ISO/TR 12417-2:2017
(Main)Cardiovascular implants and extracorporeal systems — Vascular device-drug combination products — Part 2: Local regulatory information
Cardiovascular implants and extracorporeal systems — Vascular device-drug combination products — Part 2: Local regulatory information
ISO/TR 12417-2:2017 provides region-specific information for - local submissions and approvals for vascular device-drug combination products (VDDCPs) in countries and regions around the world; - changes related to the drug containing part and how they are evaluated by the different local regions. For implanted products, this document is considered as a supplement to ISO 14630, which specifies general requirements for the performance of non-active surgical implants. ISO/TR 12417-2:2017 is considered also as a supplement to ISO 12417‑1, and any relevant device-specific standards, such as the ISO 25539 series specifying requirements for endovascular devices. Requirements listed in this document also address VDDCPs that are not necessarily permanent implants.
Implants cardiovasculaires et circuits extra-corporels — Produits de combinaison médicament-dispositif vasculaire — Partie 2: Directives règlementaires locales
General Information
Relations
Standards Content (Sample)
TECHNICAL ISO/TR
REPORT 12417-2
First edition
2017-11
Cardiovascular implants and
extracorporeal systems — Vascular
device-drug combination products —
Part 2:
Local regulatory information
Implants cardiovasculaires et circuits extra-corporels — Produits de
combinaison médicament-dispositif vasculaire —
Partie 2: Directives règlementaires locales
Reference number
ISO/TR 12417-2:2017(E)
©
ISO 2017
---------------------- Page: 1 ----------------------
ISO/TR 12417-2:2017(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2017, Published in Switzerland
All rights reserved. Unless otherwise specified, 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
Ch. de Blandonnet 8 • CP 401
CH-1214 Vernier, Geneva, Switzerland
Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
www.iso.org
ii © ISO 2017 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/TR 12417-2:2017(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Information on device- and drug-related aspects — Applicable documents for
local guidance . 4
4.1 Australia . 4
4.1.1 Australia: managing changes. 4
4.1.2 Australia: clinical evaluation requirements. 5
4.1.3 Australia: audit requirements . 5
4.2 Brazil . 5
4.2.1 Brazil: managing changes . . 5
4.2.2 Brazil: clinical evaluation requirements . 6
4.2.3 Brazil: audit requirements . 6
4.3 Canada . 6
4.3.1 Canada: managing changes . 6
4.3.2 Canada: clinical evaluation requirements . 6
4.3.3 Canada: audit requirements . . 6
4.4 European Union (EU) . 6
4.4.1 EU: managing changes . 6
4.4.2 EU: clinical evaluation requirements . 7
4.4.3 EU: audit requirements . 7
4.5 India . 7
4.5.1 India: managing changes . 7
4.5.2 India: clinical evaluation requirements . 8
4.5.3 India: audit requirements . 8
4.6 Japan . 8
4.6.1 Japan: managing changes . 8
4.6.2 Japan: clinical evaluation requirements . 8
4.6.3 Japan: audit requirements . 8
4.7 People's Republic of China (PRC) . 8
4.7.1 PRC: managing changes . 8
4.7.2 PRC: clinical evaluation requirements . 9
4.7.3 PRC: audit requirements .10
4.8 Russia .10
4.8.1 Russia: managing changes .10
4.8.2 Russia: clinical evaluation requirements .10
4.8.3 Russia: audit requirements .10
4.9 United States of America (USA) .10
4.9.1 USA: managing changes .10
4.9.2 USA: clinical evaluation requirements .11
4.9.3 USA: audit requirements .12
5 Managing changes that can impact the DCP .12
5.1 Introduction .12
5.2 Change evaluation .12
5.2.1 Identify changes .12
5.2.2 Risk evaluation .13
5.2.3 Guidance for change evaluation .14
5.2.4 Pre-market (during submission) .14
5.3 Interactions with region-specific regulatory authorities – post commercialization .14
Bibliography .23
© ISO 2017 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO/TR 12417-2:2017(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 on 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 the following
URL: 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.
A list of all parts in the ISO 12417- series can be found on the ISO website.
iv © ISO 2017 – All rights reserved
---------------------- Page: 4 ----------------------
ISO/TR 12417-2:2017(E)
Introduction
This document was prepared in order to provide local regulatory information for vascular device-drug
combination products (VDDCPs).
VDDCPs are medical devices with various clinical indications for use in the human vascular blood
system. A VDDCP incorporates, as an integral part, substance(s) which, if in final formulation separately,
can be considered to be a medicinal product (drug product) but the action of the medicinal substance is
ancillary to that of the device and supports the primary mode of action of the device.
Only regulatory issues related to drug(s) combined with the vascular device based on the ancillary
function of the VDDCP are covered by this Technical Report.
Although this document attempts to represent the state-of-the-art regarding regulatory requirements
for pre/post-approval changes, these requirements are evolving and as such, it is strongly suggested
that the applicant consult with the regulatory authority under which whose jurisdiction the VDDCP
falls. This is most easily done by accessing the local authorities’ current webpage.
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
NOTE For issues related to the primary mode of action of the vascular device, the reader might find it useful
to consider a number of other International Standards (see Bibliography).
© ISO 2017 – All rights reserved v
---------------------- Page: 5 ----------------------
TECHNICAL REPORT ISO/TR 12417-2:2017(E)
Cardiovascular implants and extracorporeal systems —
Vascular device-drug combination products —
Part 2:
Local regulatory information
1 Scope
This document provides region-specific information for
— local submissions and approvals for vascular device-drug combination products (VDDCPs) in
countries and regions around the world;
— changes related to the drug containing part and how they are evaluated by the different local
regions.
For implanted products, this document is considered as a supplement to ISO 14630, which specifies
general requirements for the performance of non-active surgical implants.
This document is considered also as a supplement to ISO 12417-1, and any relevant device-specific
standards, such as the ISO 25539 series specifying requirements for endovascular devices. Requirements
listed in this document also address VDDCPs that are not necessarily permanent implants.
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 12417-1, Cardiovascular implants and extracorporeal systems — Vascular device-drug combination
products — Part 1: General requirements
ISO 14630, Non-active surgical implants — General requirements
3 Terms and definitions
For the purposes of this document, the terms and definitions given in in ISO 12417-1, ISO 14630 and the
following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http://www.electropedia.org/
— ISO Online browsing platform: available at https://www.iso.org/obp
NOTE Potential clinical events are defined in Annex A of ISO 12417-1.
3.1
active pharmaceutical ingredient
API
drug substance
pharmacologically active (drug or medicinal) substance used as a raw material, which is coated on,
bound to or incorporated into the device to achieve an ancillary device function, such as minimizing
vascular restenosis
© ISO 2017 – All rights reserved 1
---------------------- Page: 6 ----------------------
ISO/TR 12417-2:2017(E)
3.2
batch
quantity of VDDCP at the final stage or pre-final stage of manufacture which is manufactured according
to a single manufacturing order and has undergone the same manufacturing cycle, using the same
components (e.g. same coating solution, same device size), and meets the same specifications
Note 1 to entry: Validation testing can be conducted to demonstrate that manufacturing variables do not
impact specifications such as drug content or drug release, and thereby permit such manufacturing variables
within a batch.
3.3
change
alteration to an activity to improve or maintain the composition or performance of a VDDCP
Note 1 to entry: This include small alterations to a VDDCP, a manufacturing process, or a test procedure, even
if it is not necessarily captured by a Corrective Action/Preventative Action (CAPA) system, and may require
reporting to local regional authorities
3.4
clinical event
complication, failure or device-related observation that might be observed with clinical use of a VDDCP
Note 1 to entry: Such events might not have clinical significance and might not be attributable to the VDDCP.
3.5
critical component
component whose specifications, if not met, could result in unacceptable risk to the patient, clinician or
others, or could have a significant impact on performance
3.6
device part of the VDDCP
DP
part of the VDDCP intended to treat vascular disease by temporary or long-term intervention
or implantation that does not achieve its principal intended action in or on the human body by
pharmacological, immunological or metabolic means, but might be assisted in its function by such means
3.7
drug product
medicinal product
active pharmaceutical ingredient, in its final formulation for administration to the patient (e.g. tablet,
solution, spray), that is intended to prevent, diagnose, or treat disease and that achieves its principle
intended action in or on the human body by pharmacological, immunological, or metabolic means
3.8
drug-containing part of the VDDCP
DCP
part of the VDDCP that consists of the active pharmaceutical ingredient or matrix and associated device
interfaces intended to assist in the primary mode of action of the device and/or diminish or ameliorate
an unintended effect that placement of the device part might stimulate
Note 1 to entry: Some VDDCPs have medicinal substance(s) bound with the primary intent to optimize the
surface properties of the device.
3.9
DCP interface
common boundary or interconnection between the various components of the device part(s) and the
drug-containing part(s) of a VDDCP
EXAMPLE The interface between the matrix containing the active pharmaceutical ingredient and packaging
materials with direct DCP contact, the device surface(s), the interface between the matrix and the active
pharmaceutical ingredient.
2 © ISO 2017 – All rights reserved
---------------------- Page: 7 ----------------------
ISO/TR 12417-2:2017(E)
3.10
drug content
total labelled amount of active pharmaceutical ingredient in a VDDCP
Note 1 to entry: Drug content could be expressed as µg/DCP of a certain size.
3.11
drug delivery
local interaction between the VDDCP drug and the in vivo environment, whether the drug is released
from, eluted from or remains bound to the VDDCP
3.12
drug release profile
in vitro characterization of the active pharmaceutical ingredient released from the DCP of a VDDCP
over time
Note 1 to entry: For example, the drug release might be characterized by a drug elution test, and could include a
curve shape (or profile), a drug release rate, or both.
3.13
efficacy
ability of the VDDCP to achieve the planned and desired physiological result
3.14
evaluate
appraise or analyse qualitatively
3.15
excipient
additional material, other than the API, that are intentional components of the drug-containing part
of a VDDCP
EXAMPLE Filler, extender, diluent, wetting agent, solvent, colorant, stabilizer, antioxidant, preservative, pH
maintainer, polymers, adhesives.
3.16
functionality
ability of the VDDCP to perform physically, chemically and/or mechanically, as designed
Note 1 to entry: Functionality does not include the physiological response to the VDDCP (i.e. efficacy).
3.17
matrix
organic or inorganic material, other than living cells, intentionally applied by a manufacturer to a
vascular device and designed for the purpose of drug storage, local drug activity at the surface and/or
enabling, retarding, delaying or modifying drug release
Note 1 to entry: The matrix can be permanent or temporary (dissolvable, absorbable or degradable); include
surface treatments such as primers; be a coating with or without an active pharmaceutical ingredient, or consist
of multiple excipients and/or multiple active pharmaceutical ingredients.
3.18
mode of action
means by which a product achieves an intended therapeutic effect or action
3.19
pharmacokinetics
absorption, distribution, metabolism and elimination of a drug in vivo
© ISO 2017 – All rights reserved 3
---------------------- Page: 8 ----------------------
ISO/TR 12417-2:2017(E)
3.20
primary mode of action
single mode of action of a combination product that provides the most important therapeutic action
of the combination product. The most important therapeutic action is the mode of action expected to
make the greatest contribution to the overall intended therapeutic effects of the combination product
Note 1 to entry: Additional guidance on the drug-related aspects of the drug-containing part of the VDDCP can be
found in International Conference on Harmonization Guideline IC H Q1A.
3.21
uniformity of drug content
comparison of the uniformity of the drug content between individual VDDCPs within each batch as
compared to the labelled claim
3.22
vascular device-drug combination product
VDDCP
vascular medical device (primary mode of action) that incorporates one or more active pharmaceutical
ingredients as an integral part (ancillary mode of action)
Note 1 to entry: The VDDCP can be permanently deployed (i.e. it can be an implant like a drug-eluting stent) or
temporarily deployed (i.e. it can be a drug-eluting balloon, for instance).
3.23
VDDCP specification
required list of test procedures and appropriate acceptance criteria which are numerical limits, ranges
or other criteria for the tests described
Note 1 to entry: A specification is a critical quality standard. It establishes the set of criteria to which a VDDCP
has to conform.
Note 2 to entry: Additional guidance on the drug-related aspects of the drug-containing part of the VDDCP can be
found in International Conference on Harmonization Guideline IC H Q6A.
4 Information on device- and drug-related aspects — Applicable documents for
local guidance
4.1 Australia
The following region-specific information identifies the regional regulatory authorities responsible for
VDDCPs, and provides general clinical evaluation and audit requirements for VDDCPs.
NOTE 1 Region-specific requirements might deviate from harmonized International Standards.
NOTE 2 As of the publication of this document, the following information is believed to be accurate and can
change over time. Always seek current guidance directly from the regulatory authorities in the region of interest
for up to date requirements
VDDCPs must be approved by the Department of Health through the Therapeutic Goods
Administration (TGA).
NOTE For more information, see Therapeutics Goods Administration website and for Australian regulatory
guidelines for medical devices, (ARGMD) Part 2–Pre-market Section 14. Medical devices incorporating a medicine.
4.1.1 Australia: managing changes
See website of the local authority above for the responsibilities of deciding whether a submission or
change notification is required.
4 © ISO 2017 – All rights reserved
---------------------- Page: 9 ----------------------
ISO/TR 12417-2:2017(E)
It is the responsibility of the manufacturer to decide if a submission or change notification is required.
This information is then communicated to the TGA by the Australian sponsor.
See also Table B.1 for managing changes that can impact the DCP.
4.1.2 Australia: clinical evaluation requirements
VDDCPs will require a clinical study (but it need not be a local study). If the study is conducted in
Australia, an exemption must be granted by TGA prior to initiation of the study which allows products
not included on the Australian Register of Therapeutic Goods to be supplied as part of the clinical trial.
NOTE The TGA has two pathways in Australia for clinical trials – Clinical Trial Notification (CTN) which
involves a notification to the TGA and Clinical Trial Exemption (CTX) which requires a formal approval from
the TGA. The CTX is generally for studies where the experimental device introduces a new technology, a new
material or a new concept or for trials that are considered high risk.
4.1.3 Australia: audit requirements
An appropriate quality system audit can be required prior to market approval.
NOTE For more information, see the Australian regulatory guidances for medical devices (ARGMD) on the
Therapeutics Goods Administration website.
4.2 Brazil
4.2.1 Brazil: managing changes
VDDCPs must be approved by the National Health Surveillance Agency (ANVISA). In Brazil, medical
devices are regulated by
1) the national law ”Lei 6360/1976” which regulates drugs, medical devices, cosmetics and other
sanitary products;
2) the decree ”Decreto 79094/1977” which regulates the law ”Lei 6360/1976” and the ANVISA Board
Collegiate Resolutions;
— RDC 185/2001 for the Registration,post-market changes, revalidation and cancellation of
registration of medical devices in the Brazilian Health Surveillance Agency;
— RDC 14/2011 for Establishing the technical regulations with requirements for grouping of
medical device.
NOTE For more information, see the ANVISA website
More guidance for non-active medical device registration will be given in:
“Agência Brasileira de Desenvolvimento Industrial. Manual de registro e cadastramento de materiais
de uso em saúde / ABDI. Brasília: ABDI, 2011. 306 p.”
ANVISA expects APIs must be in compliance with the Brazilian Pharmacopoeia (or other specified
compendia).
The pharmaceutical products, medicines and other products subject to sanitary surveillance are
expected to meet the standards and specifications established in the Brazilian Pharmacopoeia (see
ANVISA website)
In the absence of an official Brazilian monograph, use of a foreign official monograph is allowed. This is
regulated by the “Resolution of the Directory Collegiate (RDC) Nº 49, November 23th, 2010”
See website of the local authority above for the responsibilities of deciding whether a submission or
change notification is required.
© ISO 2017 – All rights reserved 5
---------------------- Page: 10 ----------------------
ISO/TR 12417-2:2017(E)
See also Table B.1 for managing changes that can impact the DCP.
4.2.2 Brazil: clinical evaluation requirements
VDDCPs will require a clinical study (but it need not be a local study) according RDC 56/2001. If the
study is conducted in Brazil, the clinical study protocol needs to be approved, prior to initiation of the
study, by ANVISA according RDC 39/2008. The final report for the study primary end point(s) is to be
completed prior to submission to ANVISA.
4.2.3 Brazil: audit requirements
A manufacturing audit is required prior to market approval. The manufacturing site must be certified
under RDC 59/2000 (Brazil quality system requirement) prior to submitting the product to ANVISA for
registration. An audit can be required prior to market approval if the product is not within the current
scope of the corresponding quality assurance system approval certificate.
The RDC 59/2000 certificate must be presented together with the submission dossier.
4.3 Canada
4.3.1 Canada: managing changes
VDDCPs must be approved by Health Canada.
NOTE For more information, see Health Canada website http://www.hc-sc.gc.ca
See website of the local authority above for the responsibilities of deciding whether a submission or
change notification is required.
It is the responsibility of the Health Canada to decide if a submission or change notification is required,
based on information provided by the manufacturer.
See also Table B.1 for managing changes that can impact the DCP.
4.3.2 Canada: clinical evaluation requirements
VDDCPs will require a clinical study (but it need not be a local study). It is recommended that a pre-CTA
submission be scheduled with Health Canada (see website for Pre-CTA details). If the study is conducted
in Canada, the clinical study protocol needs to be approved by Health Canada prior to initiation of the
study per the Clinical Trial Application (CTA) process (see Health Canada website for more information
of the CTA process).
4.3.3 Canada: audit requirements
An audit can be required prior to market approval if the product is not within the current scope of the
corresponding quality assurance system approval certificate.
4.4 European Union (EU)
4.4.1 EU: managing changes
VDDCPs must be assessed for conformity by a Notified Body before approval as medical devices according
to Medical Device Directive 93/42/EC.
...
Questions, Comments and Discussion
Ask us and Technical Secretary will try to provide an answer. You can facilitate discussion about the standard in here.