SIST EN ISO 5840-3:2021

Cardiovascular implants - Cardiac valve prostheses - Part 3: Heart valve substitutes implanted by transcatheter techniques (ISO 5840-3:2021)

This document is applicable to all devices intended for implantation as a transcatheter heart valve substitute.
This document is applicable to transcatheter heart valve substitutes and to the accessory devices, packaging and labelling required for their implantation and for determining the appropriate size of heart valve substitute to be implanted.
This document establishes an approach for verifying/validating the design and manufacture of a transcatheter heart valve substitute through risk management. The selection of appropriate verification/validation tests and methods are to be derived from the risk assessment. The tests can include those to assess the physical, chemical, biological and mechanical properties of heart valve substitutes and of their materials and components. The tests can also include those for preclinical in vivo evaluation and clinical evaluation of the finished heart valve substitute.
This document defines operational conditions and performance requirements for transcatheter heart valve substitutes where adequate scientific and/or clinical evidence exists for their justification.
This document includes considerations for implantation of a transcatheter heart valve substitute inside a pre-existing prosthetic device (e.g. valve-in-valve and valve-in-ring configurations).

Herz- und Gefäßimplantate - Herzklappenprothesen - Teil 3: Durch minimal-invasive Methoden implantierter Herzklappenersatz (ISO 5840-3:2021)

Dieses Dokument ist auf alle Medizinprodukte anwendbar, die für die Implantation als Transkatheter-Herzklappenersatz vorgesehen sind.
Dieses Dokument ist auf Transkatheter-Herzklappenersatz und dessen Zubehörteile anwendbar und gilt darüber hinaus für die Verpackung und die für die Implantation und Bestimmung der geeigneten Größe des zu implantierenden Herzklappenersatzes erforderliche Kennzeichnung.
Dieses Dokument legt eine Herangehensweise zur Verifizierung/Validierung des Designs und der Herstellung eines Transkatheter-Herzklappenersatzes auf der Grundlage des Risikomanagements fest. Die Auswahl der geeigneten Prüfungen und Verfahren der Verifizierung/Validierung muss sich aus der Risiko¬beurteilung ableiten. Zu diesen Prüfungen können solche zur Beurteilung der physikalischen, chemischen, biologischen und mechanischen Eigenschaften eines Herzklappenersatzes und von dessen Werkstoffen und Bauteilen gehören. Diese Prüfungen können auch die vorklinische In vivo-Bewertung und die klinische Bewertung des fertigen Herzklappenersatzes einschließen.
Dieses Dokument legt Betriebsbedingungen für und Leistungsanforderungen an Transkatheter-Herz-klappenersatz fest, sofern angemessene wissenschaftliche und/oder klinische Nachweise für deren Begründung vorliegen.
Dieses Dokument enthält Betrachtungen zur Implantation eines Transkatheter-Herzklappenersatzes in eine bereits vorhandene Prothese (z. B. Klappe-in-Klappe- und Klappe-in-Ring-Konfigurationen).

Implants cardiovasculaires - Prothèses valvulaires - Partie 3: Valves cardiaques de substitution implantées par des techniques transcathéter (ISO 5840-3:2021)

Le présent document s'applique à tous les dispositifs destinés à être implantés en tant que prothèse valvulaire par voie transcathéter.
Le présent document s'applique aux prothèses valvulaires implantées par transcathéter ainsi qu'aux dispositifs auxiliaires, à l'emballage et à l'étiquetage exigés pour leur implantation. Il s'applique également à la détermination de la taille appropriée de la prothèse valvulaire à implanter.
Le présent document établit une approche permettant de vérifier/valider la conception et la fabrication d'une prothèse valvulaire implantée par transcathéter dans une optique de gestion du risque. La sélection des méthodes et des essais de vérification/validation appropriés se fait à partir de l'appréciation du risque. Des essais peuvent être destinés à évaluer les propriétés physiques, chimiques, biologiques et mécaniques de prothèses valvulaires ainsi que celles de leurs matériaux et composants. Les essais peuvent également englober les essais destinés à l'évaluation préclinique in vivo et à l'évaluation clinique des prothèses valvulaires à l'état fini.
Le présent document définit les conditions de fonctionnement et les exigences de performance relatives aux prothèses valvulaires implantées par transcathéter lorsqu'il existe une preuve scientifique et/ou clinique adéquate pour les justifier.
Le présent document comprend des considérations relatives à l'implantation par transcathéter d'une prothèse valvulaire dans un dispositif prothétique préexistant (par exemple les configurations «valve-in-valve» et «valve-in-ring»).

Vsadki (implantati) za srce in ožilje - Proteze za srčno zaklopko - 3. del: Nadomestki srčne zaklopke, vsajeni (implantirani) s transkatetrsko metodo (ISO 5840-3:2021)

General Information

• Status: Published
• Public Enquiry End Date: 19-Mar-2019
• Publication Date: 21-Feb-2021
• ICS: 11.040.40 - Implants for surgery, prosthetics and orthotics
• Technical Committee: VAZ - Healthcare
• Current Stage: 6060 - National Implementation/Publication (Adopted Project)
• Start Date: 11-Feb-2021
• Due Date: 18-Apr-2021
• Completion Date: 22-Feb-2021
• Directive: 93/42/EEC - Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
• Mandate: M/023 - Standardization mandate to CEN/CENELEC concerning the development of European standards relating to medical devices
• Ref Project: EN ISO 5840-3:2021 - Cardiovascular implants - Cardiac valve prostheses - Part 3: Heart valve substitutes implanted by transcatheter techniques (ISO 5840-3:2021)

Relations

• Replaces: SIST EN ISO 5840-3:2013 - Cardiovascular implants - Cardiac valve prostheses - Part 3: Heart valve substitutes implanted by transcatheter techniques (ISO 5840-3:2013)
• Effective Date: 01-Mar-2021

Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 5840-3:2021
01-marec-2021
Nadomešča:
SIST EN ISO 5840-3:2013
Vsadki (implantati) za srce in ožilje - Proteze za srčno zaklopko - 3. del:
Nadomestki srčne zaklopke, vsajeni (implantirani) s transkatetrsko metodo (ISO
5840-3:2021)
Cardiovascular implants - Cardiac valve prostheses - Part 3: Heart valve substitutes
implanted by transcatheter techniques (ISO 5840-3:2021)
Herz- und Gefäßimplantate - Herzklappenprothesen - Teil 3: Durch minimal-invasive
Methoden implantierter Herzklappenersatz (ISO 5840-3:2021)
Implants cardiovasculaires - Prothèses valvulaires - Partie 3: Valves cardiaques de
substitution implantées par des techniques transcathéter (ISO 5840-3:2021)
Ta slovenski standard je istoveten z: EN ISO 5840-3:2021
ICS:
11.040.40 Implantanti za kirurgijo, Implants for surgery,
protetiko in ortetiko prosthetics and orthotics
SIST EN ISO 5840-3:2021 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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SIST EN ISO 5840-3:2021

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SIST EN ISO 5840-3:2021


EN ISO 5840-3
EUROPEAN STANDARD

NORME EUROPÉENNE

February 2021
EUROPÄISCHE NORM
ICS 11.040.40 Supersedes EN ISO 5840-3:2013
English Version

Cardiovascular implants - Cardiac valve prostheses - Part
3: Heart valve substitutes implanted by transcatheter
techniques (ISO 5840-3:2021)
Implants cardiovasculaires - Prothèses valvulaires - Herz- und Gefäßimplantate - Herzklappenprothesen -
Partie 3: Valves cardiaques de substitution implantées Teil 3: Durch minimal-invasive Methoden
par des techniques transcathéter (ISO 5840-3:2021) implantierter Herzklappenersatz (ISO 5840-3:2021)
This European Standard was approved by CEN on 22 September 2020.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.

This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and
United Kingdom.





EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION

EUROPÄISCHES KOMITEE FÜR NORMUNG

CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2021 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 5840-3:2021 E
worldwide for CEN national Members.

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SIST EN ISO 5840-3:2021
EN ISO 5840-3:2021 (E)
Contents Page
European foreword . 3

2

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SIST EN ISO 5840-3:2021
EN ISO 5840-3:2021 (E)
European foreword
This document (EN ISO 5840-3:2021) has been prepared by Technical Committee ISO/TC 150
"Implants for surgery" in collaboration with Technical Committee CEN/TC 285 “Non-active surgical
implants” the secretariat of which is held by DIN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by August 2021, and conflicting national standards shall
be withdrawn at the latest by August 2021.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 5840-3:2013.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the
United Kingdom.
Endorsement notice
The text of ISO 5840-3:2021 has been approved by CEN as EN ISO 5840-3:2021 without any
modification.

3

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SIST EN ISO 5840-3:2021

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SIST EN ISO 5840-3:2021
INTERNATIONAL ISO
STANDARD 5840-3
Second edition
2021-01
Cardiovascular implants — Cardiac
valve prostheses —
Part 3:
Heart valve substitutes implanted by
transcatheter techniques
Implants cardiovasculaires — Prothèses valvulaires —
Partie 3: Valves cardiaques de substitution implantées par des
techniques transcathéter
Reference number
ISO 5840-3:2021(E)
©
ISO 2021

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

COPYRIGHT PROTECTED DOCUMENT
© ISO 2021
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: [phone]
Email: [e-mail]
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Abbreviations. 4
5 Fundamental requirements . 5
6 Device description . 5
6.1 General . 5
6.2 Intended use . 6
6.3 Design inputs . 6
6.3.1 Operational specifications . 6
6.3.2 Performance specifications . 6
6.3.3 Implant procedure. 7
6.3.4 Packaging, labelling and sterilization . 7
6.4 Design outputs . 7
6.5 Design transfer (manufacturing verification/validation) . 7
6.6 Risk management . 7
7 Design verification and validation . 8
7.1 General requirements . 8
7.2 In vitro assessment . 8
7.2.1 General. 8
7.2.2 Test conditions, sample selection and reporting requirements . 8
7.2.3 Material property assessment . 8
7.2.4 Hydrodynamic performance assessment . 8
7.2.5 Structural performance assessment .10
7.2.6 Design- or procedure-specific testing.10
7.2.7 Device MRI compatibility .12
7.2.8 Simulated use.12
7.2.9 Human factors and usability assessment .12
7.2.10 Implant thrombogenic and haemolytic potential assessment .12
7.3 Preclinical in vivo evaluation .12
7.3.1 General.12
7.3.2 Overall requirements .13
7.3.3 Methods .14
7.3.4 Test report .15
7.4 Clinical investigations .16
7.4.1 General.16
7.4.2 Study considerations .17
7.4.3 Study endpoints .18
7.4.4 Ethical considerations .19
7.4.5 Pivotal studies: Distribution of subjects and investigators .19
7.4.6 Statistical considerations including sample size and duration .20
7.4.7 Patient selection criteria .22
7.4.8 Valve thrombosis prevention .22
7.4.9 Clinical data requirements .23
Annex A (informative) Description of the transcatheter heart valve system .28
Annex B (informative) Transcatheter heart valve substitute hazard analysis example .30
Annex C (informative) Guidelines for verification of hydrodynamic performance —
Pulsatile flow testing .32
© ISO 2021 – All rights reserved iii

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

Annex D (normative) Requirements for delivery system design and evaluation .40
Annex E (informative) Examples of design specific testing .42
Annex F (informative) Preclinical in vivo evaluation .44
Annex G (normative) Adverse event classification during clinical investigation .47
Annex H (informative) Multimodality imaging of TAVI and TMVI pre, peri and post-
implantation assessments — Examples .53
Bibliography .56
iv © ISO 2021 – All rights reserved

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/ patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www .iso .org/
iso/ foreword .html.
This document was prepared by Technical Committee ISO/TC 150, Implants for surgery, Subcommittee
SC 2, Cardiovascular implants and extracorporeal systems, in collaboration with the European Committee
for Standardization (CEN) Technical Committee CEN/TC 285, Non-active surgical implants, in accordance
with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).
This second edition cancels and replaces the first edition (ISO 5840-3:2013), which has been technically
revised.
The main changes compared to the previous edition are as follows: the engineering and clinical
requirements in the ISO 5840 series have been updated to current specifications and integrated and
harmonized across all parts.
A list of all parts in the ISO 5840 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/ members .html.
© ISO 2021 – All rights reserved v

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

Introduction
This document has been prepared for transcatheter heart valve substitutes with emphasis on providing
guidance for in vitro testing, preclinical in vivo and clinical evaluations, reporting of all in vitro,
preclinical in vivo, and clinical evaluations and labelling and packaging of the device. This process is
intended to clarify the required procedures prior to market release and to enable prompt identification
and management of any subsequent issues.
This document is used in conjunction with ISO 5840-1 and ISO 5840-2.
vi © ISO 2021 – All rights reserved

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SIST EN ISO 5840-3:2021
INTERNATIONAL STANDARD ISO 5840-3:2021(E)
Cardiovascular implants — Cardiac valve prostheses —
Part 3:
Heart valve substitutes implanted by transcatheter
techniques
1 Scope
This document is applicable to all devices intended for implantation as a transcatheter heart valve
substitute.
This document is applicable to transcatheter heart valve substitutes and to the accessory devices,
packaging and labelling required for their implantation and for determining the appropriate size of
heart valve substitute to be implanted.
This document establishes an approach for verifying/validating the design and manufacture of
a transcatheter heart valve substitute through risk management. The selection of appropriate
verification/validation tests and methods are to be derived from the risk assessment. The tests can
include those to assess the physical, chemical, biological and mechanical properties of heart valve
substitutes and of their materials and components. The tests can also include those for preclinical in
vivo evaluation and clinical evaluation of the finished heart valve substitute.
This document defines operational conditions and performance requirements for transcatheter heart
valve substitutes where adequate scientific and/or clinical evidence exists for their justification.
This document includes considerations for implantation of a transcatheter heart valve substitute inside
a pre-existing prosthetic device (e.g. valve-in-valve and valve-in-ring configurations).
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 5840-1:2021, Cardiovascular implants — Cardiac valve prostheses — Part 1: General requirements
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice
ISO 14630, Non-active surgical implants — General requirements
ISO 14971, Medical devices — Application of risk management to medical devices
IEC 62366 (all parts), Medical devices — Application of usability engineering to medical devices
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 5840-1:2021 and the
following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
© ISO 2021 – All rights reserved 1

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

— IEC Electropedia: available at http:// www .electropedia .org/
3.1
acute assessment
intra-procedural and immediate post-procedural results used to assess in vivo safety and performance
Note 1 to entry: All animals entered into acute, short-term assessment will remain under general anaesthesia for
the duration of the study.
3.2
chronic assessment
long-term results following the procedure used to assess chronic in vivo safety and performance after
the animal has recovered from anaesthesia
Note 1 to entry: The endpoints and durations of these studies should be determined by risk analysis.
3.3
delivery approach
anatomical access used to deliver the implant to the implant site (e.g. transfemoral, transapical,
transseptal)
3.4
delivery system
catheter or other system used to deliver the implant to the implant site
3.5
device migration
detectable movement or displacement of the heart valve substitute from its original position within the
implant position and without device embolization
3.6
loading
crimping
process to affix or attach a transcatheter heart valve substitute onto a delivery device and collapse
the valve (i.e. reduce its diameter) for insertion via the delivery system (3.4) (e.g. catheter), performed
either during manufacture or in the clinic
3.7
neo-LVOT
neo-left ventricular outflow tract
region between native anterior mitral leaflet/ transcatheter mitral valve implantation (TMVI) and
septal wall, proximal to the aortic valve (see Figure 1)
2 © ISO 2021 – All rights reserved

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

Key
1 TMVI
2 native anterior mitral leaflet
3 neo-LVOT
4 septal wall
Figure 1 — Neo-LVOT formation behind a mitral leaflet
3.8
neo-sinus
region between implanted transcatheter aortic valve leaflet and native aortic leaflet/leaflet of existing
bioprosthetic valve (see Figure 2)
© ISO 2021 – All rights reserved 3

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

Key
1 transcatheter aortic valve implantation (TAVI) leaflet
2 native leaflet
3 neo-sinus
4 native sinus
a
The arrow indicates the direction of the forward flow.
Figure 2 — Neo-sinus formation behind an aortic leaflet
3.9
repositioning
change in implant position of a partially- or fully-deployed transcatheter heart valve substitute via a
transcatheter technique, possibly requiring full or partial recapturing of the device
3.10
retrieval
removal of a partially- or fully-deployed transcatheter heart valve substitute via a transcatheter
technique
3.11
transcatheter heart valve system
implantable transcatheter device, delivery system (3.4), accessories, packaging, labels and
instructions for use
3.12
valve-in-ring
implantation of a transcatheter heart valve substitute into a pre-existing annuloplasty ring
3.13
valve-in-valve
implantation of a transcatheter heart valve substitute into a pre-existing heart valve substitute
4 Abbreviations
For the purposes of this document, the following abbreviations apply.
4 © ISO 2021 – All rights reserved

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

AE adverse event
AWT accelerated wear testing
CIP clinical investigation plan
COF chronic outward force
CT computed tomography
ECG electrocardiogram
EOA effective orifice area
IFU instructions for use
LA left atrium
LAA left atrial appendage
LV left ventricle, left ventricular
LVOT left ventricular outflow tract
MRI magnetic resonance imaging
MR mitral regurgitation
PMCF post-market clinical follow-up
PVL paravalvular leakage
RMS root mean square
SAE serious adverse event
TAVI transcatheter aortic valve implantation [also known as transcatheter aortic valve
replacement (TAVR)]
TEE transoesophageal echo
TMVI transcatheter mitral valve implantation [also known as transcatheter mitral valve
replacement (TMVR)]
TTE transthoracic echo
ViV valve-in-valve
ViR valve-in-ring
5 Fundamental requirements
See ISO 5840-1:2021, Clause 5.
6 Device description
6.1 General
See ISO 5840-1:2021, 6.1.
© ISO 2021 – All rights reserved 5

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

6.2 Intended use
See ISO 5840-1:2021, 6.2.
6.3 Design inputs
6.3.1 Operational specifications
See ISO 5840-1:2021, 6.3.1.
6.3.2 Performance specifications
6.3.2.1 General
See ISO 5840-1:2021, 6.3.2 for general requirements. Specific transcatheter system requirements are
listed in 6.3.2.2 to 6.3.2.4. See Reference [18] for information relevant to TMVI.
6.3.2.2 Transcatheter heart valve system
The design attributes to meet the intended performance of the transcatheter heart valve system shall
take into account at least the following:
a) the visibility of the transcatheter heart valve system under fluoroscopy or other imaging modalities;
b) the deliverability and implantability in the target population.
6.3.2.3 Implantable device
The intended performance of the transcatheter heart valve substitute shall include, but not be limited
to the following:
a) the ability to be consistently, accurately and safely loaded onto the delivery system;
b) the ability to be consistently, accurately and safely deployed;
c) the ability to be safely retrieved and/or repositioned (if applicable);
d) the ability to ensure effective fixation or anchoring within the implant site;
e) the ability to maintain structural and functional integrity throughout the anticipated lifetime of
the device;
f) the ability to conform or interact with anatomical structures within the implant site (e.g. in the
aortic position, there is potential for interaction with the coronary ostia, the anterior mitral leaflet
and the conduction system; in the mitral position, there is potential for interaction with the aortic
root, LA, LAA, LVOT and the subvalvular apparatus);
g) the ability to conform or interact with previously implanted device (e.g. surgical valve, annuloplasty
ring, transcatheter valve, valve docking device), if applicable;
h) the ability to allow forward flow with an acceptably small mean pressure difference in all
anticipated configurations;
i) the ability to prevent retrograde flow with acceptably small regurgitation, including paravalvular
leakage;
j) the ability to resist migration and embolization;
k) the ability to avoid haemolysis;
l) the ability to resist thrombus formation;
6 © ISO 2021 – All rights reserved

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SIST EN ISO 5840-3:2021
ISO 5840-3:2021(E)

m) biocompatibility;
n) the ability to maintain its functionality and sterility for a reasonable shelf life prior to implantation;
o) reproducibility of function.
6.3.2.4 Delivery system
In addit
...

SLOVENSKI STANDARD
oSIST prEN ISO 5840-3:2019
01-marec-2019
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Cardiovascular implants - Cardiac valve prostheses - Part 3: Heart valve substitutes
implanted by transcatheter techniques (ISO/DIS 5840-3:2019)
Herz- und Gefäßimplantate - Herzklappenprothesen - Teil 3: Durch minimal-invasive
Methoden implantierter Herzklappenersatz (ISO/DIS 5840-3:2019)
Implants cardiovasculaires - Prothèses valvulaires - Partie 3: Valves cardiaques de
substitution implantées par des techniques transcathéter (ISO/DIS 5840-3:2019)
Ta slovenski standard je istoveten z: prEN ISO 5840-3
ICS:
11.040.40 Implantanti za kirurgijo, Implants for surgery,
protetiko in ortetiko prosthetics and orthotics
oSIST prEN ISO 5840-3:2019 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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oSIST prEN ISO 5840-3:2019

---------------------- Page: 2 ----------------------
oSIST prEN ISO 5840-3:2019
DRAFT INTERNATIONAL STANDARD
ISO/DIS 5840-3
ISO/TC 150/SC 2 Secretariat: ANSI
Voting begins on: Voting terminates on:
2019-01-14 2019-04-08
Cardiovascular implants — Cardiac valve prostheses —
Part 3:
Heart valve substitutes implanted by transcatheter
techniques
Implants cardiovasculaires — Prothèses valvulaires —
Partie 3: Valves cardiaques de substitution implantées par des techniques transcathéter
ICS: 11.040.40
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Contents
1 Scope .1
2 Normative references .1
3 Terms and definitions .2
4 Abbreviations .5
5 Fundamental requirements .6
6 Device description .6
6.1 General .6
6.2 Intended use .6
6.3 Design inputs .6
6.4 Design outputs .8
6.5 Design transfer (manufacturing verification/validation) .8
6.6 Risk management .8
7 Design verification and validation .8
7.1 General requirements .8
7.2 In vitro assessment .8
7.3 Preclinical in vivo evaluation . 14
7.4 Clinical investigations . 18
Annex A (informative) Examples of transcatheter heart valve substitutes, components and
delivery systems . 31
Annex B (informative) Description of the transcatheter heart valve system . 38
Annex C (informative) Transcatheter heart valve substitute hazard analysis example . 40
Annex D (informative) Guidelines for verification of hydrodynamic performance – Pulsatile
flow testing . 43
Annex E (informative) Guidelines for delivery system design and evaluation . 51
Annex F (informative)  Examples of design specific testing . 53
Annex G (informative) Preclinical in vivo evaluation . 55
Annex H (normative) Adverse event classification during clinical investigation . 58
Annex I (informative) Imaging protocol . 64
Annex J (informative) Multimodality Imaging of TAVI and TMVI Pre, Peri and Post-
Implantation Assessments – Examples . 66
Bibliography . 86
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Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO
collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any
patent rights identified during the development of the document will be in the Introduction and/or on
the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO's adherence to the WTO principles in the Technical Barriers
to Trade (TBT) see the following URL: Foreword - Supplementary information
The committee responsible for this document is ISO/TC 150, Implants for surgery, Subcommittee SC 2,
Cardiovascular implants and extracorporeal systems.
This second edition of ISO 5840-3 cancels and replaces the first edition (ISO 5840-3:2013), which has
been technically revised.
ISO 5840 consists of the following parts, under the general title Cardiovascular implants — Cardiac valve
prostheses:
— Part 1: General requirements
— Part 2: Surgically implanted heart valve substitutes
— Part 3: Heart valve substitutes implanted by transcatheter techniques
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Introduction
This part of ISO 5840 has been prepared for transcatheter heart valve substitutes with emphasis on
providing guidance for in vitro testing, preclinical in vivo and clinical evaluations, reporting of all in vitro,
preclinical in vivo, and clinical evaluations and labelling and packaging of the device. This process is
intended to clarify the required procedures prior to market release and to enable prompt identification
and management of any subsequent issues.
This part of ISO 5840 is to be used in conjunction with ISO 5840 parts 1 and 2.

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Cardiovascular implants — Cardiac valve prostheses —
Part 3:
Heart valve substitutes implanted by transcatheter techniques
1 Scope
This part of ISO 5840 is applicable to all devices intended for implantation as a transcatheter heart valve
substitute (see Annex A for examples).
This part of ISO 5840 is applicable to both newly developed and modified transcatheter heart valve
substitutes and to the accessory devices, packaging and labelling required for their implantation and for
determining the appropriate size of heart valve substitute to be implanted.
This part of ISO 5840 outlines an approach for verifying/validating the design and manufacture of a
transcatheter heart valve substitute through risk management. The selection of appropriate
verification/validation tests and methods are to be derived from the risk assessment. The tests may
include those to assess the physical, chemical, biological and mechanical properties of heart valve
substitutes and of their materials and components. The tests can also include those for preclinical in vivo
evaluation and clinical evaluation of the finished heart valve substitute.
This part of ISO 5840 defines operational conditions and performance requirements for transcatheter
heart valve substitutes where adequate scientific and/or clinical evidence exists for their justification.
This part of ISO 5840 includes considerations for implantation of a transcatheter heart valve substitute
inside a pre-existing prosthetic device (e.g. valve-in-valve and valve-in-ring configurations).

2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ASTM F2079-09 Standard Test Method for Measuring Intrinsic Elastic Recoil of Balloon-Expandable
Stents
ISO 5840-1, Cardiovascular implants – Cardiac valve prostheses – Part 1: General requirements
ISO 5840-2, Cardiovascular implants – Cardiac valve prostheses – Part 2: Surgically implanted heart valve
substitutes
ISO 10555-1, Sterile, single-use intravascular catheters — Part 1: General requirements
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
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ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice
ISO 14630, Non-active surgical implants — General requirements
ISO 14971, Medical devices — Application of risk management to medical devices
ISO 25539-1, Cardiovascular implants — Endovascular devices — Part 1: Endovascular prostheses
IEC 60601, Medical electrical equipment - Part 1: General requirements for basic safety and essential
performance
IEC 62366, Medical devices — Application of usability engineering to medical devices
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 5840-1 and the following apply.
3.1
area-derived valve diameter
A
R
calculated valve diameter based on area of the implanted device (e.g. a “D-Shaped” transcatheter mitral
valve implantation (TMVI) device; see Figure 1)

NOTE 1 to entry: This approach is typically used for sizing TMVI devices where valves are designed for a non-
circular geometry.

Figure 1 — Area-derived valve diameter for a non-circular device

3.2
delivery approach
anatomical access used to deliver the implant to the implant site (e.g. transfemoral, transapical,
transseptal)
3.3
delivery system
catheter or other system used to deliver the implant to the implant site
3.4
implant loading
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process to affix or attach a transcatheter heart valve substitute onto a delivery device and collapse the
valve (e.g. reduce its diameter) for insertion via the delivery system (e.g. catheter), performed either
during manufacture or in the clinic
3.5
neo-LVOT
region between native anterior mitral leaflet/TMVI and septal wall, proximal to the aortic valve (see
Figure 2)


Figure 2 — Neo-LVOT formation behind a mitral leaflet

3.6
neo-sinus
region between implanted transcatheter aortic valve leaflet and native aortic leaflet/leaflet of existing
bioprosthetic valve (see Figure 3)

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Figure 3 — Neo-sinus formation behind an aortic leaflet

3.7
perimeter derived valve diameter
calculated valve diameter (mm) based on perimeter of the implanted device

Note to entry: this approach is typically used for sizing transcatheter aortic valve implantation (TAVI) devices where
valves are designed in circular geometries.

3.8
repositioning
change in implant position of a partially or fully deployed transcatheter heart valve substitute via a
transcatheter technique, possibly requiring full or partial recapturing of the device
3.9
retrieval
removal of a partially or fully deployed transcatheter heart valve substitute via a transcatheter technique
3.10
transcatheter heart valve system
implantable transcatheter device, delivery system, accessories, packaging, labels and instructions for use
3.11
valve-in-ring
implantation of a transcatheter heart valve substitute into a pre-existing annuloplasty ring
3.12
valve-in-valve
implantation of a transcatheter heart valve substitute into a pre-existing heart valve substitute

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4 Abbreviations
For the purposes of this part of ISO 5840, the following abbreviations apply.
AE Adverse Event
AWT Accelerated Wear Testing
CIP Clinical Investigation Plan
CT Computed Tomography
ECG Electrocardiogram
EOA Effective Orifice Area
IFU Instructions For Use
LA Left Atrium
LAA Left Atrial Appendage
LV Left Ventricle, Left Ventricular
LVOT Left Ventricular Outflow Tract
MRI Magnetic Resonance Imaging
MR Mitral Regurgitation
PVL Paravalvular Leakage
SAE Serious Adverse Event
TAVI Transcatheter Aortic Valve Implantation [also known as Transcatheter Aortic Valve
Replacement (TAVR)]
TEE Transoesophageal Echo
TMVI Transcatheter Mitral Valve Implantation [also known as Transcatheter Mitral Valve
Replacement (TMVR)]
TTE Transthoracic Echo
ViV Valve-in-Valve
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ViR Valve-in-Ring
5 Fundamental requirements
Refer to ISO 5840-1.
6 Device description
6.1 General
Refer to ISO 5840-1.
6.2 Intended use
Refer to ISO 5840-1.
6.3 Design inputs
6.3.1 Operational specifications
Refer to ISO 5840-1.
6.3.2 Performance specifications
6.3.2.1 General
Refer to ISO 5840-1 for general requirements. Specific transcatheter system requirements are listed in
6.3.2.2-6.3.2.4.
6.3.2.2 Transcatheter heart valve system
The design attributes to meet the intended performance of the transcatheter heart valve system shall
take into account at least the following:
a) the visibility of the transcatheter heart valve system under fluoroscopy or other imaging modalities;
b) the deliverability and implantability in the target population.
6.3.2.3 Implantable device
The intended performance of the transcatheter heart valve substitute shall include, but not be limited to
the following:
a) the ability to be consistently, accurately and safely loaded onto the delivery system;
b) the ability to be consistently, accurately and safely deployed;
c) the ability to be safely retrieved and/or repositioned (if applicable);
d) the ability to ensure effective fixation or anchoring within the implant site;
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e) the ability to maintain structural and functional integrity;
f) the ability to conform or interact with anatomical structures within the implant site (e.g. in the aortic
position, there is potential for interaction with coronary ostia, anterior mitral leaflet, AV node; in the
mitral position, there is potential for interaction with the aortic root, LA, LAA, LVOT and the
subvalvular apparatus);
g) the ability to conform or interact with previously implanted device (e.g. surgical valve, annuloplasty
ring, transcatheter valve, valve docking device), if applicable;
h) the ability to allow forward flow with acceptably small mean pressure difference in all anticipated
configurations;
i) the ability to prevent retrograde flow with acceptably small regurgitation, including paravalvular
leakage;
j) the ability to resist migration and embolization;
k) avoid haemolysis;
l) the ability to resist thrombus formation;
m) biocompatible;
n) maintains its functionality and sterility for a reasonable shelf life prior to implantation;
o) has reproducible function.
6.3.2.4 Delivery system
The design attributes to meet the intended performance of the delivery system shall include, but not be
limited to the following:
a) the ability to permit consistent, accurate and safe access, delivery, placement and deployment of the
transcatheter heart valve substitute to the intended implant site;
b) the ability to permit consistent and safe withdrawal;
c) the ability to resist haemolysis;
d) the ability to resist thrombus formation;
e) the ability to resist blood loss (haemostasis);
f) the ability to recapture, retrieve, reposition and/or remove the transcatheter heart valve substitute
(if applicable);
g) the ability to resist particulate generation.
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6.3.3 Implant procedure
Refer to ISO 5840-1.
6.3.4 Packaging, labelling and sterilization
Refer to ISO 5840-1.
The manufacturer shall provide information and guidance (e.g. imaging modalities and sizing procedure)
in the labelling to allow for appropriate preparation of the implant site (e.g. balloon valvuloplasty),
selection of appropriate implant size and implantation of the transcatheter heart valve substitute. The
manufacturer shall also provide MRI compatibility information in the labeling.
Annex B of this document contains a listing of terms that may be used in describing transcatheter heart
valve system components.
6.4 Design outputs
Refer to ISO 5840-1.
6.5 Design transfer (manufacturing verification/validation)
Refer to ISO 5840-1.
6.6 Risk management
Refer to ISO 5840-1.
Annex C of this document contains a hazard analysis example specific to transcatheter heart valve
substitutes that can serve as the basis for a risk analysis.
7 Design verification and validation
7.1 General requirements
In vitro assessment shall be used to mitigate the risks identified in the risk analysis. General requirements
that are applicable to all heart valve systems are provided in ISO 5840-1. Specific considerations for
transcatheter heart valve substitutes are provided in this part of ISO 5840.
7.2  In vitro assessment
7.2.1 General
Refer to ISO 5840-1.
7.2.2 Test conditions, sample selection and reporting requirements
Refer to ISO 5840-1.
For transcatheter valves, the steps of crimping or loading the implant into/onto a delivery catheter,
tracking through simulated delivery pathways, and maintaining the implant in the crimped
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configuration for a duration that mimics the worst-case clinical procedure time shall be followed in
accordance with the IFU. If retrieval and repositioning is indicated for the implant in the IFU, the
maximum allowable number of resheathing/recapturing and deployment cycles specified shall be
simulated. Any deviations of the test articles from the finished device shall be justified. The test articles
selected shall fully represent the total size range of the implant, the delivery system and accessories.
7.2.3 Material property assessment
7.2.3.1 General
Refer to ISO 5840-1.
7.2.3.2 Biological safety
Refer to ISO 5840-1.
7.2.3.3 Material and mechanical property testing
Refer to ISO 5840-1.
For ViV and ViR indications, consideration shall be given to the material properties of the existing
prosthesis, including bioprosthetic valve leaflet calcification, and their interactions with the materials of
the transcatheter heart valve system.
7.2.4 Device hydrodynamic performance assessment
Hydrodynamic testing shall be performed to provide information on the fluid mechanical performance of
the transcatheter heart valve substitute. The implant shall be deployed using the loading and deployment
steps in accordance with the product specification and appropriately placed into the test chamber to
simulate the device placement at the intended implant site. The device shall be inspected after loading,
recapturing and/or deployment prior to fixturing and testing. Annex I of ISO 5840-1 provides guidelines
for conducting and reporting steady hydrodynamic tests. Guidelines for conducting and reporting of
pulsatile hydrodynamic tests are provided in Annex D. For pulsatile flow testing, the performance of the
pulse duplicator shall be characterized by means of testing a commercially available reference valve(s)
in the valve position(s) to be evaluated (e.g. aortic and/or mitral). The measurement accuracy and
repeatability of the test system(s) shall be evaluated and documented. The hydrodynamic waveforms
produced by the pulse duplicator shall reasonably simulate physiological conditions. Representative
waveforms used to generate hydrodynamic test results shall be documented in the test report. Reference
[15] provides characteristics of reasonable aortic and mitral waveforms.
For transcatheter aortic valve substitutes, testing shall be performed to compare the device
hydrodynamic performance to the minimum performance requirements provided in Table 1. Guidelines
for designing test fixtures and test parameters are provided in Annex D, D.2.4. Testing shall be carried
out on at least three transcatheter heart valve substitutes of each size in each configuration using
requirements defined in Table D.2. The minimum performance requirements in Table 1 are provided as
a function of perimeter derived valve diameter (in mm). In addition, testing at challenge conditions shall
also be considered to evaluate the device performance over a range of anticipated implant configurations
(see Annex D, D.2.4 for examples of challenge conditions for transcatheter aortic valve substitutes).
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For transcatheter mitral valve substitutes, testing shall be performed to compare the device
hydrodynamic performance to the minimum performance requirements provided in Table 2. Guidelines
for designing test fixtures and test parameters are provided in Annex D, D.2.5. Testing shall be carried
out on at least three transcatheter heart valve substitutes of each size in each configuration using
requirements defined in Table D.3. The minimum performance requirements in Table 2 are provided as
a function of area-derived valve diameter (in mm).
For ViV and ViR indications, hydrodynamic testing shall be conducted in representative configurations of
the pre-existing prosthetic devices to compare the device hydrodynamic performance to the minimum
performance requirements provided in Tables 1 and 2.
The minimum performance values contained in Tables 1 and 2 reflect requirements against which heart
valves substitutes under test shall be evaluated. If a device does not meet these minimum performance
requirements, acceptability of the in vitro test results shall be justified by the manufacturer.

The minimum in vitro performance requirements in Tables 1 and 2 correspond to the following pulsatile
flow conditions: beat rate = 70 cycles/min, simulated cardiac output = 5,0 l/min, mean aortic
pressure = 100 mmHg, and systolic duration = 35 %. These pulsatile flow conditions are based on a
healthy normal adult and might not be applicable for paediatric device evaluation (see Annex E in ISO
5840-1 for paediatric parameters).
Table 1 — Minimum in vitro hydrodynamic device performance requirements, aortic
Deployed valve diameter within implant site (mm)
Parameter
17 19 21 23 25 27 29 31
2
EOA (cm ) greater than or equal to 0,70 0,85 1,05 1,25 1,45 1,70 1,95 2,25
Regurgitant fraction (% of forward
20
flow volume) less than or equal to*
* For in vitro testing, regurgitant fraction includes closing volume, transvalvular leakage and paravalvular leakage.

Table 2 —Minimum in vitro hydrodynamic device performance requirements, mitral
Deployed area-derived valve diameter (orifice) within
implant site (mm)
Parameter
≥ 33
23 25 27 29 31
2
EOA (cm ) greater than or equal 1,05 1,25 1,45 1,65 1,90 2,15
to*
Regurgitant fraction (% of forward
flow volume) less than or equal 20
to**
* NOTE For measured mean pressure gradients ≤2mmHg, computing of EOA is not required.
** For in vitro testing, regurgitant fraction includes closing volume, transvalvular leakage and paravalvular leakage.

For transcatheter pulmonary and tricuspid valve substitutes, minimum performance requirements are
not provided in this standard; however, the manufacturer shall justify the acceptability of hydrodynamic
performance of the devices. The test chamber shall be representative of the critical aspects of the target
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implant site (e.g. compliance, geometry, native valve or pre-existing prosthetic device) for the target
patient population.
For all transcatheter valve substitutes, additional hydrodynamic characterization testing shall be
conducted over a range of test conditions as described in Annex D.
...