ISoP Medical Device SIG Webinar on Post-marketing safety surveillance of medical devices and drug-device combination products https://isoponline.org/special-interest-groups/medical-devices-group/ PMS is an integral part of a quality management system described in ISO 13485. ISO 13485 references inclusion of applicable regulatory requirements on post market surveillance into the quality management system. Regulatory requirements are country specific and are continuously evolving. The regulatory processes for devices are significantly different than for drugs. Moreover, the requirements for drug-device combination products are not always clearly articulated. • In Europe, according to the EU MDR, post-market surveillance shall also allow a comparison to be made between the device and similar products available on the market. • The first challenge is identifying similar products on the market, that is out of the scope of this webinar. The second challenge is finding relevant information on equivalent and similar products. • Since EUDAMED does not currently have a post-marketing module, manufacturers have to rely on a large number of national databases. The focus of this webinar is on regulatory requirements in major jurisdictions. There will be another webinar coming soon that will focus on how to obtain the information required to comply with all these requirements. • With some effort, it is possible to locate information on advisory notices. • However, adverse events or incidents are not publicly available. This is a major difference from medicinal products. • In addition, certain AEs are subject to the National Competent Authority Report (NCAR) Exchange. These reports are shared between agencies and can potentially result in FSCA. So even when unable to monitor competitor product adverse event profile, it is important to know about their FSCAs.

1. Post-marketing safety surveillance
of medical devices and drug-
device combination products
January 2024
V E R O N I K A VA L D O VA , D V M
A R E T E - Z O E , L L C
1

2. Webinar
Organised by
the ISoP
Medical Device
SIG
1. Today’s webinar will be chaired by Omar Aimer the Leader of the ISoP Medical Device
SIG and ISoP Executive Committee member.
2. During the webinar:
o Please mute your microphone and switch off your camera
o You are welcome to ask questions or make comments via chat
3. If you have any additional comments/questions post-presentation, please email them to
Antoinette Ivins at support@isoponline.org.
4. This webinar is being recorded and the video will be posted on the ISoP’s website
(Member section).
HOUSEKEEPING DURING THIS WEBINAR
Post-marketing safety surveillance of medical devices and
drug-device combination products webinar.
18January 2024, 13:00 UTC / 14:00 CET Veronika Valdova

3. • Veronika Valdova, DVM is a multi-disciplined professional in the pharma and
medical device sectors, with extensive knowledge of all aspects of drug safety in
post-market surveillance and clinical research. She works with global corporations,
niche manufacturers, and startups as a freelance consultant or B2B.
• Current endeavors. Independent consultant for Navitas Life Sciences (since 2023),
Oriel STAT A MATRIX (since 2023), and several medical device manufacturers
(since 2016). Co-founder and Consultant at Arete-Zoe, LLC (since 2013).
• Experience. Pharmacovigilance officer at IVAX Pharmaceuticals in Opava, Czech
Republic (2004-6); Senior Drug Safety Officer at Stiefel Laboratories, UK (2007-
8); Pharmacovigilance Manager at Dr. Reddy's Laboratories, UK (2009);
independent consultant (2009 onwards); Inspector for medical devices at the
Czech Institute for Drug Control (2012-13); Case processor at Accenture Services
(2018-2019); Chief Scientific Officer at Veracuity (2019-2022); Co-founder and
Consultant at Arete-Zoe, LLC (since 2013), providing consultancy for drug safety
and MDD to MDR transition for device manufacturers.
• Contact: veronikav@arete-zoe.com | +420-721-079-971 | +1-631-791-8129
• Links: LinkedIn | Arete-Zoe, LLC | SlideShare
Veronika Valdova, DVM
ARETE-ZOE, LLC
January 2024 3

4. Problem statement
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
• Review of data required to support post-market surveillance (PMS) activities of medical device for
re/certification is resource intensive, time consuming, and mostly manual.
• PMS is an integral part of a quality management system described in ISO 13485.
• Regulatory requirements are country/region-specific and continuously evolving.
• The regulatory processes for devices are significantly different than for drugs. The requirements for
drug-device combination products are country-specific and not always clearly articulated.
• Multiple national databases exist that must be screened for advisory notices concerning equivalent
and similar products. Identification of equivalent and similar products remains a challenge.
• Unlike medicinal products, adverse events/incidents are not publicly available.
• Certain AEs are subject to NCAR Exchange, potentially resulting in FSCA.
4

5. Medical Device
Single Audit
Program (MDSAP)
U SA , AU ST R AL IA
C A N ADA, B R A ZI L , J A PAN
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP

6. Auditing the Medical Device Adverse Events and
Advisory Notices Reporting
PURPOSE
The purpose of auditing the Medical Device Adverse Events and
Advisory Notices Reporting is
• to verify that the medical device organization’s processes
ensure that individual device-related adverse events
• advisory notices involving medical devices are reported to
regulatory authorities within required timeframes.
OUTCOMES
As a result of the audit of the Medical Device Adverse Events and
Advisory Notices Reporting process, objective evidence will show
whether the medical device organization has:
• Defined processes to ensure individual device-related adverse
events are reported to regulatory authorities as required
• Ensured that advisory notices are reported to regulatory
authorities and authorized representatives when necessary
• Maintained appropriate records of individual device-related
adverse events and advisory notices
January 2024
MDSAP Audit Approach
MDSAP members
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
6

7. EUROPEAN UNION
January 2024
EU MDR 2017/745
EU IVDR 2017/746
8

8. Post-market surveillance obligations
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
9
Procedures in Articles 83 and 84 (Post-Market Surveillance/PMS) and 86 (Periodic Safety
Update Report/PSUR)
• Annex III Article 1.1 (PMS)
• Annex XIV, Part B (Post-Market Clinical Follow-Up/PMCF)
• MDCG 2020-7 (PMCF Plan) and MDCG 2020-8 (PMCF Report)
• MDCG 2022-21 (PSUR) and MDCG 2023-3 (Vigilance Q&A)
• Article 61, Annex XIV Part A Section 3, MCDG 2020-5 (Equivalence)
The post-market surveillance plan shall allow a correct characterisation of the
performance of the devices and shall also allow a comparison to be made
between the device and similar products available on the market.

9. Overview of drug-device combinations in the EU
January 2024
Product category Examples Regulatory agency Outcome
Integral drug-device
combinations
pMDI inhaler
Prefilled syringe
EMA or medicines
Competent Authority
NB input may be required
Marketing Authorization
(with NB opinion)
Non-integral drug-device
combinations
Dry powder inhaler co-
packed with medicine
capsules
Syringe co-packed with vial
of medicinal product
EMA or medicines
Competent Authority for the
medicinal product
NB for the delivery device
Marketing Authorization for
the medicinal product
CE certificate for the
delivery device
Devices with ancillary
medicinal substance
Drug eluting stent
Dressing with antibiotic
NB will consult with a
Competent Authority for the
medicinal aspects
CE certificate (with
consultation report from
Competent Authority
Devices intended to
administer medicines
Syringe pump
Ventilator
Notified Body CE certificate
Source: BSI. The convergence of the pharmaceutical and medical devices industries
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
10

10. Drug-Device Combination - Article 1(8)
January 2024
• Any device which, when placed on the market or put into service, incorporates, as an
integral part, a substance which, if used separately, would be considered to be a
medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC, including
a medicinal product derived from human blood or human plasma as defined in point
10 of Article 1 of that Directive, and that has an action ancillary to that of the device,
shall be assessed and authorized in accordance with this Regulation.
• However, if the action of that substance is principal and not ancillary to that of the
device, the integral product shall be governed by Directive 2001/83/EC or Regulation
(EC) No 726/2004 of the European Parliament and of the Council (34), as applicable.
In that case, the relevant general safety and performance requirements set out in
Annex I to this Regulation shall apply as far as the safety and performance of the
device part are concerned.
MDR
2017/745
MPD
2001/83/EC
Reg
(EC)
726/2004
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
12

11. Drug-Device Combination - Article 1(9)
January 2024
• Any device which is intended to administer a medicinal product as defined in point 2
of Article 1 of Directive 2001/83/EC shall be governed by this Regulation, without
prejudice to the provisions of that Directive and of Regulation (EC) No 726/2004 with
regard to the medicinal product.
• However, if the device intended to administer a medicinal product and the medicinal
product are placed on the market in such a way that they form a single integral
product which is intended exclusively for use in the given combination and which is
not reusable, that single integral product shall be governed by Directive 2001/83/EC
or Regulation (EC) No 726/2004, as applicable. In that case, the relevant general
safety and performance requirements set out in Annex I to this Regulation shall apply
as far as the safety and performance of the device part of the single integral product
are concerned.
MDR
2017/745
MPD
2001/83/EC
Reg
(EC)
726/2004
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
13

12. Drug-Device Combination - Article 117
Where, in accordance with the second subparagraph of Article 1(8) or the second subparagraph of Article
1(9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (*1), a product is governed
by this Directive, the marketing authorization dossier shall include, where available, the results of the
assessment of the conformity of the device part with the relevant general safety and performance
requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of
conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking
to the medical device.
If the dossier does not include the results of the conformity assessment referred to in the first subparagraph
and where for the conformity assessment of the device, if used separately, the involvement of a notified body
is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide
an opinion on the conformity of the device part with the relevant general safety and performance
requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with
that Regulation for the type of device in question.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
15

13. Adverse incidents
(a) any serious incident involving devices made available on the
Union market, except expected side effects which are clearly
documented in the product information and quantified in the
technical documentation and are subject to trend reporting
pursuant to Article 88 (Article 87 (a) & (b)).
January 2024
FSCAs
MIR Form 2020
any field safety corrective action (FSCA) in respect of devices
made available on the Union market, including any FSCA
undertaken in a third country in relation to a device which is also
legally made available on the Union market, if the reason for the
field safety corrective action is not limited to the device made
available in the third country
FSCA Report Form
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
21

14. Trend reports
• Manufacturers shall report any statistically significant
increase in the frequency or severity of incidents that are
not serious incidents or that are expected undesirable
side-effects that could have a significant impact on the
benefit-risk analysis, and which have led or may lead to
risks to the health or safety of patients, users or other
persons that are unacceptable when weighed against the
intended benefits.
• The manufacturer shall specify how to manage the
incidents and the methodology used for determining any
statistically significant increase in the frequency or
severity of such incidents, as well as the observation
period, in the post-market surveillance plan.
• The competent authorities may conduct their own
assessments on the trend reports
January 2024
Periodic Summary Reports
• For similar serious incidents that occur with the same
device or device type and for which the root cause has
been identified or a field safety corrective action
implemented or where the incidents are common and well
documented, the manufacturer may provide periodic
summary reports instead of individual serious incident
reports as long as the coordinating competent authority
has agreed with the manufacturer on the format, content
and frequency of the periodic summary reporting.
Trend report (Article 88)
(Article 87)
Periodic summary report
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
22

15. January 2024
Where to report The Competent Authority of the Member State
in which that incident occurred (see list).
How to report Until the vigilance module of EUDAMED is available, the national
vigilance reporting procedures will remain in place, see MEDDEV
2.12/1 Rev 8.
Who reports The Manufacturer of the medical device
involved in the adverse incident.
‘Serious Public Health Threats’ shall be reported no later than 2 days of becoming aware
‘Serious Incidents’ shall be reported no later than 10 days of becoming aware
‘Incidents’ shall be reported no later than 15 days of becoming aware
Reporting timelines
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
23

16. Vigilance & Post-Market Surveillance Requirements
January 2024
ELEMENT REGULATION REFERENCE
Post-Market Surveillance System Article 83: Post-market surveillance system of the manufacturer
Article 15: Person responsible for regulatory compliance
Post-market surveillance plan Article 84: Post-market surveillance plan
Annex III: Technical documentation on post-market surveillance
Post-market surveillance report Article 85: Post-market surveillance report
Period Safety Update report Article 86: Periodic safety update report
Vigilance Article 87: Reporting of serious incidents and field safety corrective actions
Article 88: Trend reporting
Article 89: Analysis of serious incidents and field safety corrective actions
Source: BSI. Do you know the requirements and your responsibilities for medical device vigilance reporting?
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
24

17. UNITED STATES
January 2024 25

18. USA: Medical Device Reporting
P R O C E S S
Manufacturer has developed
a process for reporting to
FDA incidents involving
device-related deaths, serious
injuries, and reportable
malfunctions that occur within
and outside the United States
if the same or similar device is
marketed to the United
States.
T I M E L I N E
Reports are due within 30
calendar days after the day
that the manufacturer
receives or otherwise
becomes aware of
information, from any source,
that reasonably suggests that
a device that is marketed may
have caused or contributed to
a death or serious injury.
MDR files must contain
• Information (or references to information)
related to the adverse event,
• All documentation of deliberations and
decision-making processes used to
determine if a device- related death,
serious injury, or malfunction was or was
not reportable to FDA
• Copies of all MDR forms and other
information related to the event
submitted to FDA.
January 2024
21 CFR 803: Medical Device Reporting
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
26

19. USA: Medical Device Reporting
• Quarterly summary: If a device has malfunctioned and this device or a similar device that is
marketed would be likely to cause or contribute to a death or serious injury, if the malfunction
were to recur, quarterly summary reporting is acceptable for most device product codes.
• Complaint vs. MDR events: If the Manufacturer maintains MDR event files as part of the
complaint file, MDR reportable events must be prominently identified.
• MDR file must contain: Evaluation of event in accordance with the QMS requirements.
• Explanation of why the manufacturer did not submit or could not obtain follow-up
• Results of the evaluation of each event.
January 2024
21 CFR 803: Medical Device Reporting
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
27

20. 5-day reports
January 2024
Manufacturer must submit reports to FDA no later than 5 workdays after the day that the manufacturer becomes
aware that:
• An MDR reportable event necessitates remedial action to prevent an unreasonable risk of substantial harm to the
public health.
• The manufacturer may become aware of the need for remedial action from any information, including any trend
analysis;
• FDA written request for a 5-day report.
• If the manufacturer receives such a written request from FDA, the manufacturer must submit, without further
requests, a 5-day report for all subsequent events of the same nature that involve substantially similar devices
for the time period specified in the written request. FDA may extend the time period stated in the original
written request if FDA determines it is in the interest of the public health.
21 CFR 803: Medical Device Reporting
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
28

21. Follow-up and reporting
January 2024
• Follow-up. Manufacturer shall submit supplemental reports within one
month of obtaining information that was not submitted in an initial
report.
• UDI. Medical device reports include the unique device identifier (UDI)
that appears on the device label or on the device package.
• ESG. Medical device reports submitted to FDA must be submitted
electronically via the Electronic Submissions Gateway (ESG) using
eSubmitter or the AS2 Gateway-to-Gateway using HL7 ICSR XML
software.
21 CFR 803: Medical Device Reporting
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
29

22. COMBINATION PRODUCT
January 2024
CO-PACKAGED
(2) Two or more separate products
packaged together in a single package or
as a unit and comprised of drug and
device products, device and biological
products, or biological and drug products;
(1) A product comprised of two or
more regulated components, i.e.,
drug/device, biologic/device,
drug/biologic, or
drug/device/biologic, that are
physically, chemically, or otherwise
combined or mixed and produced as
a single entity;
(4) Any investigational drug, device,
or biological product packaged
separately that according to its
proposed labeling is for use only with
another individually specified
investigational drug, device, or
biological product where both are
required to achieve the intended use,
indication, or effect.
CROSS-LABELED
(3) A drug, device, or biological product packaged separately that
according to its investigational plan or proposed labeling is intended
for use only with an approved individually specified drug, device, or
biological product where both are required to achieve the intended
use, indication, or effect and where upon approval of the proposed
product the labeling of the approved product would need to be
changed, e.g., to reflect a change in intended use, dosage form,
strength, route of administration, or significant change in dose; or
Part 3 Subpart A Section 3.2
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
30

23. COMBINATION
PRODUCTS
REPORTING
January 2024
FDA PMSR Guideline
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
32

24. Drug-Device Combination Products (USA)
• 21 CFR Part 4 Regulation of Combination Products
January 2024
If you are a constituent part applicant, the reporting
requirements applicable to you that are identified in
this section apply to your constituent part,
If you are a combination product applicant, the
reporting requirements applicable to you that are
identified in this section apply to your combination
product as a whole.
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
33

25. Reporting requirements applicable to both combination
product applicants and constituent part
Reporting requirements applicable to both combination product applicants and constituent part applicants.
• If you are a combination product applicant or constituent part applicant, you must comply with the reporting requirements
identified in paragraphs (b)(1), (b)(2), or (b)(3) of this section for your product based on its application type.
• (b)(1) If your combination product or device constituent part received marketing authorization under a device application,
you must comply with the requirements for postmarketing safety reporting described in parts 803 and 806 of this chapter
with respect to your product.
• (b)(2) If your combination product or drug constituent part received marketing authorization under an NDA or ANDA, you
must comply with the requirements for postmarketing safety reporting described in part 314 of this chapter with respect
to your product.
• (b)(3) If your combination product or biological product constituent part received marketing authorization under a BLA,
you must comply with the requirements for postmarketing safety reporting described in parts 600 and 606 of this chapter
with respect to your product.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
34

26. What reports must you submit to FDA for your combination
product or constituent part?
If you are a combination product applicant, you are required to submit a report as specified in this paragraph unless you
have already submitted a report in accordance with paragraph (c) of this section for the same event that: Includes the
information required under the applicable regulations identified in this paragraph, is required to be submitted in the same
manner under § 4.104, and meets the deadlines under the applicable regulations identified in this paragraph.
• (c) Reporting requirements applicable only to combination product applicants. If you are a combination product
applicant, in addition to compliance with paragraph (a) of this section, you must also comply with the reporting
requirements identified under this paragraph as applicable to your product based on its constituent parts.
• If you are a combination product applicant, you are required to submit a report as specified in this paragraph unless
you have already submitted a report in accordance with paragraph (b) of this section for the same event that:
• Includes the information required under the applicable regulations for the report identified in this paragraph;
• is required to be submitted in the same manner under § 4.104 of this chapter; and, unless otherwise specified in this
paragraph, meets the deadlines under the applicable regulations for the report identified in this paragraph.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
35

27. January 2024
FDA PMSR Guideline
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
36

28. What reports must you submit to FDA for your combination product or
constituent part?
I F Y O U R C O M B I N AT I O N
P R O D U C T C O N TA I N S A
D E V I C E C O N S T I T U E N T P A R T:
• (i) Five-day reports;
• (ii) Malfunction reports; and
• (iii) Correction or removal
reports, and maintain records
as described in § 806.20 of
this chapter for corrections and
removals not required to be
reported.
I F Y O U R C O M B I N AT I O N
P R O D U C T C O N TA I N S A
D R U G C O N S T I T U E N T P A R T:
• (i) Field alert reports; and
• (ii) Fifteen-day reports as
described in § 314.80 of this
chapter, which must be
submitted within 30 calendar
days instead of 15 calendar
days if your combination
product received marketing
authorization under a device
application.
I F Y O U R C O M B I N AT I O N P R O D U C T
C O N TA I N S A B I O L O G I C A L
P R O D U C T C O N S T I T U E N T P A R T:
• (i) Biological product deviation
reports; and
• (ii) Fifteen-day reports as described in
§ 600.80 of this chapter, which must
be submitted within 30 calendar days
instead of 15 calendar days if your
combination product received
marketing authorization under a
device application.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
37

29. CANADA
January 2024 51

30. Drug/Medical Device Combination Products (DDCPs)
The principal Mechanism of Action is achieved by
pharmacological, immunological, or metabolic means:
• The combination product will be subject to the Food and Drug
Regulations
• unless that action occurs in vitro, without reintroducing a
modified cellular substance to the patient, in which case the
product will be subject to the Medical Devices Regulations.
The principal Mechanism of Action is not achieved by
pharmacological, immunological, or metabolic means, but may be
assisted in that effect or purpose by pharmacological,
immunological, or metabolic means:
• The combination product will be subject to the Medical
Devices Regulations.
January 2024
HC Policy (2006) established a single window approach and more efficient submission processing system:
• DDCP principal mechanism of action by which the claimed effect or purpose of the product is achieved determines how the entire
product is regulated: the Food and Drug Regulations OR the Medical Devices Regulations.
• Both the principal and ancillary components shall meet acceptable standards of safety, efficacy and quality.
This policy does not apply to combinations of drugs and medical devices where the drug component and the device component
can be used separately (i.e., procedure packages and trays). The Food and Drug Regulations shall apply to the drug component
of such a product and the Medical Devices Regulations shall apply to the device component.
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
52

31. Definitions
Combination product is a therapeutic product that combines a drug component and a device component (which by themselves
would be classified as a drug or a device), such that the distinctive nature of the drug component and device component is
integrated in a singular product.
• Immunological is understood as an action in or on the body by stimulation and/or mobilization of cells and/or products involved in a
specific immune reaction.
• Metabolic is understood as an action which involves an alteration of the normal chemical processes participating in,
and available for, normal body function. The fact that a product is itself metabolized does not imply that it achieves its
principal intended action by metabolic means.
• Pharmacological is understood as an interaction between the molecules of the substance in question and a cellular
constituent, usually referred to as a receptor, which either results in a direct response, or which blocks the response to
another agent and, for the purposes of this policy, includes anti-infective activity.
Therapeutic Products Classification Committee is a committee appointed by the Director General of TPD to develop, maintain,
evaluate and recommend for approval policies, procedures and guidelines concerning the classification and review of
therapeutic products as drugs, devices or combination products; to assess submissions for combination products referred to it
and determine an appropriate classification and review mechanism for the submission.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
53

32. Reportable events in Canada
• Regulation: CMDR 59-61.1, 61.2-61.3
• Verify that the Manufacturer and the Importer of a medical device make a preliminary and final report to the minister
concerning any incident occurring inside Canada involving a device sold (authorized for sale) in Canada.
REPORTABLE EVENTS:
• Is related to the failure of the device or deterioration in its effectiveness or any inadequacy in its labeling or in its directions
for use; and
• Has led to death or serious deterioration in the state of health of a patient, user, or other person, or could do so if it were to
recur [CMDR 59(1)].
FOREIGN INCIDENTS:
• Class II-IV devices authorized for sale in Canada: No longer reportable.
• Class I: Reportable [CMDR 59(1.1)]
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
54

33. Reporting timelines in Canada
• Verify that the Manufacturer or other
person becoming aware of an event that
led to the death or serious deterioration in
the state of health of a patient, a user, or
other person provides information in a
preliminary report within 10 days after the
person becomes aware of the event or
occurrence [CMDR 60 (1)(a)(i)].
• Verify that the Manufacturer or other
person becoming aware of an event that
the recurrence of which might lead to the
death or serious deterioration in the state
of health of a patient, a user, or other
person provides information in a
preliminary report within 30 days after the
person becomes aware of the event or
occurrence [CMDR 60 (1)(a)(ii)].
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
55

34. Reporting essentials
• Manufacturers and Importers can use the “Mandatory Medical Device Problem Reporting
Form for Industry” to submit preliminary and final incident report
• Importer must have Manufacturer’s authorization to report
• If the submitter is the Importer (section 60 and 61 reports)
• verify that the Manufacturer has advised the Minister in writing that the reports the Manufacturer
and importer would have submitted were identical
• verify that the Manufacturer has permitted the importer to prepare and submit reports to the
Minister on the Manufacturer’s behalf [CMDR 61.1].
• This notification is to be done using Health Canada form “FRM-0090”.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
58

35. Serious risk of injury to human health
• Verify that the Manufacturer of a medical device submits to the Minister information regarding
serious risk of injury to human health related to the safety of the device that it becomes aware of
or receives, regarding:
• (a) Risks that have been communicated by any Regulatory Agency that is set out in the List of
Regulatory Agencies for the Purposes of Section 61.2 of the Medical Devices Regulations, or by any
person who is authorized to manufacture or sell a medical device within the jurisdiction of such a
Regulatory Agency, and the manner of the communication;
• (b) changes that have been made to the labelling of any medical device and that have been
communicated to or requested by any Regulatory Agency that is set out in the list referred to in
paragraph (a); and
• (c) recalls, reassessments and suspensions or revocations of authorizations, including licences, in
respect of any medical device, that have taken place within the jurisdiction of any Regulatory Agency
that is set out in the list referred to in paragraph (a). [CMDR 61.2(2)]
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
59

36. Serious risk of injury to human health
Serious risk of injury to human health is defined as
a hazard associated with the medical device that is
relevant to the safety of the medical device and
that, without risk mitigation, would likely:
• be life-threatening
• result in persistent or significant disability or
incapacity
• require inpatient hospitalization or prolonged
hospitalization
• result in a serious health consequence such as loss of
function or debilitating chronic pain
• result in death
• Verify that manufacturers submit notifications of
foreign risks within 72 hours after receiving or
becoming aware that a notifiable action has been
taken in response to a serious risk, whichever comes
first. [CMDR 61.2(3)]
• Foreign Risk Notifications can be submitted using the
“Medical Device Foreign Risk Notification Form for
Industry”.
• Importer must have Manufacturer’s authorization to
report [FRM-0090]
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
60

37. AUSTRALIA
January 2024 61

38. AUSTRALIA: Overview
• Manufacturers are required to implement a post-marketing system that includes
provisions for adverse event reporting
• Written agreement must exist between Manufacturer and the Australian Sponsor
• Manufacturer must report events to the TGA, or to the Sponsor, in a timely
manner to ensure that a Sponsor can meet their reporting obligations
• Australian Sponsors are required to provide Manufacturers with any information
that will assist the Manufacturer to comply with the obligations of a conformity
assessment procedure (e.g., information in relation to adverse events
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
62

39. Boundary and Combination Products
D E V I C E S U S E D T O
A D M I N I S T E R M E D I C I N E
• Medicine measures are co-
packaged with or contained within
the same pack as the medicine and
where the device is intended to be
used to measure or administer the
medicine in the pack, the entire
product is regulated as a medicine.
• EXAMPLE: Paracetamol oral liquid
and measuring syringe/cup.
• The device component does not
have to be included in the ARTG.
S I N G L E I N T E G R A L , N O T
R E U S A B L E O R
R E F I L L A B L E
• Products regulated as medicines.
• In addition to this, the relevant
Essential Principles of Schedule 1 of
the MD Regulations apply with
respect to safety and performance
related features of the device (e.g.,
a syringe or a puffer).
• EXAMPLE: Pre-filled syringe,
asthma puffer.
• The device component does not
have to be included in the ARTG.
D E V I C E S
I N C O R P O R AT I N G A
S U B S TA N C E ( I N T E G R A L )
• ‘Integral’ usually means a single
component product.
• Can be two elements packaged
together and combined into one
product immediately prior to
administration to the patient.
• Regulated as medical device
• Safety, quality and usefulness of the
medicinal substance must be
verified by the TGA (drug, herbal,
blood/plasma derivative)
• EXAMPLE: heparin coated catheter
January 2024
Boundary and combination products guidance
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
64

40. Other Combinations
B I O LO G I C A L -
M E D I C A L D E V I C E
• Biologicals presented as a combination
product with a medical device component
(i.e. integrated with the medical device),
are regulated under the Biologicals
Regulatory Framework
• Combination product will be included in
the ARTG as a biological.
• The device will be assessed according to
medical device regulatory requirements
but will not be included in the ARTG
separately.
• EXAMPLE: metal stent coated with a
matrix and endothelial cells
B I O LO G I C A L -
M E D I C I N E
• Biologicals presented as a
combination product with a
medicine component are regulated
under the Biologicals Regulatory
Framework
• Combination product will be
included in the ARTG as a biological
• EXAMPLE: CAR-T with ligand/Ab.
E X C LU D E D G O O D S
Therapeutic Goods (Excluded Goods)
determinations
• Therapeutic Goods (Medical Devices - Specified
Articles) Instrument 2020- external site
• Therapeutic Goods (Excluded Goods - Hand
Sanitisers) Determination 2020- external site
• Therapeutic Goods (Excluded Goods)
Determination 2018- external site
Therapeutic Goods (Excluded purposes)
specifications
• Therapeutic Goods (Medical Devices - Excluded
Purposes) Amendment (COVID-19 Self-Testing)
Specification 2022
January 2024
Boundary and combination products guidance
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
65

41. System or Procedure Packs (SOPPs)
New regulatory requirements apply to SOPPs since Nov 2021 supplied via the Special conformity assessment
procedure regulatory pathway (Clause 7.5 of Schedule 3 of the TGMD Reg 2002)
• Regulated by the TGA as single medical devices in their own right
• SOPPs must be included in the Australian Register of Therapeutic Goods (ARTG)
• Conformity assessment procedures for SOPPs
• Manufacturers can apply conformity assessment procedures to system or procedure packs. This relates to aspects of
the manufacturing process and demonstrating that medical devices produced by it are safe and perform as intended.
The manufacturer of a system or procedure pack may obtain market authorization evidence, issued by an independent
assessment body or regulator for the system or procedure pack;
• Manufacturer can use the special conformity assessment procedure (Clause 7.5 of Schedule 3 of the TGMD Reg
2002) if they meet the eligibility criteria for ‘medical devices used for a special purpose’ defined in Regulation 3.10.
January 2024
System or procedure packs | Therapeutic Goods Administration (TGA)
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
66

42. System or Procedure Packs
January 2024
System or procedure packs (SOPPs), defined in section 41BF of the
Therapeutic Goods Act 1989, are medical devices that are intended
to be used in a medical or surgical procedure, containing a
combination of two or more goods where:
• At least one of the goods is a medical device or in vitro diagnostic
device
• And all of the goods are packaged together; or are to be
interconnected or combined for use.
• A SOPP must include a medical device or IVD, and depending on
its intended purpose, may also include medicines, biologicals,
other therapeutic goods, or other goods that are not considered
to be therapeutic goods.
A wide range of products are assembled using a combination of
goods that includes at least one therapeutic good. Regulation
depends on the specific combination of goods in the package.
• Medicine kits and composite packs: not medical devices
• Surgical loan kits: Medical devices, not a SOPP
• Exempt from inclusion in the ARTG: packages containing
tampons, etc. supplied free of charge
• Excluded goods not regulated by the TGA but regulated by state
or territory government bodies, e.g., packages containing
medical devices for the prevention of blood-borne and sexually
transmissible diseases (e.g. HIV self-tests), supplied by charities
or other organizations.
SOPP Definition Other regulatory pathways
System or procedure packs | Therapeutic Goods Administration (TGA)
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
67

43. Products that are not medical devices or SOPPs
January 2024
• Subsection 7B(2) of the Act
• Two or more therapeutic goods, no medical
devices
• Therapeutic goods combined before
administration or administered in a particular
sequence as a single treatment.
• Therapeutic goods that do not require individual
registration or listing in the ARTG, unless they are
supplied separately.
• Regulated as medicines or biologicals
Examples: 'Cold and Flu Day and Night medication’
(tablets taken in a particular order); A vial of a
lyophilized biological or powdered medicine that is
packaged with an ampoule or vial containing a
diluent for administration of the medication in a
sequence.
• The Order No. 1 of 2010 declares articles that
are not medical devices.
• Regulated as medicines
• Article intended to administer a medicine (single
integral product intended exclusively for use in
the given combination, not reusable (but may be
multi-dose).
Examples: nasal spray medicine co-packaged with
dropper designed to attach to the medicine
container to deliver the measured eye or nasal
drops; a syringe pre-filled with a medicine; vaginal
tablets co-packaged with a vaginal applicator. The
applicator is specifically used for the insertion of the
tablets into the vagina and is used at the same time
as each of the tablets from the package is
administered.
Composite packs Kits Not medical devices
• Subsection 7B of the Act
• One or more goods supplied in a single
package for use as a unit, one must be a
therapeutic good
• Contains no medical devices
• Not a composite pack. Individual goods can be
used independently
• Therapeutic goods such as medicines,
biologicals or other must be separately listed in
ARTG
• Depending on the indications and contents, kits
are regulated as a medicine, biological, or
other therapeutic good.
Examples: Medicine kits. NOT: first aid kit, SARS-
CoV-Ag test kit, hair-lice kit (contain devices)
System or procedure packs | Therapeutic Goods Administration (TGA)
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
68

44. Reporting essentials
• Regulatory agency (RA):
Therapeutic Goods
Administration (TGA)
• Who reports: Sponsors and
Manufacturers
• Reporting system: Medical
Device Incident Reporting
(MDIR) system
• How to guidance: Medical
device incident reporting
(MDIR) guide
• Database: Database of
Adverse Event Notifications
(DAEN) - medical devices
• Naming and grouping
conventions: Global
Medical Device
Nomenclature - GMDN
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
69

45. Reporting essentials
S E R I O U S T H R E AT T O
P U B L I C H E A LT H
• Verify that the Manufacturer or
other person becoming aware
of an event that represents a
serious threat to public health
provides information as soon
as practicable.
• The Sponsor is to report the
event within 48 hours.
L E D T O D E AT H , S E R I O U S
D E T E R I O R AT I O N I N T H E
S TAT E O F H E A LT H
• Verify that the Manufacturer or
other person becoming aware of
an event that led to the death or
serious deterioration in the state of
health of a patient, a user, or other
person provides information as
soon as practicable.
• The Sponsor is to report the event
within 10 days.
R E C U R R E N C E M I G H T L E A D T O
D E AT H , S E R I O U S D E T E R I O R AT I O N
I N T H E S TAT E O F H E A LT H
• Verify that the manufacturer or
other person becoming aware of
an event that the recurrence of
which might lead to the death or
serious deterioration in the state of
health of a patient, a user, or other
person provides information as
soon as practicable.
• The Sponsor is to report the event
within 30 days.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
70

46. JAPAN
January 2024 71

47. Reporting obligations
• Marketing Authorization Holders are required to implement post market safety activities in
accordance with domestic (Japanese) regulatory requirements in addition to the QMS
requirements.
• The persons operating the Registered Manufacturing Sites are not required to report any
adverse event directly to a Regulatory Authority but shall report any adverse event which
meets the criteria specified by the Ordinance for Enforcement of PMD Act Article 228-20 to
the Marketing Authorization Holder [MHLW MO169: 55-3; (Old: 62.6)].
• The person operating the Registered Manufacturing Site shall provide events which meet the
criteria defined by the Ordinance for Enforcement of PMD Act Article 228-20.2 to the
Marketing Authorization Holder in a timely manner.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
72

48. Reporting obligations
M A L F U N C T I O N
E V E N TS
Malfunction events which may
cause or may have caused health
damage:
• Serious event (domestic and
foreign)
• Unlabeled non-Serious event
(domestic)
A DV E R S E R E A C T I O N
E V E N TS
Adverse Reaction events which
were caused or might have been
caused by the malfunction of a
medical device
• Serious event (domestic and
foreign)
• Unlabeled non-Serious event
(domestic)
A C T I O N TA K E N
Any action taken for preventing the
occurrence or expansion of public health
hazard in relation to a medical device which
is marketed in foreign countries and is
equivalent to the one marketed in Japan.
The action includes but not limited to:
• Suspension of manufacturing, importing
or selling
• Recall
• Abolishment
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
73

49. Reporting obligations in Japan
Study report that indicates:
• Possibility of event of cancer and other serious illness, injury or death caused by malfunction of a
medical device (domestic and foreign), or by infectious disease arising from usage of a device
(domestic and foreign)
• Significant occurrence rate change of event etc. caused by malfunction of a medical device
(domestic and foreign)
• Significant occurrence rate change of infectious disease caused by usage of a medical device
(domestic and foreign)
• The fact that a medical device is less effective than claimed when approved.
January 2024
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
74

50. Combination products
Combination products. The products marketed as a single drug, medical device, or cellular and tissue-based
product that combine two or more types of drug, device, processed cell, etc. that are expected to fall under the
category of drugs, medical devices, or cellular and tissue-based products if marketed individually.
• (2) Combination products shall include the following products:
• (a) Set products (combination products in which the constituting drugs etc. are not indivisible and each can be
marketed individually as either a drug, medical device, or cellular and tissue-based product.)
• (b) Kit products (“kit products” specified in the Handling of Kit and Other Products that Combine Solutions etc. to
Injections (PAB/ELD Notification No. 2-98 by the director of the First Evaluation and Registration Division, the director
of the Second Evaluation and Registration Division, and the director of the Biological Products Division of
Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, dated March 12, 1986)
• (c) Products in which the constituting drugs etc. cannot be marketed individually, such as medical devices etc. that
cannot be separately used from drugs (excluding kit products)
January 2024
“Handling of Approval Application for Combination Products” (Notification No. 1024-(2) of the Evaluation and Licensing Division, PFSB,
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
75

51. Combination products
January 2024
“Handling of Approval Application for Combination Products” (Notification No. 1024-(2) of the Evaluation and Licensing Division, PFSB,
That shall be the subject of combination products specified in Notification 1024(2)
“Medical Devices Approved for
Integral Marketing with Drugs”
specified in Article 114-60-2 of
the Ministerial Ordinance for
Enforcement of the Act for
Ensuring etc. the Quality,
Efficacy, and Safety of Drugs,
Medical Devices, etc.
(Ordinance of the Ministry of
Health and Welfare No. 1 of
1961. Hereinafter referred to
as the “Ministerial Ordinance
for Enforcement”.)
(5) “Drugs Approved for Integral
Marketing with Devices”
specified in Article 98-2, and
Article 228-20-3 of the
Ministerial Ordinance for
Enforcement of the Act for
Ensuring etc. the Quality,
Efficacy, and Safety of Drugs,
Medical Devices, etc.
(Ordinance of the Ministry of
Health and Welfare No. 1 of
1961. Hereinafter referred to as
the “Ministerial Ordinance for
Enforcement”.)
“Cellular and Tissue-based
Products Approved for Integral
Marketing with Devices etc.”
specified in Article 137-60 of the
Ministerial Ordinance for
Enforcement of the Act for
Ensuring etc. the Quality, Efficacy,
and Safety of Drugs, Medical
Devices, etc. (Ordinance of the
Ministry of Health and Welfare No.
1 of 1961. Hereinafter referred to
as the “Ministerial Ordinance for
Enforcement”)
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
77

52. DEVICES: Adverse Event Reporting (Domestic)
January 2024
Malfunction, failure, breakage, leak, fault, etc.
Possibility of health
damage
Description in the
package insert/IFU
Report’s due date
Serious Unknown (unanticipated) 30 days
Known (anticipated) 15 days (unexplained
increased incidence)
30 days (all other)
Non-serious Unknown Annual reports
Known N/A
Health damage (in case relation with the medical
device cannot be denied)
Possibility of health
damage
Description in the
package insert/IFU
Report’s due date
Serious Death Known/unknown 15 days
Except
death
Unknown 15 days
Known 15 days (unexplained
increased incidence)
30 days (all other)
Non-serious Unknown Annual reports
Known N/A
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
78

53. DEVICES: Adverse Event Reporting (Foreign)
January 2024
Malfunction, failure, breakage, leak, fault, etc.
Health damage (in case relation with the medical
device cannot be denied)
Possibility of health
damage
Description in the
package insert/IFU
Report’s due date
Serious Unknown (unanticipated) 30 days
Known (anticipated) 15 days (unexplained
increased incidence)
30 days (all other)
Non-serious Unknown N/A
Known N/A
Possibility of health
damage
Description in the
package insert/IFU
Report’s due date
Serious Death Unknown 15 days
Known 15 days (unexplained
increased incidence)
30 days
Except
death
Unknown 15 days
Known 15 days (unexplained
increased incidence)
30 days
Non-serious Unknown N/A
Known N/A
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
79

54. DEVICES: Adverse Event Reporting (Other)
January 2024
PMDA
Adverse Infection Report
Health damage Description in the
package insert/IFU
Report’s due date
Domestic Serious Unknown 15 days
Known 15 days
Non-serious Unknown 15 days
Known N/A
Foreign Serious Unknown 15 days
Known 15 days
Non-serious Unknown N/A
Known N/A
30 days
Study reports
15 days
Field Safety Corrective Actions
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
80

55. Combination products in Japan
(3) Adverse drug reactions and malfunctions shall be reported by the applicant of the Clinical Trial
Notification for investigational combination product.
• However, in the cases of the above section (2),
• Adverse drug reactions and malfunctions related to the investigational combination product
(excluding adverse drug reactions and malfunctions related to drugs etc. constituting the
investigational combination product) shall be reported by the applicant of the Clinical Trial
Notification for the investigational combination product, and
• Adverse drug reactions and malfunctions related to the drugs etc. that constitute the
investigational combination product shall be reported by the applicant of the Clinical Trial
Notification for that drug etc.
January 2024
Clinical trials: Handling of Adverse Drug Reactions and Malfunctions
“Handling of Approval Application for Combination Products” (Notification No. 1024-(2) of the Evaluation and Licensing Division, PFSB,
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
82

56. Combination products in Japan
• (1) Regarding combination products that correspond to drugs, malfunctions caused by the device that constitutes the
product shall be reported by the marketing authorization holder of the combination product in accordance with
• Article 68-10-1 of the Act on Drugs, Medical Devices etc
• and Article 228-20-3 of the Ministerial Ordinance for Enforcement.
• Previously approved combination products are required to to develop the system and report from November 2016.
• (2) Regarding combination products that correspond to medical devices or cellular and tissue-based products, adverse drug
reactions and malfunctions caused by drugs etc. that constitute the product shall be reported by the marketing authorization
holder of the combination product in accordance with
• Article 68-10-1 of the Act on Drugs, Medical Devices etc.
• and Article 228-20-2 or 4 of the Ministerial Ordinance for Enforcement.
• (3) Refer to the “Reporting on Adverse Drug Reactions etc. of Drugs etc.” (PFSB Notification No. 1002-20, dated December
2, 2014) regarding the method of reporting adverse drug reactions etc. related to combination product etc.
January 2024
Handling of Post-marketing Adverse Drug Reactions and Malfunctions
“Handling of Approval Application for Combination Products” (Notification No. 1024-(2) of the Evaluation and Licensing Division, PFSB,
EUROPE USA JAPAN
AUSTRALIA
CANADA
MDSAP
83

57. THANK YOU
January 2024
Veronika Valdova
https://www.linkedin.com/in/veronikavaldova/
veronikav@arete-zoe.com
https://www.aretezoe.com/
84

58. QUESTIONS
January 2024 85