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

Status
Withdrawn
Publication Date
20-Nov-2017
Current Stage
9599 - Withdrawal of International Standard
Completion Date
07-Jul-2022
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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
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ISO/TR 12417-2:2017(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2017, Published in Switzerland

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ii © ISO 2017 – All rights reserved
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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
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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
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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
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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
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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

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.
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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
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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.
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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.
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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.
...

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