ISO/TR 12417-2:2022

TECHNICAL ISO/TR
REPORT 12417-2
Second edition
2022-07
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 2022
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ii
Contents Page
Foreword .v
Introduction . vi
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 General . 4
4.2 Australia . 4
4.2.1 General . 4
4.2.2 Australia: Managing changes . 5
4.2.3 Australia: Clinical evaluation requirements . 5
4.2.4 Australia: Audit requirements . 5
4.3 Brazil . 5
4.3.1 Brazil: Managing changes . 5
4.3.2 Brazil: Clinical evaluation requirements . 6
4.3.3 Brazil: Audit requirements. 6
4.4 Canada . 6
4.4.1 Canada: Managing changes . 6
4.4.2 Canada: Clinical evaluation requirements . 6
4.4.3 Canada: Audit requirements . 6
4.5 European Union (EU). 6
4.5.1 EU: Managing changes . 6
4.5.2 EU: Material inclusion and labelling requirements . 7
4.5.3 EU: Clinical evaluation requirements . 7
4.5.4 EU: Audit requirements . 7
4.6 India . 7
4.6.1 India: Managing changes . . 7
4.6.2 India: Clinical evaluation requirements . 8
4.6.3 India: Audit requirements . 8
4.7 Japan . 8
4.7.1 Japan: Managing changes. 8
4.7.2 Japan: Clinical evaluation requirements . 8
4.7.3 Japan: Audit requirements . 8
4.8 People's Republic of China (PRC) . 8
4.8.1 PRC: Managing changes . . 8
4.8.2 PRC: Clinical evaluation requirements . 9
4.8.3 PRC: Audit requirements . 10
4.9 Russia . 10
4.9.1 Russia: Managing changes . 10
4.9.2 Russia: Clinical evaluation requirements . 10
4.9.3 Russia: Audit requirements . 10
4.10 United States of America (USA) . 10
4.10.1 USA: Managing changes . 10
4.10.2 USA: Clinical evaluation requirements. 11
4.10.3 USA: Audit requirements . 11
5 Managing changes that can impact the DCP .12
5.1 General .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 . 13
iii
5.2.4 Pre-market . 14
5.3 Interactions with region-specific regulatory authorities — Post-commercialization . 14
Bibliography .22
iv
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.
This second edition cancels and replaces the first edition (ISO/TR 12417-2:2017), which has been
technically revised.
The main changes are: editorial changes have been made regarding the use of requirements,
recommendations, permissions and possibilities.
A list of all parts in the ISO 12417 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.
v
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 document.
Although this document attempts to represent the state-of-the-art regarding regulatory requirements
for pre and 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 1 For issues related to the primary mode of action of the vascular device, the reader can find it useful to
consider a number of other International Standards given in the Bibliography.
NOTE 2 Potential clinical events are defined in ISO 12417-1:2015, Annex A.
vi
TECHNICAL REPORT ISO/TR 12417-2:2022(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 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. This
document also addresses 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 ISO 12417-1, ISO 14630 and the
following apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
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
3.2
batch
quantity of VDDCP at the final stage or pre-final stage of manufacture which has undergone the same
manufacturing cycle, using the same components (e.g. same coating solution, same device size), and
meets the same specifications
3.3
change
alteration to an activity or to the VDDCP to improve or to maintain the composition or performance of
a VDDCP
Note 1 to entry: This term includes 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 can require
reporting to local regional authorities.
3.4
clinical event
complication, failure or device-related observation that can be observed with clinical use of a VDDCP
Note 1 to entry: Such events can possibly not have clinical significance and can possibly not be attributable to the
VDDCP.
3.5
critical component
component whose specifications, if not met, can result in unacceptable risk to the patient, clinician or
others, or can 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 PMOA in or on the human body by pharmacological,
immunological, or metabolic means, but can be assisted in its function by such means
3.7
drug product
medicinal product
API, in its final form for administration to the patient (e.g. tablet, solution, spray), that is intended to
prevent, diagnose or treat disease, and that achieves its principal intended action in or on the 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 can stimulate
Note 1 to entry: Some VDDCPs can have an incorporated medicinal or drug substance primarily intended to
optimize the DP properties of the VDDCP.
3.9
drug-containing part interface
DCP interface
interface between the matrix containing the API and packaging materials with direct DCP contact or
device surface(s), or interface between the matrix and the API
3.10
drug content
total labelled amount of active pharmaceutical ingredient in a VDDCP
Note 1 to entry: Drug content can 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 can be characterized by a drug elution test and can include either a
curve shape (or profile) or 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 either physically, chemically or mechanically, or all, 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
Note 1 to entry: This can be a primary or ancillary mode of action.
3.19
pharmacokinetics
absorption, distribution, metabolism and elimination of a drug in vivo
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
Note 1 to entry: 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 2 to entry: Additional guidance on the drug-related aspects of the drug-containing part of the VDDCP can be
[29]
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 that incorporates one or more APIs as an integral part (ancillary mode of
action) to that of the device, but not necessarily to the VDDCP PMOA
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).
3.23
vascular device-drug combination product specification
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
[37]
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 General
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 can deviate from harmonized International Standards.
NOTE 2 At the publication of this document, the following information is believed to be accurate and can
change over time. Current guidance can be directly obtained from the regulatory authorities in the region of
interest.
4.2 Australia
4.2.1 General
VDDCPs are approved by the department of health through the Therapeutic Goods Administration
(TGA).
NOTE For more information, see the Therapeutics Goods Administration website and for Australian
regulatory guidelines for medical devices, see Reference [136].
4.2.2 Australia: Managing changes
See the website of the local authority above for the responsibilities of deciding whether a submission or
change notification is subject to requirements.
It is the responsibility of the manufacturer to decide if a submission or change notification is subject to
requirements. This information is then communicated to the TGA by the Australian sponsor.
See also Table 2 for managing changes that can impact the DCP.
4.2.3 Australia: Clinical evaluation requirements
VDDCPs are subject to requirements for a clinical study (but it need not be a local study). If the study
is conducted in Australia, an exemption is 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.
4.2.4 Australia: Audit requirements
An appropriate quality system audit can be required prior to market approval.
[81]
NOTE For more information, see ARGMD on the Therapeutics Goods Administration website.
4.3 Brazil
4.3.1 Brazil: Managing changes
VDDCPs are approved by the National Health Surveillance Agency (ANVISA). In Brazil, medical devices
are regulated by
a) the national law ”Lei 6360/1976” which regulates drugs, medical devices, cosmetics and other
sanitary products,
b) 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.
ANVISA expects that APIs are 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, the use of a foreign official monograph is allowed.
See website of the local authority above for the responsibilities of deciding whether a submission or
change notification is subject to requirements.
See also Table 2 for managing changes that can impact the DCP.
4.3.2 Brazil: Clinical evaluation requirements
VDDCPs are subject to requirements for 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 completed prior to submission to ANVISA.
4.3.3 Brazil: Audit requirements
A manufacturing audit is subject to requirements prior to market approval. The manufacturing site is
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 manufacturing RDC 59/2000 certificate or ISO 13485 MDSAP certificate is presented together with
the submission dossier.
4.4 Canada
4.4.1 Canada: Managing changes
VDDCPs are approved by Health Canada.
[137]
NOTE For more information, refer to the Health Canada website .
See the website of the local authority given above for the responsibilities of deciding whether a
submission or change notification is subject to requirements.
It is the responsibility of the Health Canada to decide if a submission or change notification is subject to
requirements based on information provided by the manufacturer.
See also Table 2 for managing changes that can impact the DCP.
4.4.2 Canada: Clinical evaluation requirements
VDDCPs are subject to requirements for a clinical study (but it need not be a local study). It is suggested
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).
4.4.3 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.
4.5 European Union (EU)
4.5.1 EU: Managing changes
VDDCPs are assessed for conformity by a Notified Body before approval as medical devices according to
Medical Device Regulation (EU) 2017/745. The Notified Body seeks a scientific opinion or consultation
from one of the competent authorities (national regulatory authorities designated by member states) or
the European Medicines Agency and from an Expert Panel review ((56) of Regulation (EU) 2017/745.).
MEDDEV 2.1/3 is a guideline explaining the consultation process for VDDCPs as well as the necessary
documentation to be provided for consultation.
Per the European Pharmacopoeia (EP), APIs follow the API monograph if one exists. If APIs are imported,
then the authenticity of API GMP status can be verified per the Falsified Medicines Directive 2011/62.
NOTE 1 The Notified Bodies, competent authorities, and more information on the EU regulatory framework is
contained within Reference [138].
NOTE 2 MEDDEV 2.1/3-related information can be found in Reference [138].
The NB-MED is an organization of the Notified Bodies that published a guidance document (NB-MED/
2.5.2 /rec2) which comprises recommendations accepted by the European Forum of Notified Bodies
Medical Devices (NB-MED). Although they set out information on matters relating to the directives,
this information is for guidance only, to help the user to meet their obligations, whether the user is a
manufacturer, a Notified Body or an interested party.
It is the responsibility of the Notified Body to decide if a submission or change notification is subject to
requirements, based on information provided by the manufacturer.
NOTE 3 MEDDEV 2.1/3, Borderline products, drug delivery products and medical devices incorporating, as an
integral part, an ancillary medicinal substance or an ancillary human blood derivative.
See also Table 2 for examples of how to manage changes that can impact the DCP.
4.5.2 EU: Material inclusion and labelling requirements
Under the conformity assessment procedures per Annex I, General Safety and Performance
Requirements (GSPR)s, justification and updates to the technical documentation can be required for the
inclusion of materials, chemicals, or substances deemed to be potential hazardous to patients, users,
and/or the environment. Per Annex I GSPRs, labelling of medical devices can require additional patient
and user notifications to comply with regional requirements.
4.5.3 EU: Clinical evaluation requirements
VDDCPs are subject to requirements for a clinical evaluation as given in European Union medical device
regulations. A clinical study is performed unless it is duly justified to rely on existing clinical data.
Prior to submission of a clinical evaluation that includes a clinical study, it is possible that the study
design can be discussed with the relevant Notified Body and the drug consultation body.
If a study is needed, there are country-specific requirements. The approval of clinical studies
applications in the EU is the responsibility of the individual Member States (see Reference [138]).
4.5.4 EU: 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.
For Class III VDDCPs incorporating as an integral part an API, conformity assessment is performed.
4.6 India
4.6.1 India: Managing changes
VDDCPs are approved by the Drugs Controller General of India (DCGI) and are governed by The Drugs
and Cosmetic Act 1940 and rules 1945.
NOTE For more information, see Reference [139] for the responsibilities of deciding whether a submission
or change notification is subject to requirements.
4.6.2 India: Clinical evaluation requirements
VDDCPs are subject to requirements for a local clinical study. The clinical study protocol needs to be
approved prior to initiation of the study. The final report for the study primary end point(s) is completed
prior to submission for approval.
4.6.3 India: Audit requirements
A manufacturing audit can be required prior to market approval.
4.7 Japan
4.7.1 Japan: Managing changes
VDDCPs are Class IV devices and are approved by the Minister of Health, Labour and Welfare (MHLW)
as medical devices.
The application for approval of VDDCPs is submitted to Pharmaceuticals and Medical Devices Agency
(PMDA).
NOTE 1 For more information, see Reference [140].
VDDCPs are subject to requirements for applicable local approval.
NOTE 2 See also the Bibliography for local guidelines.
See website of the local authority above for the responsibilities of deciding whether a submission or
change notification is subject to requirements.
See also Table 2 for examples of how to manage changes that can impact the DCP.
4.7.2 Japan: Clinical evaluation requirements
VDDCPs are subject to requirements for a clinical study. A consultation with PMDA helps to determine
if already existing international data is sufficient, or if some additional data is needed to be collected
locally. Clinical Trial Notification (CTN) needs to be submitted to PMDA prior to initiation of the
study. In the case of the first trial for the device in Japan, the clinical study protocol and investigator’s
brochure are submitted with the CTN and endorsed by MHLW/PMDA from a safety and ethics point
of view. The final report for the study primary end point(s) is completed prior to submission of the
marketing application to PMDA.
NOTE See Reference [158] on Good Clinical Practice for Medical Devices (GCP).
4.7.3 Japan: Audit requirements
A manufacturing audit can be required prior to market approval.
4.8 People's Republic of China (PRC)
4.8.1 PRC: Managing changes
VDDCPs are approved by the National Medical Products Administration of China (NMPA) (formerly
CFDA, State FDA or SFDA).
VDDCPs are subject to requirements for applicable GB National Standards and YY medical industrial
standards (see Table 1 for codes).
VDDCPs without country of origin approval cannot be submitted to NMPA. In addition, the API is also to
have country of origin approval or need to have been approved by NMPA prior to submission to NMPA.
NOTE 1 Table 1 gives an overview of regional-standard codes and abbreviations.
Table 1 — Chinese standard codes and abbreviations
Code Type of standard Institution
GB Mandatory national standard SAC
GB/T Recommended national standard SAC
GB/Z National standardization, technical document SAC
YY Mandatory medical industrial standard NMPA
YY/T Recommended medical industrial standard NMPA
Key
SAC: Standardization Administration of China
NMPA: China Food and Drug Administration
[141]
NOTE 2 For more information, see the NMPA website for general information on device registration .
NOTE 3 Refer also the Bibliography for local guidelines.
See the website of the local authority above for the responsibilities of deciding whether a submission or
change notification is subject to requirements.
See also Table 2 for managing changes that can impact the DCP.
NOTE 4 The term of validity of the Medical Device License is 5 years according to the new NMPA regulation.
NMPA Regulation for the Supervision and Administration of Medical device (No. 739 Order) can be found (in
Chinese language) in Reference [141] and NMPA Provision of Administration for Medical Device Registration
(Regulation #4) can be found (in Chinese language) in Reference [142].
According to Order #739 if a substantial change of the design, raw materials, manufacturing process,
intended use, forms of operation, etc. for Class II and Class III medical devices that are already
registered, and those changes can possibly affect the safety and effectiveness or efficacy of medical
devices, the registration applicant submits a change application to the original registration authority. If
a non-substantial change occurs that will not affect the safety and effectiveness of the medical devices,
the registration applicant files the change on record with the original registration authority.
According to the Regulation #4, in case of any changes to the content of the Medical Device license for a
Class II and Class III Medical Device and its Annexes (e.g. product technical requirement), the applicant
submits the application to the original authority for the changes and submits the documents according
to the appropriate requirements.
— For changing the product name, model, specification, structure and components, intended use/
indication, product technical requirement, manufacturing site of import medical devices etc., these
are change of permission items (CP), the applicant submits the application and relevant documents
to the original regulatory authority for approval.
— For changing the name and/or domicile of the applicant or changing the name and/or the domicile of
the deputy agent, these are change of registration items (CR), the applicant submits the application
and relevant documents to the original regulatory authority for approval of the changes. For
changing the manufacturing site address of a China domestic medical device on the medical device
license, the applicant submits the application and relevant documents to the original regulatory
authority after the manufacturing site is approved.
4.8.2 PRC: Clinical evaluation requirements
VDDCPs are subject to requirements for a clinical evaluation or a clinical study.
NMPA Provisions of medical device clinical trials No. 5 regulation can be found (in Chinese language) in
Reference [143] where both non-drug elution and drug elution devices are discussed.
NOTE 1 Further guidance for the regulatory requirements for the conduct of a clinical trial is provided in the
document “Regulations for the Supervision and Administration of Medical Devices (Order #739)” in Reference
[141] (in Chinese language).
NOTE 2 For further guidance on the technical requirements for a clinical study for a coronary drug-eluting
stent refer to “Notification on guidance for coronary drug-eluting stent clinical trial” in Reference [144] (in
Chinese language).
4.8.3 PRC: Audit requirements
A manufacturing audit is subject to requirements prior to market approval. There are several
scenarios. For imported medical device of Class III implanted device, NMPA have the right to audit the
manufacturer at any time. It can be possible to invite NMPA’s officials to inspect the quality system.
NOTE For general information, please see website of the local authority above for the responsibilities of
deciding whether a submission or change notification is subject to requirements.
4.9 Russia
4.9.1 Russia: Managing changes
Russian regulations are rapidly evolving with documents from the EurAsian economic commission
coming into force in 2016. Review of current Russian regulations is not informative at this time and
for these reasons Russian regulatory information is not present in Table 2. Please refer to currently
available digital resources for confirmation of the requirements.
NOTE 1 The Federal Service for Control in Healthcare is the approving state registration for medical devices.
The Federal Service for Control in Healthcare reports to the Ministry of Health.
NOTE 2 Manufacturers of VDDCPs issue a declaration of conformity (GOST R) that is submitted for certification
body review and registration in the state database.
NOTE 3 APIs are in compliance with the Russian Pharmacopoeia.
4.9.2 Russia: Clinical evaluation requirements
VDDCPs are subject to requirements for a summary of available clinical data. If a study is conducted in
Russia, the clinical study protocol needs to be approved prior to initiation of the study. The final report
for the study primary end point(s) is completed prior to submission.
4.9.3 Russia: Audit requirements
A manufacturing audit is not required prior to market approval in all cases, for imported VDDCPs.
4.10 United States of America (USA)
4.10.1 USA: Managing changes
VDDCPs are approved or determined to be substantially equivalent to a marketed device and cleared
for market by the US Food and Drug Administration (FDA). For VDDCPs in which the primary mode of
action is from the device (e.g. stents and balloons), FDA's Center for Devices and Radiological Health
(CDRH) has primary review responsibility and consults with the Center for Drug Evaluation and
Research (CDER) regarding drug-related issues. For VDDCP, early interaction with FDA is suggested.
Information on the USFDA presubmission process can be found in Reference [145].
NOTE 1 Information on general FDA policies and procedures can be found in Reference [146].
NOTE 2 Information on FDA review of combination products can be found in Reference [147].
NOTE 3 There are many FDA guidance documents applicable to submissions for VDDCPs. These guidance
documents can be found in Reference [148].
If APIs are in compliance with the United States Pharmacopoeia (USP), this is noted in submissions to
the FDA.
NOTE 4 Refer also to the Bibliography for local guidelines.
It is the responsibility of the manufacturer to decide if a submission or change notification is subject to
requirements, using guidance from the USFDA website. The USFDA determines if the selected approach
is appropriate or if additional submissions are needed.
See website of the local authority above for the responsibilities of deciding whether a submission or
change notification is subject to requirements.
Additionally, it can be helpful to see the following USFDA Guidance documents given in Reference [149].
NOTE 1 Changes or modifications during the conduct of a clinical investigation are given in Reference [149].
NOTE 2 Refer to Reference [150] when deciding when to submit a 510(K) for a change to an existing device
(K97–1).
NOTE 3 Refer to Reference [151] for Guidance for industry and FDA staff: modification to devices subject to
pre-market approval (PMA), the PMA supplement decision making process.
NOTE 4 Refer to Reference [152] for Guidan
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