
the evaluation of clinical data. This should cover:
(a) the proper assignment of responsibilities to suitably qualified persons involved in the
clinical evaluation [e.g. clinical evaluator(s), information retrieval expert(s), clinical
investigator(s)];
(b) the integration of clinical evaluation into the quality system as a continuous process, to
be specifically inter-related to, and informed by, preclinical evaluation and risk
management;
(c) standard operating procedures to assure proper planning, conduct, evaluation, control
and documentation of scoping, identification of clinical data (section 5), literature
searching (section 6.1), collection of clinical experience (section 6.2), clinical
investigation (section 6.3 and EN ISO 14155), appraisal of clinical data (section 7),
analysis of clinical data (section 8), concluding, reporting (section 9) and update of
clinical evaluation, including PMCF (MEDDEV 2.12/2);
(d) Document control as part of overall documentation of procedures, reporting,
qualifications and technical documentation/design dossier(s);
(e) identification and evaluation of undesirable side effects and of clinical performance(s).
This involves identification of known or reasonably foreseeable hazards and
verification of unfavourable and favourable outcome(s), qualification of their
severity/magnitude and of their probability of occurrence. (It is part of the
manufacturer’s documented risk analysis based on both favourable and unfavourable
data identified as relevant in order to give a balanced view).
10.2.2. Review of the technical documentation of representative samples
The Notified Body is required to assess the technical documentation for class IIa and class IIb
devices on a representative basis. Clinical evaluation data should be assessed by the Notified
Body for at least one representative sample for each device subcategory for class IIa devices
and at least one representative sample for each generic device group for class IIb devices.
Further representative samples have to be assessed as part of the annual surveillance
assessment cycle.
Regarding the choice of representative sample(s) the notified body will consider the novelty
of the technology, similarities in design, technology, manufacturing and sterilisation methods,
the intended use and the results of previous relevant assessments. Assessment of
representative samples includes assessment of clinical evaluation data according to the criteria
outlined in this document rather than solely confirming that the manufacturer has a clinical
evaluation procedure in place.
The criteria for the technical documentation assessment on a representative basis outlined in
NBOG BPG 2009-4 should be applied.
page 23 of 46
When performing the assessment on samples of a manufacturer’s clinical evaluation, the
Notified Body will follow the steps indicated in section 10.1 of this document.
The Notified Body, when reviewing samples of the manufacturer’s clinical data evaluation,
should pay special attention to the following:
(a) whether or not the data is relevant to the device, its intended use(s) or medical
procedure(s) involved and adequately cover the related clinical performance, safety
and benefit/risk relation
(b) where the manufacturer, in the selected sample, has chosen the “literature route”,
whether the criteria defined in section 6.1 have been applied;
(c) where the manufacturer, in the selected sample, has selected the “clinical
investigations route”, whether the criteria defined in section 6.3 have been applied.
10.3. NOTIFIED BODY SPECIFIC PROCEDURES AND EXPERTISE
A Notified Body should have formal procedures in place controlled by their quality system
relating to the assessment of clinical evaluations provided by medical device manufacturers.
These procedures should also cover the review of updates to clinical evaluation data during
their scheduled surveillance activities and at the time of changes to or extensions of EC
design-examination/EC type-examination certificates.
Notified Bodies should establish and implement internal policies and procedures for the
assessment of clinical evaluations in order to:
(a) ensure that suitable resources, especially relevant regulatory knowledge and clinical
competence necessary for such evaluation, are available within
5
the Notified Body and
by contracting external clinical experts if required.
Such expertise should be sufficient to identify and estimate the risks and benefits
associated with the use of the medical devices. The evaluation team should be able to
evaluate a risk analysis and the risk management strategy performed by the
manufacturer.
The evaluation team should understand the device technology as well as the medical
procedure.
Such an evaluation may require input from a qualified medical practitioner (for
example physician, dentist, nurse etc.), as appropriate for the particular device, who
has clinical experience in the pathology of the condition being treated, the usual
treatment, the therapeutic alternatives etc.
When examining the results of clinical investigations, the evaluation team shall have
knowledge in planning, conduct and interpretation of clinical investigations. All
evaluators should be appropriately trained and qualified.
Particular attention should be drawn to training of external experts on the conformity
assessment procedure(s), relevant guidance, standards and the context of the
5
Annex XI.3 of Directive 93/42/EEC. This presupposes the availability of sufficient scientific staff within the organisation
who possess experience and knowledge sufficient to assess the medical functionality and performance of devices for which it has
been notified, having regard to the requirements of this Directive and, in particular, those set out in Annex I.
page 24 of 46
assessment they are providing. The Notified Body should be responsible for reviewing
the opinion of these experts, taking account of their level of knowledge of the
provisions of the Directives.
The opinion of an external clinical expert may form part of the assessment conducted
by the notified body. The opinion and conclusions of the notified body, in part based
on this external opinion, should be clearly documented.
The impartiality and the potential for conflict of interest of an external expert reviewer
should be assessed and documented by the notified body.
(b) review the evaluation of clinical data provided by the manufacturer;
(c) document the opinion with rationale of all experts involved;
(d) ensure that any external experts involved are impartial and independent from any
parties involved, having due regard to any conflict of interest which may compromise
impartiality (see also MEDDEV 2.10/1);
(e) document the result of their assessment. This is achieved through a specific report
which may be part of, or may be referenced, in the overall audit report, design / type
examination report (as per 10.1.2 of this document) or the report on the assessment of
representative samples’ documentation;
(f) preserve confidentiality of the information and data received from the manufacturer,
especially within the terms for contracting external experts.
page 25 of 46
APPENDICES
A: A possible format for the literature search report 28
B: A possible methodology for documenting the screening and selection of
literature within a literature search report 29
C: Some examples to assist with the formulation of criteria 30
D: A possible method of appraisal 32
E: A possible format for a clinical evaluation report 34
F: Clinical evaluation checklist for Notified Bodies 37
page 26 of 46
APPENDIX A
A POSSIBLE FORMAT FOR THE LITERATURE SEARCH REPORT
1. Device name/model
2. Scope of the literature search [should be consistent with scope of clinical evaluation]
3. Methods
(i) Date of search
(ii) Name of person(s) undertaking the literature search
(iii) Period covered by search
(iv) Literature sources used to identify data:
- scientific databases – bibliographic (e.g. MEDLINE, EMBASE),
specialised databases (e.g. MEDION)
- systematic review databases (e.g. Cochrane Collaboration)
- clinical trial registers (e.g. CENTRAL),
- adverse event report databases (e.g. MAUDE)
- reference texts
Include justification for choice of sources and describe any supplemental
strategies (e.g. checking bibliography of articles retrieved, hand searching of
literature) used to enhance the sensitivity of the search.
(v) Database search details:
- search terms (key words, indexing headings) and their relationships
(Boolean logic)
- medium used (e.g. online, CD-ROM (including publication date and edition))
Attach copy of downloaded, unedited search strategy.
(vi) Selection criteria used to choose articles
4. Outputs
(i) Attach copy of literature citations retrieved from each database search
(ii) Data selection process
Attach flow chart and associated tables showing how all citations were assessed
for suitability for inclusion in the clinical evaluation (see Appendix B).
Notes:
EMBASE Excerpta Medica published by Elsevier
CENTRAL The Cochrane Central Register of Controlled Trials
MAUDE US FDA’s Manufacturer And User Facility Device Experience database
MEDION Database that indexes literature on diagnostic tests
MEDLINE Published by US National Library of Medicine
page 27 of 46
APPENDIX B:
A POSSIBLE METHODOLOGY FOR DOCUMENTING THE SCREENING AND SELECTION OF
LITERATURE WITHIN A LITERATURE SEARCH REPORT
6
6
Adapted from Moher D, Cook DJ, Eastwood S, Olkin I, Rennie, D & Stroup DF . Improving the quality of
reports and meta-analyses of randomised controlled trials: the QUORUM statement. Quality of Reporting of
Meta-analyses. Lancet 1999; 354:1896-1900
Literature retrieved for more detailed
assessment
Literature with relevant useable data
included in the clinical evaluation, by
outcome:
• Device performance*
• Device safety*
• Device comparability
(if applicable)
Potentially relevant literature identified
through the search
(copy of all citations)
Literature excluded from clinical
evaluation, with reasons
Literature excluded, with reasons
*some literature will address issue of both performance and safety
page 28 of 46
APPENDIX C:
SOME EXAMPLES TO ASSIST WITH THE FORMULATION OF CRITERIA
7
_________________________________________________________________________________________________________________________________________________________________________________________________________________________-_________
The following are examples of questions to ask to assist with the formulation of criteria for
data appraisal for different type of data sets. These examples are not meant to be
comprehensive with regards to study types or all potential questions.
Randomised controlled trial
Clinical investigation where subjects are randomised to receive either a test or reference
device or intervention and outcomes and event rates are compared for the treatment groups.
• Were the inclusion and exclusion criteria specified?
• Was the assignment to the treatment groups really random?
• Was the treatment allocation concealed from those responsible for recruiting subjects?
• Was there sufficient description about the distribution of prognostic factors for the
treatment groups?
• Were the groups comparable at baseline for these factors?
• Were outcome assessors blinded to the treatment allocation?
• Were the care providers blinded?
• Were the subjects blinded?
• Were all randomised participants included in the analysis?
• Was a point estimate and measure of variability reported for the primary outcome?
Cohort study
Data are obtained from groups who have and have not been exposed to the device (e.g.
historical control) and outcomes compared.
• Were subjects selected prospectively or retrospectively?
• Was an explicit description of the intervention provided?
• Was there sufficient description about how the subjects were selected for the new
intervention and comparison groups?
• Was there sufficient description about the distribution of prognostic factors for the
new intervention and comparison groups?
• Were the groups comparable for these factors?
• Did the study adequately control for potential confounding factors in the design or
analysis?
• Was the measurement of outcomes unbiased (i.e. blinded to treatment group and
comparable across groups)?
• Was follow-up long enough for outcomes to occur?
• What proportion of the cohort was followed up and were there exclusions from the
analysis?
• Were drop-out rates and reasons for drop-out similar across intervention and
unexposed groups?
7
Adapted from: Guidelines for the assessment of diagnostic technologies. Medical Services Advisory
Committee; Commonwealth of Australia 2005.
page 29 of 46
Case–control study
Patients with a defined outcome and controls without the outcome are selected and
information is obtained about whether the subjects were exposed to the device.
• Was there sufficient description about how subjects were defined and selected for the
case and control groups?
• Was the disease state of the cases reliably assessed and validated?
• Were the controls randomly selected from the source of population of the cases?
• Was there sufficient description about the distribution of prognostic factors for the
case and control groups?
• Were the groups comparable for these factors?
• Did the study adequately control for potential confounding factors in the design or
analysis?
• Was the new intervention and other exposures assessed in the same way for cases and
controls and kept blinded to case/control status?
• How was the response rate defined?
• Were the non-response rates and reasons for non-response the same in both groups?
• Was an appropriate statistical analysis used?
• If matching was used, is it possible that cases and controls were matched on factors
related to the intervention that would compromise the analysis due to over-matching?
Case series
The device has been used in a series of patients and the results reported, with no control group
for comparison.
• Was the series based on a representative sample selected from a relevant population?
• Were the criteria for inclusion and exclusion explicit?
• Did all subjects enter the survey at a similar point in their disease progression?
• Was follow-up long enough for important events to occur?
• Were the techniques used adequately described?
• Were outcomes assessed using objective criteria or was blinding used?
• If comparisons of sub-series were made, was there sufficient description of the series
and the distribution of prognostic factors?
page 30 of 46
APPENDIX D:
A POSSIBLE METHOD OF APPRAISAL
_________________________________________________________________________________________________________________________________________________________________________________________________________________________-_________ ___
There are many methods that can be used to appraise and weight clinical data. An example of
possible appraisal criteria is given in Tables D1 and D2. The criteria may be worked through
in sequence and a weighting assigned for each dataset. The data suitability criteria can be
considered generic to all medical devices (Table D1), however the actual method used will
vary according to the device considered.
To assess the data contribution criteria of the suitable data, the evaluator should sort the data
sets according to source type and then systematically consider those aspects that are most
likely to impact on the interpretation of the results (Table D2). There is scope for the
evaluator to determine what types of issues are most important in relation to the nature,
history and intended clinical application of the device. The criteria used in the example below
are based around the sorts of issues that could be considered for devices of higher risk, such
as characteristics of the sample, methods of assessing the outcomes, the completeness and
duration of follow-up, as well as the statistical and clinical significance of any results.
In this example, the weightings would be used to assess the strength of the datasets’
contribution to demonstrating overall performance and safety of the device (Stage 3, see
section 8). As a general guide in using this example, the more level 1 grades, the greater the
weight of evidence provided by that particular dataset in comparison to other datasets,
however, it is not intended that the relative weightings from each category be added into a
total score.
Table D1 Sample Appraisal Criteria for Suitability
Sutability Criteria Description Grading System
Appropriate device Were the data generated from the
device in question?
D1
D2
D3
Actual device
Equivalent device
Other device
Appropriate device
application
Was the device used for the same
intended use (e.g., methods of
deployment, application, etc.)?
A1
A2
A3
Same use
Minor deviation
Major deviation
Appropriate patient
group
Where the data generated from a
patient group that is representative of
the intended treatment population
e.g., age, sex, etc.) and clinical
condition (i.e., disease, including
state and severity)?
P1
P2
P3
Applicable
Limited
Different population
Acceptable report/data
collation
Do the reports or collations of data
contain sufficient information to be
able to undertake a rational and
objective assessment?
R1
R2
R3
High quality
Minor deficiencies
Insufficient information
page 31 of 46
Table D2 Sample Appraisal Criteria for Data Contribution
Data Contribution Criteria Description Grading System
Data source type Was the design of the study
appropriate?
T1
T2
Yes
No
Outcome measures Do the outcome measures
reported reflect the intended
performance of the device?
O1
O2
Yes
No
Follow up Is the duration of follow-up long
enough to assess whether
duration of treatment effects and
identify complications?
F1
F2
Yes
No
Statistical significance Has a statistical analysis of the
data been provided and is it
appropriate?
S1
S2
Yes
No
Clinical significance Was the magnitude of the
treatment effect observed
clinically significant?
C1
C2
Yes
No
page 32 of 46
APPENDIX E:
A POSSIBLE FORMAT FOR A CLINICAL EVALUATION REPORT
___________________________________________________________________________
1. General details
State the proprietary name of the device and any code names assigned during device
development.
Identify the manufacturer(s) of the device.
2. Description of the device and its intended application
Provide a concise physical description of the device, cross referencing to relevant sections of
the manufacturer’s technical information as appropriate. The description should cover
information such as:
• materials, including whether it incorporates a medicinal substance (already on the market
or new), tissues, or blood products;
• the device components, including software and accessories;
• mechanical characteristics; and
• others, such as sterile vs. non-sterile, radioactivity etc.
State the intended application of the device – single use/reusable; invasive/non invasive;
implantable; duration of use or contact with the body; organs, tissues or body fluids contacted
by the device.
Describe how the device achieves its intended purpose.
3. Intended therapeutic and/or diagnostic indications and claims
State the medical conditions to be treated, including target treatment group and diseases.
Outline any specific safety or performance claims made for the device
4. Context of the evaluation and choice of clinical data types
Outline the developmental context for the device. The information should include whether the
device is based on a new technology, a new clinical application of an existing technology, or
the result of incremental change of an existing technology. The amount of information will
differ according to the history of the technology. Where a completely new technology has
been developed, this section would need to give an overview of the developmental process
and the points in the development cycle at which clinical data have been generated. For long
standing technology, a shorter description of the history of the technology (with appropriate
references) could be used. Clearly state if the clinical data used in the evaluation are for an
equivalent device. Identify the equivalent device(s) and provide a justification of the
equivalency, cross-referenced to the relevant non-clinical documentation that supports the
claim.
State the Essential Requirements relevant to the device in question, in particular, any special
design features that pose special performance or safety concerns (e.g. presence of medicinal,
page 33 of 46
human or animal components) that were identified in the device risk management
documentation and that required assessment from a clinical perspective.
Outline how these considerations were used to choose the types of clinical data used for the
evaluation. Where published scientific literature has been used, provide a brief outline of the
searching/retrieval process, cross-referenced to the literature search protocol and reports.
5. Summary of the clinical data and appraisal
Provide a tabulation of the clinical data used in the evaluation, categorised according to
whether the data address the performance or the safety of the device in question. (Note: many
individual data sets will address both safety and performance.) Within each category, order
the data according to the importance of their contribution to establishing the safety and
performance of the device and in relation to any specific claims about performance or safety.
Additionally, provide a brief outline of the data appraisal methods used in the evaluation,
including any weighting criteria, and a summary of the key results.
Include full citations for literature-based data and the titles and investigation codes (if relevant)
of any clinical investigation reports.
Cross-reference the entry for each piece of data to its location in the manufacturer’s technical
documentation.
6. Data analysis
6.1 Performance
Provide a description of the analysis used to assess performance.
Identify the datasets that are considered to be the most important in contributing to the
demonstration of the overall performance of the device and, where useful, particular
performance characteristics. Outline why they are considered to be “pivotal” and how they
demonstrate the performance of the device collectively (e.g. consistency of results, statistical
significance, clinically significance of effects).
6.2 Safety
Describe the total experience with the device, including numbers and characteristics of
patients exposed to the device; and duration of follow-up of device recipients.
Provide a summary of device-related adverse events, paying particular attention to serious
adverse events.
Provide specific comment on whether the safety characteristics and intended purpose of the
device requires training of the end-user.
6.3 Product Literature and Instructions for Use
State whether the manufacturer’s proposed product literature and Instructions for Use are
consistent with the clinical data and cover all the hazards and other clinically relevant
information that may impact on the use of the device.
page 34 of 46
7. Conclusions
Outline clearly the conclusions reached about the safety and performance of the device from
the evaluation, with respect to the intended use of the device. State whether the risks
identified in the risk management documentation have been addressed by the clinical data.
For each proposed clinical indication state whether:
• the clinical evidence demonstrates conformity with relevant Essential Requirements;
• the performance and safety of the device as claimed have been established; and
• the risks associated with the use of the device are acceptable when weighed against the
benefits to the patient
page 35 of 46
APPENDIX F
Clinical evaluation checklist for Notified Bodies
Ref Requirement Fulfilled Comment
0 Conformity without Clinical Data
0.1 Any demonstration of conformity without clinical data
(Annex 7.1.5 of 90/385/EEC and Annex X.1.1d of
93/42/EEC) must be adequately justified and based on
• the output of the risk management process
• viewed in the context of the device-body interaction
• the intended clinical performance
• the claims of the manufacturer.
Adequacy of demonstration of conformity based on
performance evaluation, bench testing and pre-clinical
evaluation in the absence of clinical evaluation must be
duly substantiated.
The notified body must review the manufacturer’s
justification, the adequacy of data presented and whether
or not conformity is demonstrated.
• Is the manufacturer’s justification adequate?
• Is the performance evaluation, bench testing and pre-
clinical evaluation adequate to demonstrate
conformity to the Essential Requirements?
Yes
No
N/A.
1 Clinical Evaluation, General
Clinical literature
Published
Unpublished
Equivalence demonstrated
Clinical investigation
1.1 The manufacturer should include in the technical
documentation a statement on the route(s) applied to
retrieve the clinical data used to affix the “CE”
marking.
The statement should make clear whether that
clinical data was obtained from the published
literature or the results of clinical investigations or a
Yes
No
N/A.
Combination of literature and investigation data
page 36 of 46
Comment combination of both and shall include an adequate
justification of the route(s) selected and a
demonstration of equivalency (technical, biological,
clinical) and adequacy if clinical data from similar
devices have been used
1.2 The Clinical Evaluation Report and the full clinical
data used for CE marking should be included within
the technical documentation
Yes
No
N/A.
1.3 The manufacturer has clearly documented the
objectives and the scope of the clinical evaluation
and specified the clinical ER’s [e.g. clinical
performance(s), safety, risks and favourable
benefit/risk ratio related to intended use, target
group(s) and indication(s)] to be met
Yes
No
N/A.
1.4 The manufacturer has clearly outlined the performed
steps and procedures of clinical evaluation according
to this MEDDEV (specifically sections 5 to 9),
adequate justification given for deviations
Yes
No
N/A.
2 Clinical investigation route
2.1 Need for clinical investigation
2.1.1 Classification of device
Is the device an implantable or class III medical
device or an active implantable medical device?
Yes
No
N/A.
2.1.2 If a clinical investigation is not presented for an
implantable or class III MD or an AIMD, has this
been adequately justified by the manufacturer in his
risk analysis and clinical evaluation?
Yes
No
N/A.
2.1.3 If clinical literature is presented for equivalent
devices, is this clinical data when taken together with
the available pre clinical data sufficient to
demonstrate conformity with the essential
requirements covering safety and performance of the
device in question under normal conditions of use?
Yes
No
N/A.
page 37 of 46
2.1.4 If clinical literature is presented for equivalent
devices, are there gaps in either the demonstration of
compliance with each relevant essential requirement
or in the demonstration of equivalence that needs
addressing through the means of a specifically
designed clinical investigation(s)?
Yes
No
N/A.
2.1.5 If clinical literature is presented for equivalent
devices, is the data sufficient to address the clinical
hazards identified in the risk analysis?
If no, a clinical investigation(s) will be needed.
The objectives of the clinical investigation(s) should
focus on those aspects not sufficiently addressed by
the available data.
Yes
No
N/A.
2.2 Conduct of clinical investigation
2.2.1 Were the relevant annexes of the medical devices
Directives (Annex 7 AIMD, Annex X MDD) and the
relevant standards (EN ISO 14155-1, -2) taken into
account?
Yes
No
N/A.
2.2.2 Requirements for clinical investigations
2.2.3 Identification of relevant documentation, the
following documentation should be requested and
reviewed by the notified body:
2.2.4 Copy of the Protocol submitted to the Competent
Authority or other regulatory agency for which no
grounds for objection were raised
Yes
No
N/A.
2.2.5 Copy of the letter of “no objection”/approval from
Competent Authority/Authorities (if available) or
other approval from the relevant regulatory
agency(ies), together with any comments made
arising from regulatory review
Yes
No
N/A.
2.2.6 Copy of the Ethics Committee opinion(s) and
comments arising from their review or a summary of
all Ethics Committee opinions and any
comments/conditions arising from their reviews
Yes
No
N/A.
page 38 of 46
2.2.7 Copy of the signed and dated final report Yes
No
N/A.
2.3 Information to be checked – the following
information should be checked by the notified
body
2.3.1 Letter of “no objection” from the Competent
Authority(ies)
Yes
No
N/A.
2.3.2 Clinical Investigation Plan (CIP): Is the CIP, used for the
clinical investigation, the same as that submitted to the
Competent Authority?
8
Yes
No
N/A.
2.3.3 If parameters are not as set out in the original CIP, the
rationale for non-adherence
Yes
No
N/A.
2.3.4 Identification of any changes to CIP and rationale for any
such changes
Yes
No
N/A.
2.3.5 Where the clinical investigation(s) was performed outside
the EU, the manufacturer must demonstrate that the use of
the device (including clinical practice and techniques) and
patient population are equivalent to those for which the
device will be used within the EU (if relevant).
Yes
No
N/A.
2.3.6 For drug-device combinations, have any issues or
concerns raised as part of the clinical assessment of the
medicinal substance by the medicinal competent authority
or EMEA been considered and/or resolved?
Yes
No
N/A.
2.4 Final report of investigation
The report should be reviewed and should include the
following information
2.4.1 Summary – a structured abstract should be provided, Yes
8 Particular attention should be paid to: number of patients entered; objectives of investigation(s) (in particular which Essential Requirements are being addressed); duration of investigation(s) and patient follow up (short and long-term); end points in terms of
diagnostic tools and patient assessment; inclusion and exclusion criteria
.
page 39 of 46
presenting the essentials of the study
9
No
N/A.
2.4.2 Introduction – a brief statement placing the study in the
context of the development of the medical device in
question and an identification of guidelines followed in
the development of the Protocol
Yes
No
N/A.
2.4.3 Materials and methods
10
Yes
No
N/A.
2.4.4 Summary of the clinical investigation plan
11
Yes
No
N/A.
2.4.5 Results – this section should contain summary
information with a description of the analysis and results
12
Yes
No
N/A.
2.4.6 Discussions and conclusions
13
Yes
No
N/A.
2.4.7 Signature – the final report should be signed off by the Yes
9
Including title of investigation(s); identification of the medical device(s), including names, models as relevant for complete identification; name of sponsor; statement
indicating whether the investigation(s) was performed in accordance with CEN/ISO Standards; objectives; subjects; methodology; investigation(s) initiation and completion
dates, including date of early termination, if applicable; results; conclusions; authors of report; date of report.
10
Including device description; summary description of the device and its intended use, together with any modifications performed during the investigation.
11
Including the clinical investigation objectives; the investigation design; type of investigation; investigation end points; ethical considerations; subject population;
inclusion/exclusion criteria; sample size; treatment and treatment allocation; investigation variables; concomitant medications/treatments; duration of follow up; statistical
analysis including investigation hypothesis or pass/fail criteria, sample size calculation, statistical analysis methods.
12
Including the investigation initiation date; investigation completion/suspension date; the disposition of patients/devices; the patient demographics; clinical investigation
plan compliance; the analysis to include safety report, including a summary of all adverse events and adverse device events seen in the investigation, including a discussion of
the severity, treatment required, resolution and assessment by the investigator of relation to treatment; performance or efficacy analysis; any sub group analysis for special
population; a description of how missing data, including patients lost to follow up or withdrawn, were dealt with in the analysis.
13
Including the performance and safety results of the study; the relationship of risks and benefits; clinical relevance and importance of the results, particularly in the light of
other existing data and discussion of comparison with “state of the art”; any specific benefits or special precautions required for individual subjects or at risk groups; any
implications for the conduct of future studies.
page 40 of 46
sponsor, the co-ordinating clinical investigator (if
appointed) and principal investigator at each centre
No
N/A.
2.4.8 Annex to the report, containing clinical investigation plan,
including amendments, list of investigators and their
institutions, list of other parties involved, list of monitors,
list of statisticians (if applicable), list of Ethics
Committees and their approval letters.
Yes
No
N/A.
2.5 NB assessment of the clinical investigation(s) data
presented
2.5.1 Have any identified pass/fail criteria of the
investigation(s) been met?
Yes
No
N/A.
2.5.2 Have the results and conclusions of the clinical
investigation(s) demonstrated compliance with the
identified relevant essential requirements?
Yes
No
N/A.
2.5.3 Are the claims made in the device labelling substantiated
by clinical data when taken together with the relevant
pre-clinical data?
Yes
No
N/A.
2.5.4 Has the risk analysis demonstrated that the risks
associated with the use of the device, as set out by the
manufacturer, are acceptable when balanced against the
benefits to the patient?
Yes
No
N/A.
2.5.5 Was the assessment performed in a critical and objective
manner?
Yes
No
N/A.
3 Clinical literature data
A critical evaluation of relevant scientific literature that is currently available relating to safety, performance, design characteristics
and intended purpose in the form of a written report
3.1 Methodology
3.1.1 A critical evaluation of relevant scientific literature has
been presented
Yes
No
N/A.
3.1.2 A search protocol for the identification, selection,
collation and review of relevant publications should be
Yes
No
page 41 of 46
written. N/A.
3.1.3 The objective of the literature review should be clearly
defined
Yes
No
N/A.
3.1.4 The types of studies that are relevant to the objective of
the literature review should be specified
Yes
No
N/A.
3.1.5 Data should be taken from recognised scientific
publications. Unpublished data should also be taken into
account in order to avoid publication bias.
Yes
No
N/A.
3.1.6 The literature review should state:
3.1.6.1 sources of data, extent of the searches of databases or
other sources of information
Yes
No
N/A.
3.1.6.2 rationale for the selection/ relevance of the published
literature
Yes
No
N/A.
3.1.6.3 reasons for believing that all relevant references, both
favourable and unfavourable, have been identified
Yes
No
N/A.
3.1.6.4 criteria for exclusion of particular references together
with a justification for this exclusion.
Yes
No
N/A.
3.1.6.5 detailed description of the different stages of
literature search (including identification, appraisal,
analysis and conclusion of hits)
Yes
No
N/A.
3.2 Relevance of data presented
3.2.1 A literature review should clearly establish the extent
to which the literature relates to the specific
characteristics and features of the device under
consideration.
Yes
No
N/A.
3.2.2 If the published studies do not directly refer to the
device in question, the manufacturer must
Yes
No
page 42 of 46
demonstrate equivalence with the device, which is
the subject of the published reports.
N/A.
3.2.3 To be equivalent, the devices should have similarity
with regard to the clinical, technical and biological
parameters with special attention to the performance,
principles of operation and materials; or if there are
differences identified, an assessment and
demonstration of the significance these might have
on safety and performance must be set out14.
Yes
No
N/A.
3.2.4 The manufacturer must be able to demonstrate the
adequacy of the data in addressing the aspects of
conformity set out in the objective
Yes
No
N/A.
3.3 NB Assessment of clinical data
The literature review should make clear the
significance that is attached to particular references
based on a number of factors. These include:
3.3.1 relevance of the author’s background and expertise in
relation to the particular device and/or medical procedure
involved
Yes
No
N/A.
3.3.2 whether the author’s conclusions are substantiated by the
available data
Yes
No
N/A.
3.3.3 whether the literature reflects the current medical practice
and the generally acknowledged “state of the art“
technologies
Yes
No
N/A.
3.3.4 whether references are taken from recognised scientific
publications and whether or not they have been reported
Yes
No
14
Equivalence means:
Clinical: used for the same clinical condition or purpose, at the same site in the body, in similar population (including age, anatomy, physiology); have similar relevant
critical performance according to expected clinical effect for specific intended use.
Technical: used under similar conditions of use; have similar specifications and properties e.g. tensile strength, viscosity, surface characteristics; be of similar design; use
similar deployment methods (if relevant); have similar principles of operation.
Biological: use same materials in contact with the same human tissues or body fluids.
page 43 of 46
in peer reviewed journals N/A.
3.3.5 the extent to which the published literature is the outcome
of a study/studies which have followed scientific
principles in relation to design
15
Yes
No
N/A.
3.4 Critical evaluation of the literature
The literature review should contain a critical evaluation of the literature. This critical evaluation should:
3.4.1 be written by a person suitably qualified in the relevant
field, and reviewed and approved by an expert
knowledgeable in the “state of the art” and able to
demonstrate objectivity
Yes
No
N/A.
3.4.2 contain a short description of the medical device, its
intended functions, description of the intended purpose
and application of use
Yes
No
N/A.
3.4.3 contain an analysis of all the available data considered,
both favourable and unfavourable
Yes
No
N/A.
3.4.4 establish the extent to which the literature relates to the
specific characteristics and features of the device being
assessed, taking due account of the extend of similarity
between the device(s) covered by the literature and the
device under assessment
Yes
No
N/A.
3.4.5 demonstrate that those aspects of the use of the device,
including performance, addressed in the clinical part of
the risk analysis are met as claimed by the manufacturer,
and that the device fulfils its intended purpose as a
medical device
Yes
No
N/A.
3.4.6 analyse the identified hazards, the associated risks and the
appropriate safety measures of patients, medical staff and
Yes
No
15
For example in having demonstrable and appropriate endpoints, inclusion and exclusion criteria, an appropriate and validated number of patients submitted, carried out for
an appropriate duration, providing evidence and analysis of all adverse incidents, deaths, exclusions, withdrawals and subjects lost follow-up and identifying an appropriate
statistical plan of analysis. Ideally, evidence should be generated from a clinical trial (controlled if appropriate), properly designed cohort/case controlled study, well
documented case histories or sequential reports conducted by appropriate experienced experts, whether in relation to the device itself or an equivalent device. If unpublished
data is being included in the assessment, the literature review will need to weigh the significance that is attached to each report.
page 44 of 46
third parties involved in the study/studies N/A.
3.4.7 contain a risk analysis relevant to the device design,
materials and procedures involved, taking into account
any adverse events, results of post-market surveillance
studies, modifications and recalls (if known)
Yes
No
N/A.
3.4.8 contain a description of the methods of weighting of
different papers and the statistical methods of analysis
employed taking into account the assessment methods, the
type and duration of study and the heterogeneity of the
population included within the study
Yes
No
N/A.
3.4.9 include an analysis of the market experience of the same
or similar devices, including the results of post-marketing
studies, post-market surveillance and short- and long-term
adverse events
Yes
No
N/A.
3.4.10 contain a list of publications appropriately cross-
referenced in the evaluation
Yes
No
N/A.
3.4.11 if the clinical data relates to an equivalent device, contain
a statement that equivalence with all the relevant
characteristics has been demonstrated
Yes
No
N/A.
3.4.12 include a conclusion
16
with a justification, including an
assessment of any probable benefit to health from the use
of the device as intended by the manufacturer, against
probable risks of injury or illness from such use taking
account of the “state of the art”. The conclusions should
make clear how the objectives of the literature review
have been met and identify any gaps in the evidence
necessary to cover all relevant aspects of safety and
performance
Yes
No
N/A.
3.4.13 The critical evaluation should be signed and dated by the
author
Yes
No
16
Conclusions should consider the claimed use - indications, contra-indications and instructions for use proposed by the manufacturer.
page 45 of 46
N/A.
3.5 NB Assessment of the critical evaluation of literature
presented by the manufacturer
3.5.1 Are the manufacturers’ conclusions valid? Yes
No
N/A.
3.5.2 Is the data, taken together with the available pre clinical
data, sufficient to demonstrate compliance with the
essential requirements covering safety and performance of
the device in question under normal conditions of use?
17
Yes
No
N/A.
3.5.3 Are the claims made in the device labelling substantiated
by the clinical data taken together with the pre-clinical
data?
Yes
No
N/A.
3.5.4 Was the assessment performed in a critical and objective
manner?
Yes
No
N/A.
4 Post-market clinical follow up – the notified body
should check and review the manufacturer’s post
market clinical follow up plan:
4.1 Has the manufacturer presented an appropriate plan for
post-market clinical follow up in line with appropriate
guidance?
Yes
No
N/A.
4.2 If no post-market clinical follow up plan is presented, has
this been adequately justified by the manufacturer?
Yes
No
N/A.
4.3 Has the manufacturer an adequate post-market
surveillance system in place?
Yes
No
N/A.
4.4 Has the manufacturer committed to inform the NB of
significant updates to their clinical evaluation arising from
Yes
No
17
If not, identify gaps in the demonstration of compliance with the relevant essential requirements or in the demonstration of equivalence that need addressing through the
means of a specifically designed clinical investigation(s).
page 46 of 46
PMS/PMCF? N/A.
5 Notified Body Decision Making
5.1 In reviewing the evaluation of clinical data submitted by the manufacturer the NB must decide whether the manufacturer
has adequately
5.1.1 described and verified the intended characteristics and
performances related to clinical aspects
Yes
No
N/A.
5.1.2 performed a risk analysis and estimated the undesirable
side effects
Yes
No
N/A.
5.1.3 concluded on the basis of documented justification that
the risks are acceptable when weighed against the
intended benefits
Yes
No
N/A.
5.2 NB assessment of benefit/risk presented in the clinical
evaluation data
5.2.1 the listing and characterisation of the clinical performance
of the device intended by the manufacturer and the
expected benefits for the patient
Yes
No
N/A.
5.2.2 the use of the list of identified hazards to be addressed
through evaluation of clinical data
Yes
No
N/A.
5.2.3 the adequate estimation of the associated risks for each
identified hazard by:
a) characterising the severity of the hazard;
b) estimating and characterising the probability of
occurrence of the harm (or health impairment or loss of
benefit of the treatment) (document with rationale)
Yes
No
N/A.
5.2.4 the decision on the acceptability of risks in relation to
each identified hazard
Yes
No
N/A.
31.07.2014
Datei
PD
