Medical Devices Regulation (MDR) 2017/745 - Clinical investigations See more https://www.aretezoe.com/medical-devices

1. CLINICAL
INVESTIGATIONS
MEDICAL DEVICES REGULATION (MDR) 2017/745
CHAPTER VI
PAGE 1

2. General
requirements
to
demonstrate
conformity
 Article 63 to 80, Annex XV
 Sponsor/Legal representative (EU) required to establish
compliance
 Ensure rights, safety, dignity and well-being of subjects
 Subject to scientific and ethical review
 Investigator shall be the person exercising the profession
and have the necessary scientific knowledge
PAGE 2

3. General Requirements
 Test device under normal conditions of use
 Establish/verify that the device is suitable for
intended purpose and performs as required
 Establish/verify clinical benefits
 Establish/verify clinical safety
 Determine undesirable side effects
 Assess benefit: risk
PAGE 3
(Article 62)

4. Conditions
SPONSOR’S OBLIGATIONS
 Authorization by Member States required
 Ethics committee has not issued a negative
opinion
 Protection of vulnerable populations
 The anticipated benefits outweigh the risks
 Investigational devices conform to Annex I
requirements (technical and biological safety
testing, pre-clinical investigation)
SUBJECTS’ RIGHTS
 Informed consent
 Physical and mental integrity
 Data protection
 No undue influence for subjects to participate
 Medical care for subjects provided by
qualified medical personnel
PAGE 4
(Article 62)

5.  Study needs to be conducted in line with ethical principles
 Appropriate plan of investigation
 Adequate number of observations
 Investigational procedures appropriate to the device
 Appropriate research methodology
 Representative clinical environment, normal conditions, target population
 Appropriate study endpoints
 Technical and functional features aligned with design
 Investigators shall have access to data about the device
 Clinical investigation report shall contain critical evaluation of data
PAGE 5
(General Requirements, Annex XV, Chapter I)
General Requirements

6. PAGE 6
 Written, dated, signed
 Subject or legally designated
representative
 Protection of vulnerable populations
(Article 63 to 68)
Informed consent

7.  Clear, concise, understandable
 Enables subject to understand the nature, objectives, implications, risks and inconveniences,
conditions and duration, treatment alternatives
 Subject’s rights including the right to refuse
 Prior interview with a member of the investigation team
 Applicable damage compensations
 Unique clinical investigation number
 Attention to information needs of special populations
 Clinical investigation report and summary made available to subjects once complete
PAGE 7
Informed consent

8. PAGE 8
(Article 63 to 68)
Vulnerable populations
Incapacitated subjects:
 Consent of legally designated
representative
 The subject shall be part of the
consent procedure
 Subject did not refuse to participate
 No incentives
 Clinical investigation cannot be
conducted any other way
 Clinical investigation directly relates
to the subject’s condition
 Direct benefit to subject expected

9. (Article 63 to 67)
Vulnerable populations
PAGE 9
Minors:
 Consent of legally designated
representative
 Child shall be part of the consent
procedure
 Information conveyed to children
appropriately to their age
 The child did not explicitly refuse
 No incentives to participate
 Investigation of conditions relevant to
minors
 Direct benefit for the child

10. Pregnant and breastfeeding women:
 Clinical investigation has the potential to produce a direct benefit for
the pregnant or breastfeeding woman, her embryo, fetus or child
 Expected benefits outweigh the risks and burdens involved
 Avoid any adverse impact on the health of the child
 No incentives or financial inducements
(Article 63 to 67)
Vulnerable populations
PAGE 10

11. (Article 63 to 67)
Vulnerable populations
PAGE 11
Member States may maintain additional measures regarding persons
performing mandatory military service, persons deprived of liberty,
persons who, due to a judicial decision, cannot take part in clinical
investigations, or persons in residential care institutions.

12.  Sudden medical emergency, no prior consent
 Expectation of direct clinical benefit
 Consent not obtainable within therapeutic
window
 No previously expressed objections to participate
 Clinical investigation relates directly to medical
condition that prevents prior consent
(Article 68)
Emergency situations
PAGE 12
 Clinical investigation is only possible in an
emergency situation
 Clinical investigation poses only a minimal risk
compared to the standard treatment
 Consent shall be sought following intervention
 The subject (legal representative) has the right
to object to the use of data

13. (Article 68)
PAGE 13
Damage
compensation
 Responsibility of Member States to ensure
systems for compensation exist
 Insurance or guarantee appropriate to the
nature and extent of the risk

14. Application for clinical
investigation
 Article 70, Chapter II of Annex XV
 Sponsor applies to Member State
 Electronic system on clinical
investigations
 EU-wide unique ID #
 Incomplete or out of scope applications
can be amended within 10 days
 Member State may request additional
information
PAGE 14

15. Application Documentation
PAGE 15
Sponsor’s details
Investigation title
Clinical evaluation
plan
Device details
Target population
Clinical and non-
clinical evaluation
Existing clinical
data, literature
Labeling,
instructions for
use, training
Clinical procedures
Rationale,
objectives
Design
methodology
Monitoring
Record-keeping
Method of analysis
Statement of
conformity Annex I
Ethic committee
Proof of insurance
Informed consent
Description of data
protection
Application Form Investigator’s Brochure
Clinical Investigation
Plan
Other Information
Chapter II of Annex XV

16. Application form
 Sponsor’s and manufacturer’s details
 Title of the clinical investigation
 Status of the application, changes
 Clinical evaluation plan
 Clinical trial registration number if medicine
 All sites if multicenter
 Description of the investigational device
 Incorporated medicinal substance, human blood or plasma,
non-viable tissues or cells
PAGE 16
Chapter II of Annex XV

17. Application form
 Summary of the clinical investigation
plan: objectives, subjects, inclusion
criteria, design, dates
 Comparator device
 Evidence that the investigational site
are capable of conducting the
investigation as planned
 Anticipated start date and duration
 Notified body
 Statement that the device conforms
with Annex I requirements
PAGE 17

18. Investigator’s brochure (IB)
 Clinical and non-clinical information on the investigational device
 Identification and description of the device, intended purpose, risk classification
 Design and manufacturing of the device
 Manufacturer's instructions for installation, maintenance, cleaning, storage and handling
 Labeling, instructions for use, required training
PAGE 18
Chapter II of Annex XV

19. Investigator’s brochure (IB)
 Pre-clinical evaluation
 Existing clinical data: scientific literature, clinical data
 Summary of the benefit-risk analysis, side effects, contraindications and warnings
 Information on incorporated a medicinal substance
 Details how relevant general safety and performance requirements were fulfilled
 Clinical procedures and diagnostic tests used in clinical investigation
PAGE 19
Chapter II of Annex XV

20. Clinical investigation plan
Rationale, objectives
Design methodology
Monitoring, conduct
Record-keeping
Method of analysis
PAGE 20
 Clinical Investigation ID #
 Sponsor, investigator at each site
 Financing, sponsor-investigator agreement
 Synopsis, objectives, hypothesis, design, endpoints
 Measures to minimize bias
 Monitoring plan
 Data management
 Statement of compliance
 Informed consent process
 Safety reporting
 Criteria for follow-up, termination and halt
Chapter II of Annex XV

21. Other information
 Statement of conformity with Annex I
 Opinion of ethic committee
 Proof of insurance
 Patient information sheet, informed
consent
PAGE 21
Chapter II of Annex XV
 Description of measures to
comply with data protection
and confidentiality
requirements
 Upon request: technical
documentation, risk analysis,
test reports

22. Clinical Investigation may start
PAGE 22
Class I devices, non-invasive class IIa and class IIb devices:
 Immediately after validation date of the application
 No state-wide negative opinion issued by an ethics committee
Other investigational devices:
 Authorization by Member State required
 Member State concerned has notified the sponsor of its authorization
 No state-wide negative opinion issued by an ethics committee
 The Member State shall notify the sponsor within 45 days
 The Member State may extend by 20 days to consult experts
Article 70

23. Assessment by member
states
 Avoid conflict of interest
 Assessment done jointly by a team
 Design, data reliability and robustness
 Compliance with requirements
 Risk minimization solutions adequate
 Annex XV requirements
 Sterilization procedures
 Conditions when application shall be
refused by Member State
PAGE 23
Article 71

24. Conductofa
Clinical
Investigation
PAGE 24
• Sponsor and investigator shall ensure that the clinical
investigation is conducted according to approved plan
• Sponsor ensures adequate monitoring
• Information shall be recorded, processed, handled and
stored in manner that enables accurate reporting
• Implement appropriate data protection measures
• Member States are responsible for site inspections
• Sponsor has procedures for emergencies

25. Electronic system on
clinical investigations
 Maintained by the European
Commission
 ID # for clinical investigations
 Applications, notifications
 Duty to protect proprietary
information
 Interoperability with clinical trial
registry
 No personal data of subjects
available
 User interface in all official EU
languages
PAGE 25

26. Clinical investigations: devices bearing CE marking
(PMCF INVESTIGATION)
Where a clinical investigation is to be conducted to further assess a device which already bears
the CE marking, involving additional procedures for subjects that are invasive or burdensome,
the sponsor shall notify the Member States and submit relevant documentation with the
application.
PAGE 26

27. Substantial
modifications to
clinical investigations
 Sponsor shall notify the Member
State of any modifications that
may have significant impact on
patient safety
 Subject to ethics committee
approval
PAGE 27

28. Corrective measures
by member states
 Revoke authorization
 Suspend/terminate investigation
 Request modification
 All measures reportable in
electronic system
PAGE 28

29. Information at the end of clinical investigation
 Sponsor shall inform all Member
States where the investigation takes
place
 Last visit of last subject equals end of
clinical investigation
 15 days for notifications
 1 year to submit clinical investigation
report and summary
 EC shall issue guidelines on reports
 Summary stays in Eudamed
PAGE 29

30. Coordinated assessment
procedure
 Single application
 Multicentric clinical investigations
have one coordinating Member State
 Validation of application (7 days)
 Draft assessment report to other
Member States (38 days)
 Final assessment report sponsor (45
days)
 For IIb and III can be extended by 50
days
PAGE 30

31. Grounds for refusal
Member State can disagree with the
conclusion of coordinating Member
State:
 The subjects would receive inferior
treatment compared to normal practice
 Infringement of national law
 Subject safety concerns
 Data reliability and robustness concerns
 Negative opinion of ethics committee
 Noncompliance
PAGE 31

32. Reporting adverse events
Recorded by sponsor:
 Any adverse event considered critical in the
investigation plan
 All serious events regardless causality
Record and Report:
 Serious events, causal relationship
 Device deficiencies that could have resulted in
serious adverse events
 Any new findings
PAGE 32

33. Other obligations of sponsors
 Keep documentation and provide it to
competent authorities upon request
 10 years (implantable 15 years)
 Appoint a monitor
 Follow-up of subjects
 Good clinical practice
 Write clinical investigation report
PAGE 33