Transcatheter aortic heart
valves in Europe
A market surveillance study

RIVM Letter report 2017-0170
B. Roszek et al.

Transcatheter aortic heart
valves in Europe
A market surveillance study

RIVM Letter report 2017-0170
B. Roszek et al.

RIVM Letter report 2017-0170

Colophon

© RIVM 2018
Parts of this publication may be reproduced, provided acknowledgement
is given to: National Institute for Public Health and the Environment,
along with the title and year of publication.
DOI 10.21945/RIVM-2017-0170

B. Roszek (author), RIVM
E.K. Lamme (author), RIVM
A.W. van Drongelen (author), RIVM
A. Oostlander (author), RIVM
R.E. Geertsma (author), RIVM
Contact:
R.E. Geertsma
Centre for Health Protection
robert.geertsma@rivm.nl
This investigation has been performed by order and for the account of
Dutch Health and Youth Care Inspectorate, within the framework of
project V/080168.

This is a publication of:
National Institute for Public Health
and the Environment
P.O. Box 1 | 3720 BA Bilthoven
The Netherlands
www.rivm.nl/en
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Synopsis

Transcatheter aortic heart valves in Europe
A market surveillance study
Malfunctioning heart valves can be replaced by a prosthesis. In recent
years, new techniques have been developed with less impact on
patients, for example the use of a catheter to insert the prosthesis. The
first of these ‘transcatheter aortic valve implantation devices’ (TAVI)
became available in Europe in 2007. Since that time, more than 300,000
TAVIs have been implanted, and new generations of the devices have
been developed.
As part of their market surveillance tasks, the Health and Youth Care
Inspectorate (IGJ) commissioned RIVM to assess the technical
documentation of five TAVI devices. None of the files contained items
that were assessed as ‘insufficient’, and one file contained only ‘good’ or
‘almost good’ items. The other four files contained one to two items
assessed as ‘moderate’.
In the file items “clinical evaluation” and “post-market surveillance data”
some shortcomings were found with the implication that product safety
and the safe use of the devices are insufficiently guaranteed with regard
to these issues. Shortcomings in the file do not necessarily mean that
the device is of insufficient quality. By maintaining complete and
accurate files, manufacturers underpin the safety of their products for
patients. Manufacturers are required to investigate carefully any
shortcomings in their files, and to resolve these in order to comply with
the regulations. Manufacturers have indicated that they are currently
working to improve their files in order to comply with the new
regulations on medical devices published in 2017.
Keywords: transcatheter aortic heart valve, product safety, technical
documentation assessment

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Publiekssamenvatting

Transkatheter aorta hartkleppen in Europa
Een onderzoek in het kader van markttoezicht
Slecht functionerende hartkleppen kunnen worden vervangen door een
prothese. Hiervoor zijn de afgelopen jaren nieuwe technieken ontwikkeld
die minder belastend zijn voor de patiënt, bijvoorbeeld het inbrengen
van de prothese via een katheter. De eerste van deze zogeheten
transkatheter aortaklep vervangende implantaten (TAVI) kwamen in
2007 beschikbaar in Europa. Sindsdien zijn wereldwijd meer dan
300.000 TAVI’s geplaatst, en zijn de producten verder ontwikkeld.
Vanwege haar taak als toezichthouder heeft de Inspectie voor
Gezondheidszorg en Jeugd (IGJ) het RIVM gevraagd de technische
documentatie te beoordelen van vijf TAVI-producten. Geen van de
dossiers bevatte onderdelen die onvoldoende waren, en één dossier had
alleen maar onderdelen die goed of bijna goed waren. De andere vier
dossiers hadden één tot twee onderdelen van middelmatige kwaliteit.
In de dossieronderdelen “klinische evaluatie” en “post-market
surveillance” zijn enkele tekortkomingen gevonden waardoor de
productveiligheid en een veilig gebruik van de producten onvoldoende
zijn gegarandeerd op deze punten. Een tekortkoming in het dossier
betekent niet direct dat het product minderwaardig is. Met volledige en
correcte dossiers onderbouwen fabrikanten de veiligheid van het product
voor de patiënt. Regelgeving vereist dat fabrikanten de tekortkomingen
in hun dossiers zorgvuldig onderzoeken en oplossen. Fabrikanten geven
aan dat zij hun dossiers momenteel verbeteren om te kunnen voldoen
aan de nieuwe regelgeving voor medische hulpmiddelen uit 2017.
Kernwoorden: transkatheter aorta hartkleppen, productveiligheid,
dossierbeoordeling

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Contents

1

Introduction — 9

2
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10

Assessment of technical documentation — 11
Overall quality of the technical documentation — 12
Device description — 12
Instructions for use — 13
Risk analysis — 13
Biocompatibility — 13
Biological safety — 14
Clinical evaluation — 14
Summary and analysis of post-market surveillance data — 15
Potential impact of findings on patient safety — 15
Conclusions assessment of technical documentation — 17

3

Conclusion — 19
References — 21
Annex 1: Checklist for Dutch request transcatheter heart valve
implantation systems — 23
Annex 2: Method of the assessment of technical
documentation — 26
Annex 3: Assessment form — 29
Annex 4: Results of the assessment of technical
documentation — 41

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1

Introduction

The replacement of malfunctioning heart valves by a prosthesis using
open heart surgery is a well-established procedure. However, patients at
high risk of mortality during surgery are generally not eligible for this
procedure [Iung, Baron et al. 2003; Bach, Siao et al. 2009]. Over the
years, less invasive techniques have been developed like
ministernotomy, minithoracotomy and transcatheter implantation. The
first transcatheter aortic valve implantation devices (TAVI) became
available in Europe in 2007. Since that time, more than 300,000
implantations have been performed worldwide [Puri, Chamandi et al.
2017]. The “first generation” transcatheter heart valves showed
promising outcomes, however, various associated complications were
observed. Therefore, several “second generation” transcatheter heart
valves have been developed.
Regulators in Europe have been interested in the rapid developments
occurring in the area of TAVI for some time. In the Netherlands, the
Health and Youth Care Inspectorate (IGJ) regularly commissions RIVM
to investigate a high risk medical product. In order to gain more insight
on the state of affairs for TAVI in Europe, the Inspectorate
commissioned RIVM to perform an investigation on TAVI. The
investigation consists of the following parts:
1. Compiling an overview of transcatheter heart valves that are CE
marked or in clinical investigations.
2. Literature research for available clinical data.
3. Assessment of technical documentation of selected TAVI devices
available on the EU market.
4. Laboratory evaluation of selected biocompatibility parameters of
the selected TAVI devices.
In this report, the results of part 3 are described. The following
questions will be addressed:
- Do the technical files of the selected TAVI provide adequate proof
of conformity with the requirements of the Medical Devices
Directive (MDD) [European Commission, 1993+2007]?
- In case of shortcomings, do these lead to a concern for patient
safety?

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2

Assessment of technical documentation

In order to show compliance with the Medical Devices Directive (MDD)
[European Commission, 1993+2007], manufacturers of medical devices
have to compile a file with technical documentation.
From each manufacturer that had one or more CE-marked TAVI devices,
as identified in part 1 of the investigation 1, the most recently CE-marked
device was included in this investigation. The following manufacturers
submitted the requested technical documentation: Abbott (product from
recently acquired St Jude Medical), Boston Scientific Corporation (both a
product from BSC and product from recently acquired Symetis),
Edwards Lifesciences LLC, and Medtronic plc. JenaValve Inc was
excluded because their product was no longer on the market at the start
of the investigation. Direct Flow was excluded because the company was
out of business. NVT GmbH did not want to cooperate; the German
Competent Authority was asked to follow up on this. Thus, in total five
products were included for assessment of the technical documentation.
A predefined selection of the technical documentation was requested
from the manufacturers for assessment (see Annex 1). The method
used for assessment of the documentation was adapted from previous
investigations [Keizers et al., 2016, 2017; Van Drongelen et al., 2016;
IGZ, 2013] and is described in detail in Annex 2.
In short, a form was developed in order to enable a structured and
uniform assessment of the technical documentation (see Annex 3). The
form included technical documentation items (e.g. risk analysis), which
were in turn subdivided into sub-items (e.g. risk control/mitigation). For
every sub-item, presence of adequate information was assessed. The
MDD, MEDDEV guidance documents and harmonised European
standards as relevant were used as a basis for the assessment of the
various (sub-)items. If adequate information was missing (a
shortcoming), this was noted on the form. The overall conclusion per
technical documentation item was based on the shortcomings identified,
if any, and translated into a ‘good’, ‘almost good’, ‘moderate’ or
‘insufficient’ score based on the expert judgement of the assessors. In
case all sub-items were adequately addressed, the technical
documentation item was scored ‘good’. If shortcomings were identified
with little or no potential impact on patient safety according to the
expert judgement of the assessors, the technical documentation item
was scored ‘almost good’. However, in case shortcomings were
considered to have a potential impact on patient safety, the technical
documentation item was scored ‘moderate’ or ‘insufficient’, as judged
appropriate. To facilitate a consistent assessment, two assessors
assessed the documentation independently. Assessment forms were

1

http://www.rivm.nl/Onderwerpen/M/Medische_hulpmiddelen/Hartkleppen/Overview_of_transcatheter_heart_va
lve_systems_CE_marked_and_in_Clinical_Investigations

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compared and any discrepancies were discussed and resolved for a final
assessment.
After the assessment, the manufacturers were informed about the
results and were given the opportunity to check on factual
inconsistencies. In case a manufacturer was of the opinion that the
assessment of a specific (sub-)item contained factual inconsistencies,
the manufacturer was requested to either state where the specific
information could be found in the original submitted documentation or
provide additional documentation which contained the specific
information. In the latter case, only documentation dated latest 10th May
2017, the date of initial information request, was considered.
The following paragraphs summarize the anonymized results of the
technical documentation assessment, starting with an overview of the
overall findings per transcatheter aortic valve system. The results reflect
the assessment scores after processing of any additional information
provided by the manufacturers. The subsequent paragraphs describe the
findings per documentation item. The detailed results of the assessment
of the technical documentation are presented in Table 4.1 (Annex 4). At
the end of this chapter, an evaluation is given of the potential impact on
patient safety of shortcomings found in the documentation.
2.1

Overall quality of the technical documentation
The overall results of the assessment are shown in Table 2.1. None of
the technical documentation sets scored ‘insufficient’ for any item but
also none of the sets scored entirely ‘good’ at all items. One
documentation set had only ‘good’ or ‘almost good’ items, whereas the
other four sets had one or two ‘moderate’ file items.
Table 2.1 Overview of the assessment of the technical documentation of TAVI
systems

File item
Device description
Instructions for use
Risk analysis

TAVI1
Almost
good
Good
Almost
good

TAVI2

TAVI3

TAVI4

TAVI5

Good

Good

Good

Good

Good

Good

Moderate

Moderate

Good
Almost
good

Good

Good

Good
Almost
good
Almost
good
Almost
good

Biocompatibility

Good

Almost
good

Biological safety

Good

Good

Almost
good

Good

Good

Moderate

Moderate

Moderate

Good

Good

Good

Moderate

Clinical evaluation
S&A PMS data

Almost
good
Good

Abbreviations:
PMS – post-market surveillance
S&A – summary and analysis
TAVI – transcatheter aortic valve implantation

2.2

Device description
The device description of four technical documentation sets complied
with all aspects checked in the assessment. One file was considered
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‘almost good’ due to a shortcoming in the description of any novel
features. Features of the system such as valve and catheter delivery
system were described in general, but no specific attention was paid to
which of the features was novel. Therefore, it was not clear how this
device differs from a previous generation of the TAVI system.
2.3

Instructions for use
No shortcomings were found in any of the instructions for use (IFU). IFU
were submitted in Dutch and/or English. Indications, important aspects
of the use (e.g. trained user), contraindications, and other transcatheter
aortic valve-related topics were mentioned. Thus, all IFUs complied with
the aspects checked in the assessment.

2.4

Risk analysis
All risk analyses had one or more shortcomings. One risk management
plan was not submitted, although the manufacturer indicated that it was
available. Nevertheless, several risk management issues that should be
part of the plan were described in the provided risk management file
and therefore the risk analysis of this device was scored ‘almost good’.
All risk analyses contained a date/version number and referred to the
harmonised European standard on risk management for medical devices
[EN ISO 14971, 2012]. Also the risk control/mitigation as well as the
acceptability of residual risks were addressed in all cases.
Required general risk categories (see Annex 3, Attachment II), based on
hazards derived from EN ISO 14971, were not fully addressed in three
cases: information on ‘Disposal and scrapping’ of the medical device was
missing.
The item ‘Contraindications and TAVI-related risk topics’ (see Annex 3,
Attachment I) had shortcomings in two cases. In both cases,
contraindications addressed in the IFU were not or only partially
analysed in the risk analysis. Following the manufacturer’s check on
factual inconsistencies in the assessment by RIVM, both manufacturers
indicated to incorporate the RIVM’s feedback in future updates of the
risk analysis documents. However, the outcome of the current
assessment could not be changed on the basis of this statement and
therefore the files of these two manufacturers were scored ‘moderate’
for risk analysis.

2.5

Biocompatibility
The EN ISO 10993 series of standards was used by all manufacturers. In
general, the evaluation of the biocompatibility was properly performed,
with only two shortcomings leading to ‘almost good’ scores. In both
cases, shortcomings related to absence or limited information regarding
‘any history of clinical use or human exposure data’ and ‘existing
toxicology/biocompatibility data’. For example, only a standard
operation procedure was submitted and no literature review regarding
these aspects was submitted. However, all applicable biocompatibility
tests were conducted and submitted. In all cases, the medical device
passed all biocompatibility tests.

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2.6

Biological safety
This item refers to management of biological safety aspects related to
the use of animal tissue in medical devices, e.g. contamination by
viruses or TSE agents, as described in the EN ISO 22442 series of
standards. Two technical documentation files had a shortcoming in their
description of the system for starting material record-keeping. This
aspect is required for the traceability of any components from sources to
the finished medical device. In both cases a general description was
provided without details resulting in an ‘almost good’ score. All other
aspects related to biological safety were covered in all files, i.e. a list of
materials of animal origin, information on selection of sources,
harvesting, processing, preservation, testing and handling of tissues of
animal origin, process validation and, where applicable, information on
conformity with Commission Regulation (EU) No 722/2012 [European
Commission, 2012] was ensured.

2.7

Clinical evaluation
The clinical evaluation is an extensive item in the technical
documentation file and comprises 13 sub-items (see Annex 3, item 4.4).
The reference document for clinical evaluation is the MEDDEV guidance
document on this topic [European Commission, 2016]. One technical
documentation file complied with all aspects checked in the assessment.
Four files each had one shortcoming. Three of them resulted in a
‘moderate’ score for this documentation item and one in ‘almost good’.
A shortcoming was found for the choice of clinical data types, in
particular in relation to the use of the equivalence principle. In case the
characteristics of two medical devices are similar to a large extent (i.e.
equivalent), it can be assumed that there would be no clinically
significant difference in their safety and performance. Consequently, the
so-called equivalence principle can be used, which means the clinical
data of one device can be used in the clinical evaluation of the other
device without conducting a new clinical investigation. This principle can
only be used if literature provides strong evidence. In addition, clinical,
technical, and biological characteristics of the two products should be
included in the demonstration of equivalence according to the MEDDEV
guidance document on clinical evaluation [European Commission, 2016].
In this case, the technical equivalence was not fully demonstrated. In
particular, it was not substantiated whether added components in the
design of the medical device could trigger clinically significant
differences in the safety and performance of the medical device.
Two other shortcomings were related to inconsistency of medical device
literature and the IFU with clinical data. In particular, not all exclusion
criteria as mentioned in the clinical evaluation report were used to
define contraindications for inclusion in the IFU.
The fourth shortcoming was found for the safety and performance
claims, which were not clearly expressed. Specific claims should be
included. The indications for use, contraindications and warnings were
mentioned, however, these are not formulated as claims. The
manufacturer did not elaborate on this aspect when the opportunity was

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given to check on factual inconsistencies in the assessment. Therefore,
the item was scored ‘almost good’.
2.8

Summary and analysis of post-market surveillance data
The summary and analysis of the post-market surveillance (PMS) data
of four technical documentation sets complied with all aspects checked
in the assessment. In one case, a shortcoming was found related to the
sources used for collecting PMS data. In particular, only complaints were
taken into consideration. Other, more proactive sources, e.g. expert
user groups, post-market clinical follow-up studies, literature reviews,
implant registries, and experience with similar devices made by the
same or other manufacturers should also be used.

2.9

Potential impact of findings on patient safety
This paragraph analyses whether the findings described above
potentially affect patient safety. Shortcomings in the technical
documentation could imply that product safety and safe use of the
device are insufficiently guaranteed. This in turn could have impact on
patient safety. On the other hand, the impact of shortcomings could be
counterbalanced by available information in other parts of the file, the
file could be poorly maintained while the device is of high quality, or the
manufacturer could have omitted to provide crucial parts of the
documentation. Thus, while it is important that the technical
documentation is providing all the necessary information in the correct
section of the file, shortcomings in the file do not necessarily have
impact on patient safety.
Device description and Instructions for use
The shortcoming in the device description, absence of the description of
any novel features, is not considered to have impact on patient safety.
The instructions for use did not contain shortcomings in any of the
technical file documentations.
Risk analysis
For the risk analysis, the most frequently observed shortcoming was the
absence of addressing disposal/scrapping of the medical device, which is
considered to have no direct impact on patient safety. Not analysing
risks related to contraindications and precautions potentially has impact
on patient safety because measures to mitigate these risks could be
missed. However, given the fact that the contraindications and
precautions are provided to the experienced user, the potential impact is
expected to be limited.
Biocompatibility
The shortcoming for biocompatibility in two technical documentation
files was caused by not performing a literature review. A literature
review is important as a first step in a biological evaluation [EN ISO
10993-1, 2009]. This is required in order to take account of the existing
knowledge and the generally acknowledged state of the art, regarding
the evaluation of biocompatibility of particular products. Furthermore,
the review is used to prevent unnecessary animal tests being
performed. However, in all cases, a standard set of tests was performed
according to applicable standards (EN ISO 10993-series) and the results
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did not indicate problems. Consequently, in these cases the potential
impact on patient safety of not performing the literature review is
counterbalanced by the data from testing and thus a negligible impact
on patient safety is expected.
Biological safety
In two files only a general description of their traceability system was
provided. A system for record-keeping allowing traceability from sources
of starting materials, e.g. animal tissues, to the finished medical device
is important. In case of unexpected adverse events, it is necessary to be
able to trace all devices produced from the same source. If this is not
possible, it potentially has an impact on patient safety. Since a system
was present in both cases, and the other aspects related to biological
safety, e.g. detailed information regarding materials of animal origin,
process validation and conformity to the TSE Regulation (where
applicable) were covered, potential impact on patient safety is expected
to be very limited.
Clinical evaluation
In one clinical evaluation substantiation of the technical equivalence was
limited. Insufficient substantiation of the equivalence principle
potentially has an impact on patient safety. On the other hand, using a
combination of the equivalence principle – i.e. using data obtained with
a (partially) equivalent device – and data obtained from studies with
manufacturer’s own device (direct clinical evidence), can also provide
the necessary full data set. It is not clear from the technical
documentation file which clinical data were obtained from studies with
the manufacturer’s own device, and which data from other devices were
included based on equivalence. Therefore, it cannot be determined
whether direct clinical evidence could counterbalance the potential
impact on patient safety posed by the limited substantiation of
equivalence. Thus, this shortcoming is judged to have potential impact
on patient safety.
Another shortcoming was a discrepancy between exclusion criteria in the
clinical investigation and contraindications in the IFU. Exclusion criteria
shape the intended patient population by defining which types of
patients need to be excluded from a clinical investigation.
Contraindications in the IFU indicate patient characteristics, e.g.
comorbidities, in which case the device should not be used. For patients
with characteristics corresponding to the exclusion criteria from the
clinical investigation, benefit and risk of using the device have not been
evaluated, and thus a contraindication is considered appropriate.
Therefore, all exclusion criteria mentioned in the clinical investigation
should be mentioned as contraindication in the IFU, which was not the
case in this technical documentation file. Using a device in a category of
patients which were excluded from the clinical investigation could lead to
an inferior performance and unexpected complications. Therefore, this
shortcoming is judged to have potential impact on patient safety.
PMS data
Using complaints as the only source for PMS led to a shortcoming for
one technical documentation file. Other sources, especially (pro)active
ones, should be used to obtain more comprehensive PMS data. Not
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using such sources means missing the opportunity to improve the
functionality and safety of the medical device. Therefore, this
shortcoming is judged to have potential impact on patient safety.
2.10

Conclusions assessment of technical documentation
The content of the technical documentation varied between the included
products. None of the technical documentation sets scored ‘insufficient’
for any item, but also none of the sets scored entirely ‘good’ at all items.
Although it is important that the technical documentation is providing all
the necessary information, shortcomings in the file do not necessarily
mean that the device is of insufficient quality. An analysis of the
shortcomings showed that the potential impact of most shortcomings on
patient safety can be considered negligible or limited. However, the
shortcomings related to the clinical evaluation and the post market
surveillance data could imply that product safety and safe use of the
devices concerned are insufficiently guaranteed.
Given the fact that the quality and safety of medical devices is required
to be substantiated by the information in the files according to the
regulatory system for medical devices, this outcome should be reason
for manufacturers to carefully consider and resolve the shortcomings in
order to substantiate the quality and safety of their medical devices.
Several manufacturers have indicated they are continuing to improve
their files during the transition they are currently making to compliance
with the recently published new regulation for medical devices
[European Commission, 2017]. Two of the main changes this regulation
includes, are strengthening the requirements for clinical evaluation and
post-market surveillance.

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3

Conclusion

In this study, we have assessed the technical files from five
manufacturers marketing transcatheter heart valves in Europe. All
technical documentation files contained a number of shortcomings. The
potential impact on patient safety is expected to be limited for most
shortcomings. However, all the shortcomings need to be adequately
addressed by the manufacturers in order to substantiate the quality and
safety of their products as required in the regulatory system. To arrive
at this over-all conclusion, two questions were addressed as described
below.
Do the technical files of the selected TAVI provide adequate proof of
conformity with the requirements of the Medical Devices Directive
(MDD)?
All technical files showed two or more shortcomings, and thus full
conformity with the MDD was not shown. None of the technical
documentation sets had ‘insufficient’ items and one had only ‘good’ or
‘almost good’ items. The other four sets had one to two ‘moderate’ file
items.
In case of shortcomings, do these lead to a concern for patient safety?
The regulatory system for medical devices depends to a large extent on
the quality of the submitted technical documentation. Therefore, any
shortcomings in that documentation could imply that product safety and
safe use of the device are insufficiently guaranteed. However,
shortcomings in a technical documentation file do not necessarily mean
that the device is of insufficient quality. An analysis of the shortcomings
in the technical documentation showed that the potential impact of most
shortcomings on patient safety can be considered negligible or limited.
However, the shortcomings related to the clinical evaluation and the
post-market surveillance data could imply that product safety and safe
use of the devices concerned are insufficiently guaranteed.
Manufacturers should carefully consider and resolve the shortcomings in
order to substantiate the quality and safety of their medical devices as
required in the regulatory system.

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Institute for Public Health and the Environment, Bilthoven, the
Netherlands. RIVM Report 2015-0100, 2016.
Puri R, Chamandi C, Rodriguez-Gabella T, Rodés-Cabau J. "Future of
transcatheter aortic valve implantation—evolving clinical indications."
Nature Reviews Cardiology, 2017.
Van Drongelen AW, de Bruijn ACP, van Elk M, Lamme EK, van der
Maaden T, Roszek B, Schooneveldt BC, and Janssen R. Blood glucose
meters. Performance of devices on the Dutch market. National Institute
for Public Health and the Environment. Bilthoven, the Netherlands. RIVM
Report 2016-0087, 2016.

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Annex 1: Checklist for Dutch request transcatheter heart
valve implantation systems

1. Device description
The device description should cover the following elements:
a) a general description including its intended use/purpose;
b) the intended patient population and medical condition treated
and other considerations such as patient selection criteria;
c) the mode of action;
d) the risk class and applicable classification rule according to MDD
93/42/EEC, Annex IX;
e) an explanation of any novel features;
f) a description of the accessories, other medical devices and other
products that are not medical devices, which are intended to be
used in combination with it;
g) a description or complete list of the variants of the device;
h) a general description of the key functional elements:
• its parts/components,
• its composition,
• its functionality;
i) labelled pictorial representations (e.g. diagrams, photographs,
and drawings), clearly indicating key parts/components, including
sufficient explanation to understand the drawings and diagrams;
j) a description of the materials incorporated into key functional
elements and those making either direct contact with a human
body or indirect contact with the body;
k) the relevant CE mark certificate(s) issued by the notified body,
e.g. EC Design Examination Certificate Directive 93/42/EEC on
Medical Devices, Annex II (4).
2. Instructions for use
The instructions for use of the device as described in essential
requirement 13, including requirements 7.5 and 9.1 (MDD 93/42/EEC,
Annex I).¹
¹ For the purpose of the investigation, the instructions for use should be
the ones associated with the medical device as marketed in the
Netherlands; if the device is currently not marketed in the Netherlands,
at least an English version should be provided.
3. Risk management plan and risk analysis
This documentation should contain a full report (NOT a summary) of the
risks identified during the risk analysis process and how these risks have
been controlled to an acceptable level. Preferably, this risk analysis
should be based on recognised standards, be consistent with the
manufacturer’s risk management plan, and be in English. For this
investigation, the documentation should include:
a) The risk management plan;
b) The risk analysis, containing the following elements:
•
date/version number;
•
reference to any standards used, e.g. EN ISO 14971;
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all hazard categories (for example: Table Annex E of the
current standard EN ISO 14971) identified or, appropriately,
declared not applicable;
•
estimates of associated risk;
•
risk control, i.e. control measures that are consistently
described in line with essential requirement 2 (MDD
93/42/EEC, Annex I);
•
(overall) justification/acceptability of residual risks in relation
to anticipated benefits;
c) the risk management report, ensuring that the risk management
plan is appropriately implemented, residual risks are acceptable
and appropriate methods are in place to obtain relevant
production and post-production information.
•

4.

Product verification and validation – relevant parts for this
investigation;
4.1. General
The documentation should summarise the results of verification and
validation studies undertaken to demonstrate conformity of the device
with the essential requirements that apply to it. For this investigation,
the information should cover the following items:
a) biocompatibility (see 4.2);
b) biological safety (see 4.3);
c) clinical evaluation (see 4.4);
d) where no testing has been undertaken, the documentation should
incorporate a rationale for that decision.
4.2. Biocompatibility
Detailed information should be included on:
a) a structured biological evaluation programme including
documented, informed decisions that assess the
advantages/disadvantages and relevance of
i. the physical and chemical characteristics of the various
candidate materials;
ii. any history of clinical use or human exposure data (including
data in published literature);
iii. any existing toxicology and other biological safety data on
product and component materials, breakdown products and
metabolites (including data in published literature);
iv. the selection of appropriate tests;
b) the tests conducted;
c) standards applied;
d) protocols (“standard operating procedures”) of the in vitro and in
vivo studies conducted;
e) analysis of data;
f) summary of results and conclusion.
4.3

Biological safety (for devices using animal tissue or their
derivatives)
Substantiation of the choices made in relation to the bullet points below
shall include reference to existing data in published literature where
possible. Detailed information should be included on:
a) a list of all materials of animal origin used in the device and a
justification for their use;
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b) detailed information concerning the selection of sources, the
harvesting, processing, preservation, testing and handling of
tissues, cells and substances of animal origin;
c) process validation results to substantiate that manufacturing
procedures are in place to minimize biological risks, in particular,
with regard to viruses and other transmissible agents; where
such procedures would lead to unacceptable degradation of a
device/material, substantiation why other risk control measures
are sufficient;
d) description of the system for record-keeping to allow traceability
from sources to the finished device;
e) where applicable, information on how conformity with the
requirements of the Commission Regulation (EU) No 722/2012
has been ensured.
4.4
Clinical evaluation
The documentation should contain the clinical evidence that
demonstrates conformity of the device with the essential requirements
that apply to it. The clinical evaluation report should contain the
following elements:
a) the proprietary name of the medical device and any code names
assigned during device development;
b) identification of the manufacturer of the medical device;
c) description of the medical device and its intended application;
d) intended therapeutic indications;
e) safety and performance claims made for the medical device;
f) context of the evaluation;
g) choice of clinical data types, i.e. clinical data used for the
evaluation can be published scientific literature, clinical
investigation(s), or a combination of scientific literature and
clinical investigations(s);
h) description of clinical follow-up;
i) safety analysis of the medical device, including serious adverse
events that occurred;
j) performance analysis of the medical device;
k) summary of the clinical data and appraisal;
l) consistency of medical device literature and instructions for use
with clinical data;
m) conclusions.
More information on the contents of the clinical evaluation report is
available in MEDDEV 2.7/1 and on the website of the International
Medical Device Regulators Forum (www.imdrf.org).
5. Summary and analysis of PMS data
The submitted documentation should contain a PMS report of the last
four years, or the period since introduction on the market if less than
four years, containing the following elements:
a) summary of PMS data, including specification of the frequency
of separate adverse events, complaints, side effects,
complications, and description of other experiences related to
the use of the product;
b) sources used to obtain PMS data;
c) analysis of PMS data;
d) actions taken based on the analysis of PMS data.
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Annex 2: Method of the assessment of technical
documentation

Identification and selection of manufacturers and devices
Identification of the manufacturers was performed by RIVM based on
scientific literature and web searches. Of manufacturers having CEmarked TAVI systems, the latest TAVI generation was selected for
inclusion in the investigation.
Technical documentation requested
IGJ requested a relevant part of the technical documentation of the
selected TAVI systems from the accompanying manufacturers in order
to assess the information and report on the assessment anonymously in
an RIVM letter report. With the letter requesting the technical file, a
checklist was enclosed which described details on the items to be
submitted (see Annex 1). The checklist was developed by RIVM and was
largely based on the Summary Technical Documentation (STED) from
the Global Harmonisation Task Force 2, modified in some places to fit
better with the requirements of the MDD. It was decided for this study
that the information requested was directly related to the TAVI systems
and not related to the procedures of the manufacturers (e.g. the PMS
procedure). The following information was requested from the
manufacturers:
• Device description
• Instructions for use (IFU)
• Risk management plan and risk analysis
• Product verification and validation – relevant parts for this
investigation:
o General
o Biocompatibility
o Biological safety (for devices using animal tissue or their
derivatives)
o Clinical evaluation
• Summary and analysis of post-market surveillance (PMS) data.
Following receipt, the documentation was checked for completeness and
any missing documentation was requested once more by IGJ.
Assessment method
An assessment form (see Annex 3) was developed in order to enable a
structured and uniform assessment of the documentation sets.
For each section of the checklist from Annex 1, a file item was included
and for each item a set of sub-items was listed (largely based on the
sub-items listed in the STED). The MDD, the MEDDEV guidance
document 2.7.1/Rev4 on clinical evaluation and harmonised European
standards as relevant were used as a basis for the assessment of the
2

The Global Harmonization Task Force (GHTF) was the predecessor of the current International Medical Device
Regulators Forum (IMDRF). IMDRF aims to accelerate international medical device regulatory harmonization
and convergence. GHTF final documents are still current and can be accessed on the IMDRF website. As the
work of IMDRF progresses, these documents will be reviewed and published as IMDRF documents. For more
information, see http://www.imdrf.org/index.asp.

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particular (sub-)items on risk management (EN ISO 14971),
biocompatibility (EN ISO 10993 series) and biological safety (EN ISO
22442 series). In general, the assessment was based on the presence or
adequate description of each particular sub-item in the documentation.
Only the shortcomings were noted in the assessment form.
The device description was mainly used as background information for
the assessment. For the IFU, it was checked whether specific TAVIrelated risks (see Annex 3, Attachment I) were mentioned. For the
assessment of the risk analysis, it was checked whether these TAVIrelated risks were addressed as well as whether general hazard
categories (see Annex 3, Attachment II), as derived from the
harmonised standard for risk management of medical devices [EN ISO
14971, 2012] were covered. For the item product verification the
documentation should summarise the results of verification and
validation studies undertaken to demonstrate conformity of the device
with the essential requirements that apply to it. For this investigation,
the information should at least cover the following items:
biocompatibility, biological safety and clinical evaluation. For
biocompatibility, it was checked whether appropriate tests were
performed. The biological safety of the medical device was checked
because of the presence of materials from animal tissue or their
derivatives and the associated risks. It should be demonstrated that the
biological risk is minimized. For the clinical evaluation, a list of TAVIrelated topics to be covered was drawn up and checked (see Annex 3,
Attachment III). For the summary and analysis of PMS data it was
checked whether PMS was adequately performed.
To facilitate consistent assessment, two assessors assessed the
documentation independently. Assessment forms were compared and
any discrepancies were discussed and resolved for a final assessment.
This method has also been used for previous investigations on metal-onmetal hip implants, silicone breast implants, blood glucose meters and
dermal fillers.
Quality of technical documentation items
Using expert judgement of the RIVM, the overall conclusion for the
technical documentation items was obtained based on the shortcomings
in relation to the potential impact of the finding on patient safety.
If the shortcoming had no relation to patient safety or was more of an
‘administrative’ nature according to the expert judgement of the
assessors, the conclusion was ‘almost good’. If there was a relation to
patient safety the conclusion was ‘moderate’. If there were several
shortcomings related to patient safety the conclusion was ‘insufficient’.
Items scored ‘good’ if every sub-item was adequately addressed and no
shortcomings were observed.
Manufacturer’s check on factual inconsistencies
Manufacturers received the result of the assessment of the requested
file items in the attached assessment form. In case the manufacturer
was of the opinion that the assessment contained factual
inconsistencies, he was given the opportunity to respond and point out
these inconsistencies before the assessment was made final.
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Two kinds of factual inconsistencies were considered:
- The manufacturer submitted information but it did not appear to
be taken into account for a specific file item or sub-item. The
manufacturer was requested to specify the name of document
and page number(s);
- The appropriate documentation to cover a specific item of the
assessment did exist at the time, but was not submitted. As the
investigation was based on the situation at the moment of the
submission request, any documentation dating from after 10 May
2017, the date of the request for the technical documentation
items, was not taken into consideration during the reassessment.

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Annex 3: Assessment form

Medical device code
Notified body (code and name)
1

Device description

1.a

General description, including intended
use / purpose
Intended patient population and
medical conditions treated and other
considerations such as patient selection
criteria
The mode of action and delivery
approach
The risk class and applicable
classification rule according to MDD
93/42/EEC, Annex IX
An explanation of any novel features

1.b

1.c
1.d
1.e
1.f

1.g
1.h

1.i

1.j

1.k

Shortcomings

Reference

A description of the accessories, other
medical devices and other products
that are not medical devices, which are
intended to be used in combination
with it
A description or complete list of the
variants of the device
A general description of the key
functional elements: its parts /
compartments; its composition and its
functionality
Labelled pictorial representations (e.g.
diagrams, photographs, and drawings),
clearly indicating key parts /
components, including sufficient
explanation to understand the drawings
and diagrams
A description of the materials
incorporated into key functional
elements and those making either
direct contact with a human body or
indirect contact with the body
The relevant CE mark certificate(s)
issued by the notified body, e.g. EC
Design Examination Certificate
Directive 93/42/EEC on Medical
Devices, Annex II (4)

Conclusion:

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Version

Date

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2

IFU

2.a
2.b

Indications for use
Important aspects of the use of the
TAVI (trained user)
Contraindications and TAVI-related risk
topics (attachment I)
IFU in Dutch or English

2.c
2.d

Shortcomings

Reference

Version

Date

Reference

Version

Date

Conclusion:

3

Risk analysis

3.a

This documentation should contain a
full report (NOT a summary) of the
risks identified during the risk analysis
process and how these risks have been
controlled to an acceptable level.
Preferably, this risk analysis should be
based on recognised standards, be
consistent with the manufacturer’s risk
management plan, and be in English.
For this investigation, the
documentation should include:
Risk management plan

3.b

The risk analysis, containing the
following elements:
Dated / version number risk analysis;
Reference to any standards used, e.g.
EN ISO 14971;
All hazard categories cf EN ISO 14971
(see attachment II) identified or,
appropriately, declared not applicable;
Contraindications and TAVI-related risk
topics addressed (attachment I);
Estimates of associated risk;

3.c

Risk control, i.e. control measures that
are consistently described in line with
essential requirement 2 (MDD
93/42/EEC, Annex I);
Acceptability of residual risks addressed
in relation to anticipated benefits
Conclusions: the risk management
report, ensuring that the risk
management plan is appropriately
implemented, residual risks are
acceptable and appropriate methods
are in place to obtain relevant
production and post-production
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Shortcomings

RIVM Letter report 2017-0170

information

Conclusion:

4

Product verification and validation
– relevant parts for this
investigation
The documentation should summarise
the results of verification and validation
studies undertaken to demonstrate
conformity of the device with the
essential requirements that apply to it.
For this investigation, the information
should cover the items 4.2 / 4.3 and
4.4.
Where no testing has been undertaken,
the documentation should incorporate a
rationale for that decision.

Shortcomings

4.2

Biocompatibility

Shortcomings

4.2.a

A structured biological evaluation
program including documented,
informed decisions that assess the
advantages / disadvantages and
relevance of
i. the physical and chemical
characteristics of the various candidate
materials;
ii. any history of clinical use or
human exposure data (including data in
published literature);
iii. any existing toxicology and other
biological safety data on product and
component materials, breakdown
products and metabolites (including
data in published literature);
iv. the selection of appropriate tests

4.2.b

Tests conducted

4.2.c

Standards applied (ISO 10993-series)

4.2.d
4.2.e

Protocols of the in-vitro and in-vivo
studies conducted
Analysis of data

4.2.f

Summary of results and conclusions

4.1

Reference

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RIVM Letter report 2017-0170

Conclusion:

4.3

4.3.a
4.3.b

4.3.c

4.3.d
4.3.e

4.4

Biological safety
Substantiation of the choices made in
relation to the bullet points below shall
include reference to existing data in
published literature where possible.
Detailed information should be included
on:
A list of all materials of animal origin
used in the device and a justification
for their use
Detailed information concerning the
selection of sources, the harvesting,
processing, preservation, testing and
handling of tissues, cells and
substances of animal origin
Process validation results to
substantiate that manufacturing
procedures are in place to minimize
biological risks, in particular, with
regard to viruses and other
transmissible agents; where such
procedures would lead to unacceptable
degradation of a device / material,
substantiation why other risk control
measures are sufficient
Description of the system for recordkeeping to allow traceability from
sources to the finished device
Where applicable, information on how
conformity with the requirements of the
Commission Regulation (EU) No
722/2012 has been ensured

Clinical evaluation
The documentation should contain the
clinical evidence that demonstrates
conformity of the device with the
essential requirements that apply to it.
The clinical evaluation report should
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Shortcomings

Reference

Version

Date

Reference

Version

Date

Conclusion:

Shortcomings

RIVM Letter report 2017-0170

contain the following elements:

4.4.a
4.4.b
4.4.c
4.4.d
4.4.e
4.4.f
4.4.g

4.4.h
4.4.i
4.4.j
4.4.k
4.4.l
4.4.m

The proprietary name of the medical
device and any code names assigned
during device development
Identification of the manufacturer of
the medical device
Description of the medical device and
its intended application
Intended therapeutic indications
Safety and performance claims made
for the medical device
Context of the evaluation
Choice of clinical data types, i.e. clinical
data used for the evaluation can be
published scientific literature, clinical
investigation(s), or a combination of
scientific literature and clinical
investigations(s)
Description of clinical follow-up
Safety analysis of the medical device,
including serious adverse events that
occurred
Performance analysis of the medical
device
Summary of the clinical data and
appraisal
Consistency of medical device literature
and instructions for use with clinical
data (see attachment III)
Conclusions
Conclusion:

5

Summary & analysis of PMS data

5.a

The submitted documentation should
contain a PMS report of the last four
years, or the period since introduction
on the market if less than four years,
containing the following elements:
Sources used to obtain PMS data

5.b

Shortcomings

Reference

Summary of PMS data, including
specification of the frequency of
separate adverse events, complaints,
side effects, complications, and
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description of other experiences related
to the use of the product

5.c

Analysis of PMS data and conclusions

5.d

Actions taken based on the analysis of
PMS data

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Conclusion:

RIVM Letter report 2017-0170

Attachment I
Contraindications and risks based on literature for TAVI
IFU

RA

IFU

RA

1. Contraindications
Left ventricular or atrial thrombus
Vascular conditions (stenosis, tortuosity, calcification)
Congenital aortic stenosis or unicuspid or bicuspid aortic valve
Inability to tolerate anti-platelet / anti-coagulant therapy
Active systemic infection (sepsis or endocarditis)
Hypersensitivity to contrast agents that cannot be premedicated
Hypersensitivity to e.g. aspirin, all thienopyridines, heparin,
nickel, titanium, tantalum, bovine-derived materials or polyurethanes
Non-valvular aortic stenosis
Presence of mitral or aortic bioprothesis
Evidence of intracardial mass or vegetation
Coronary artery disease / untreated clinically significant
coronary artery disease requiring revascularization
Severe deformation of chest
Significant aortic disease
Severe ventricular dysfunction with ejection fraction < 30% or
20%
Cerebrovascular events (stroke / CVA / TIA) < 6 months
Hypertropic cardiomyopathy with or without obstruction (HOCM)
Recent emboli
Patient refusing blood transfusion
Pregnancy
Creatine clearance < 20 ml/min
Uncontrolled atrial fibrillation
Renal failure therapy
Previous aortic mechanical valve replacement

2. Complications / side effects / adverse events
Stroke / CVA / TIA
Death (all-cause / cardiovascular mortality)
Vascular complications (major / minor complications)
Bleeding (life-threatening / major / minor bleeding)
Pacemaker implantation
Myocardial infarction (peri-procedural MI (<72 h after index
procedure), spontaneous MI (>72 h after index procedure))
Acute kidney injury (stage 1, 2 or 3) / renal failure
Allergic reaction / hypersensitivity / inflammation
Infection
Severe allergic reaction (anaphylactic shock)
Cardiac arrhythmias
Haemolysis
Prosthetic valve dysfunction - regurgitation
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Prosthetic valve dysfunction - stenosis
Prosthetic valve dysfunction - thrombosis
Endocarditis
Pulmonary embolism
Thrombosis
Haemodynamic instability
Device embolisation (valve or delivery system components)
Coronary obstruction
Conversion to open surgery
Unplanned use of cardiopulmonary bypass
Ventricular septal perforation
Cardiac tamponade (evidence of a new pericardial effusion
associated with haemodynamic instability)
Valve malpositioning (valve migration, valve embolization,
ectopic valve deployment)
IFU

RA

IFU

RA

3. Operational specifications
Principles of operation / specific instruction for implanting
Intended device delivery approach
Specific instructions for device preparation
Expected device lifetime
Shelf-life
Shipping / storage limits
Sterility
Visibility under fluoroscopy or other imaging modalities
Warnings regarding handling and implanting the device
Crush / force resistance
Instruction for re-sterilisation method / max number (if
applicable)
Magnetic resonance safety

4. Risk factors, other than side effects
Virus, BSE or other transmissible agent
Embolization of debris
Bio-incompatibility
Package opened or damaged
Paravalvular leak
Inability to complete implant procedure
Unintended anatomical interactions
Plastic deformation of prosthesis support structure
Prosthesis is prematurely deployed

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Attachment II
This appendix provides a selection of categories of risks and
subsequent examples, and is based on hazards described in the
standard EN ISO 14971:2007, corrected 2012 Medical devices –
Application of risk management to medical devices.
Biological hazards
- Contamination with bacteria
- Contamination with viruses
- Contamination with endotoxins
- Re- or cross infection
Biocompatibility
- Allergencity / irritancy
- Cytotoxicity
- Acute systemic toxicity
- Animal implantation
Chemical hazards
- Acids and alkalis
- Residues, e.g. cleaning
- Contaminating agents
- Manufacturing additives or adjuvants
- Corrosion
Use error
- Use by unskilled / untrained personnel
- Inadequate equipment
- Inadequate implantation / procedure
- Inadequate patients
- Mismatch
Hazardous phenomena linked to inadequate labelling
- Incomplete instructions for use
- Inadequate description of performance characteristics
- Inadequate specification of intended use
- Inadequate disclosure of limitations
Hazardous phenomena linked to inadequate operating
instructions
- Inadequate specification of accessories to be used with the
medical device
- Incompatibility of consumables / accessories / other medical
devices
- Inadequate specification of pre-use checks
- Over-complicated (operating) instructions
Hazardous phenomena linked to insufficient warnings about
- Of complications / side effects
- Of single-use medical devices
Incomplete requirements
- Inadequate specification of:
• design parameters
• performance requirements
• end of life
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Manufacturing processes
- Insufficient control of changes to manufacturing processes
- Insufficient control of materials / materials compatibility
information
- Insufficient control of manufacturing processes
- Insufficient control of subcontractors
Transport and storage
- Inadequate packaging
- Contamination or deterioration
- Inappropriate environmental conditions
Environmental factors
- Physical, e.g. heat, pressure, time
- Chemical, e.g. corrosions, contamination
- Mechanical, e.g. accidental mechanical damage
Cleaning, disinfection and sterilization
- Lack / inadequate specification for, validated sterilization
procedures, if applicable cleaning / disinfection
- Inadequate conduct of cleaning, disinfection and sterilization
Disposal and scrapping
- No or inadequate information provided
Formulation
- (Bio)degradation
- Inadequate warning of hazards associated with incorrect
formulations
Potential for use errors triggered by design flaws, such as
- Missing instructions for use
- Ambiguous or unclear device state
- Ambiguous or unclear presentation of settings, measurements
or other information
Failure modes
- Unexpected loss of mechanical integrity
- Deterioration in function (e.g. change in resistance to flow) as
a result of ageing
- Loss of sterility

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Attachment III
Clinical evaluation of TAVIs
1. Indications
Patients with aortic valve insufficiency (regurgitation)
Patients with symptomatic severe (native / calcific) aortic stenosis
who are considered high surgical risk
Patients with symptomatic severe (native / calcific) aortic stenosis
who are considered intermediate surgical risk
Patients with previously implanted failing aortic surgical
bioprosthesis
2. Contraindications
Left ventricular or atrial thrombus
Vascular conditions (stenosis, tortuosity, calcification)
Congenital aortic stenosis or unicuspid or bicuspid aortic valve
Inability to tolerate anti-platelet / anti-coagulant therapy
Active systemic infection (sepsis or endocarditis)
Hypersensitivity to contrast agents that cannot be premedicated
Hypersensitivity to e.g. aspirin, all thienopyridines, heparin, nickel,
titanium, tantalum, bovine-derived materials or poly-urethanes
Non-valvular aortic stenosis
Presence of mitral or aortic bioprothesis
Evidence of intracardial mass or vegetation
Coronary artery disease / untreated clinically significant coronary
artery disease requiring revascularization
Severe deformation of chest
Significant aortic disease
Severe ventricular dysfunction with ejection fraction < 30% or 20%
Cerebrovascular events (stroke / CVA / TIA) < 6 months
Hypertropic cardiomyopathy with or without obstruction (HOCM)
Recent emboli
Patient refusing blood transfusion
Pregnancy
Creatine clearance < 20 ml/min
Uncontrolled atrial fibrillation
Renal failure therapy
Previous aortic mechanical valve replacement
3. Safety and performance
Stroke / CVA / TIA
Death (all-cause / cardiovascular mortality)
Vascular complications (major / minor complications)
Bleeding (life-threatening / major / minor bleeding)
Pacemaker implantation
Myocardial infarction (peri-procedural MI (<72 h after index
procedure), spontaneous MI (>72 h after index procedure))
Acute kidney injury (stage 1, 2 or 3) / renal failure
Allergic reaction / hypersensitivity / inflammation
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Infection
Severe allergic reaction (anaphylactic shock)
Cardiac arrhythmias
Haemolysis
Prosthetic valve dysfunction - regurgitation
Prosthetic valve dysfunction - stenosis
Prosthetic valve dysfunction - thrombosis
Endocarditis
Pulmonary embolism
Thrombosis
Haemodynamic instability
Device embolisation (valve or delivery system components)
Coronary obstruction
Cardiac tamponade
Bio-incompatibility
Amount of contrast dye
Hospital length of stay
Magnetic resonance safety
4. Device and procedural success
Device success
Procedural success

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Annex 4: Results of the assessment of technical
documentation

Table 5.1 Overview of the assessment of technical documentation of TAVI systems after the
manufacturer’s check on factual inconsistencies – Where shortcomings were found, this is
indicated with sh.

File item

Device description
General description, including intended use / purpose
Intended patient population and medical conditions
treated and other considerations such as patient
selection criteria
The mode of action and delivery approach
The risk class and applicable classification rule
according to MDD 93/42/EEC, Annex IX
An explanation of any novel features
A description of the accessories, other medical
devices and other products that are not medical
devices, which are intended to be used in
combination with it
A description or complete list of the variants of the
device
A general description of the key functional elements:
its parts / compartments; its composition and its
functionality
Labelled pictorial representations (e.g. diagrams,
photographs, and drawings), clearly indicating key
parts / components, including sufficient explanation
to understand the drawings and diagrams
A description of the materials incorporated into key
functional elements and those making either direct
contact with a human body or indirect contact with
the body
The relevant CE mark certificate(s) issued by the
notified body, e.g. EC Design Examination Certificate
Directive 93/42/EEC on Medical Devices, Annex II
(4)General description
IFU
Indications for use
Important aspects of the use of the TAVI (trained
user)
Contraindications and TAVI-related risk topics
(attachment I)
IFU in Dutch or English
Risk analysis
Risk management plan
Dated / version number risk analysis
Reference to any standards used, e.g. EN ISO 14971
All hazard categories cf EN ISO 14971 (see
attachment II) identified or, appropriately, declared

TAVI
1

TAVI
2

TAVI
3

TAVI
4

TAVI
5

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RIVM Letter report 2017-0170

not applicable
Contraindications and TAVI-related risk topics
addressed (attachment I)
Estimates of associated risk
Risk control, i.e. control measures that are
consistently described in line with essential
requirement 2 (MDD 93/42/EEC, Annex I)
Acceptability of residual risks addressed in relation to
anticipated benefits
Conclusions: the risk management report, ensuring
that the risk management plan is appropriately
implemented, residual risks are acceptable and
appropriate methods are in place to obtain relevant
production and post-production information
Biocompatibility
The physical and chemical characteristics of the
various candidate materials
Any history of clinical use or human exposure data
(including data in published literature)
Any existing toxicology and other biological safety
data on product and component materials,
breakdown products and metabolites (including data
in published literature)
The selection of appropriate tests
Tests conducted
Standards applied (ISO 10993-series)
Protocols of the in-vitro and in-vivo studies
conducted
Analysis of data
Summary of results and conclusions
Biological safety
A list of all materials of animal origin used in the
device and a justification for their use
Detailed information concerning the selection of
sources, the harvesting, processing, preservation,
testing and handling of tissues, cells and substances
of animal origin
Process validation results to substantiate that
manufacturing procedures are in place to minimize
biological risks, in particular, with regard to viruses
and other transmissible agents; where such
procedures would lead to unacceptable degradation
of a device / material, substantiation why other risk
control measures are sufficient
Description of the system for record-keeping to allow
traceability from sources to the finished device
Where applicable, information on how conformity
with the requirements of the Commission Regulation
(EU) No 722/2012 has been ensured
Clinical evaluation
The proprietary name of the medical device and any
code names assigned during device development
Identification of the manufacturer of the medical
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RIVM Letter report 2017-0170

device
Description of the medical device and its intended
application
Intended therapeutic indications
Safety and performance claims made for the medical
device
Context of the evaluation
Choice of clinical data types, i.e. clinical data used for
the evaluation can be published scientific literature,
clinical investigation(s), or a combination of scientific
literature and clinical investigations(s)
Description of clinical follow-up
Safety analysis of the medical device, including
serious adverse events that occurred
Performance analysis of the medical device
Summary of the clinical data and appraisal
Consistency of medical device literature and
instructions for use with clinical data (see attachment
III)
Conclusions
Summary and analysis of PMS data
Sources used to obtain PMS data
Summary of PMS data, including specification of the
frequency of separate adverse events, complaints,
side effects, complications, and description of other
use-related experiences of the product
Analysis of PMS data and conclusions
Actions taken based on the analysis of PMS data

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Abbreviations:
IFU – instructions for use
PMS – post-market surveillance
TAV – transcatheter aortic valve
TAVI – transcatheter aortic valve implantation

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RIVM
Committed to health and sustainability