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10.2 Evaluation of Medical Devices in Europe 225
● Application Form
Presents information on the sponsor, the device, the proposed locations and commence-
ment dates for studies, etc.
● Investigators Brochure.
● Clinical Investigation Plan.
● Other documentation
For example proof of insurance cover, informed consent form that will be used, data
protection measures (personal data).
Figure 10.3 Documentation required for a Clinical Investigation application.
10.2.3 Performance Evaluation of IVDs
Although the terminology and some of the details dier, the process of conrming
the general safety and performance requirements of IVDs share many of the
principles and procedural steps already outlined for other medical devices. The
manufacturer must conduct and document a systematic performance evaluation to
demonstrate the scientic validity, analytical performance and clinical performance
of the IVD. Similarly, it should be based on a review of relevant scientic literature
and available data and should establish what further performance studies may be
required. Again, it should be a continuous process that encompasses information
obtained through the post- manufacturing performance follow-up (PMPF) plan.
In the case of class C and D devices, the performance evaluation report must be
updated at least annually to reect new data obtained via the PMPF plan.
10.2.4 Performance Studies of IVDs
Performance studies that require surgically invasive sample-taking (blood or tis-
sue sampling) specically for the purpose of the study, involve additional invasive
procedures, or are interventional clinical performance studies that may inuence
patient management, must be authorised. Studies utilisingurine or saliva samplesor
left-over blood or tissue samples do not require authorisation but the personal data
rights of the individual must be protected and ethical considerations require that
informed consent be obtained for the use of these samples for research purposes.
Many institutions use a general consent form when taking samples from patients.
The application process and timelines for approval of performance studies are the
same as for clinical investigations: an application is submitted to Member States
via EUDAMED and the authorities are allowed 10 days to validate and 45 days to
assess it. Interventional clinical performance studies and studies involving signi-
cantly invasive procedures or that may otherwise put subjects at risk require suc-
cessful assessment of the application by the authorities before the study can com-
mence whereas all other studies can go ahead once the application has been vali-
dated and there is no objection froman ethics committee. Studies must be conducted
on the basis of a clinical performance study plan (CPSP, see Figure 10.4) and the
results and conclusions documented in a performance study investigation report.
226 10 Authorisation of Medical Devices
The identication number of the clinical performance study
Identication of the sponsor
Identication of the investigator(s)
Start date and planned duration
Identication of the device
Specimen type
Overall synopsis of the study
A description of the expected risks and benets
The instructions for use of the device or test protocol
A description of and justication for the design of the clinical performance study
The analytical performance
Clinical performance parameters to be determined by the study
Information on the study population
Information on use of data out of left-over specimens
Monitoring plan
Data management
Decision algorithms
Policy regarding any amendments
Accountability regarding the device, control of access
Statement of compliance with the recognised ethical principles
Informed consent process
Procedures for safety recording and reporting
Criteria and procedures for suspension or early termination
Criteria and procedures for follow-up of subjects
Procedures for communication of test results (to subjects)
Policy as regards the establishment of the clinical performance study report
List of the technical and functional features of the device
Bibliography
Figure 10.4 Information to be contained in a Clinical Performance Study Plan (CPSP).
The requirements for notication of the end of the study, preparation of the study
report, the summary for public consumption and adverse reporting are identical to
those for clinical investigations.
10.3 Evaluation of Medical Devices in the US
The conduct of studies of medical devices in the US that have not been
cleared/approved by the FDA is regulated via Investigational Device Exemp-
tion (IDE) regulations set out in 21 CFR Part 812. Considering the type of device
and the level of associated risk involved, investigations may be conducted as IDE
exempted studies, abbreviated requirement studies or studies subject to full IDE
requirements.
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10.3 Evaluation of Medical Devices in the US 227
10.3.1 Exempted Investigations
Exempted investigations may be conducted where the studies pose negligible risk to
subjects. These include:
● Investigations of devices that have already received FDA-clearance due to the fact
that they were already on the market before medical devices were regulated or
were shown to be substantially equivalent to one,
● Diagnostic devices that are non-invasive, do not require signicantly risky sam-
pling procedures and do not introduce energy (e.g. X-rays, ultrasound) into the
subject. Study results may not be relied on for diagnosis,
● Devices undergoing consumer preference, rather than safety and eectiveness
testing,
● Devices for veterinary use or intended for research on or with laboratory animals
and
● Custom devices, provided the studies are not being used to establish safety and
eectiveness for commercial distribution.
While there is no FDA involvement in such investigations, ethical considerations
and institutional regulations would generally dictate that informed consent and the
approval of the local institutional review board (IRB) be obtained. However, due to
the negligible risks involved these are likely to be a formality and will not involve
extensive review or scrutiny.
10.3.2 Abbreviated Requirement Investigations
Many investigations that do not involve highly invasive devices, risky procedures
and/or frail patients can be conducted under abbreviated requirements applicable to
devices that are not considered signicant risk devices. The sponsor does not have to
submit an IDE application to the FDA. Instead, review and approval of such studies
is the responsibility of IRBs. However, where there is any doubt, it is good prac-
tice to get advance conrmation from the FDA that the device can be designated
as a non-signicant risk device. The investigations are subject to some of the mea-
sures associated with a standard IDE investigation, such as study monitoring by the
sponsor, recording and reporting of adverse events and the prohibition on promo-
tion or advertising. A comparison of the dierences in requirements between the
investigation of a non-signicant risk device and a signicant risk device is shown
in Table 10.1.
10.3.3 IDE Investigations
Investigations involving signicant risk devices require prior approval by the FDA.
A device is considered signicant risk if it presents a potential for serious risk to
the health, safety or welfare of a subject. Implants, devices that are life-supporting
228 10 Authorisation of Medical Devices
Table 10.1 Comparison of requirements for investigations involving non-significant
risk vs. significant risk devices.
NSR SR
Requirement S I S I
Submit an IDE application to FDA
√
Report adverse eects to sponsor
√ √
Report adverse eects to IRB
√ √ √ √
Report adverse eects to FDA
√
Report withdrawal of IRB approval to sponsor
√ √
Submit progress reports to sponsor, monitor and IRB
√ √
Report deviations from investigational plan to sponsor and IRB
√
Obtain document and retain records of informed consent
√ √
Report use of device without informed consent to sponsor and IRB
√ √
Compile records of adverse eects and complaints
√ √
Maintain all records of correspondence
√ √
Maintain records of device shipment use and disposal
√ √
Document day and time of use of each device
√
Maintain signed investigator agreements
√ √
Investigator list to FDA every six months
√
Progress reports to IRB at least yearly
√ √
Yearly progress reports to FDA
√
Final study report to FDA
√
Final study report to IRB’s
√ √
Monitor study and ensure compliance with protocol
√ √
Notify IRB’s if an investigational device has been recalled
√ √
Comply with promotion and advertising prohibitions
√ √ √ √
Comply with investigational device labelling requirements
√ √
NSR = non-signicant risk device investigations; SR = signicant risk device investigations.
S = sponsor; I = investigator.
Requirement dierences are shaded.
or sustaining and devices that are of substantial importance in diagnosing, treat-
ing or mitigating disease or otherwise preventing health impairment generally fall
into this category. An IDE application must be submitted to the FDA Center for
Devices and Radiological Health (CDRH), accompanied by the information out-
lined in Figure 10.5. The required content of an Investigational Plan is shown in
Figure 10.6. The FDA are allowed 30 days to review and approve or reject the appli-
cation. Changes to an approved IDE must be submitted to the FDA for approval
as a supplemental IDE unless the changes are emergency changes necessitated to
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10.3 Evaluation of Medical Devices in the US 229
Investigational Plan
Reports of previous investigations and a summary of the proposed investigational plan or
the plan itself.
Methods, Facilities, Controls
A description of the methods, facilities, and controls used for the manufacture, processing,
packing, storage, and, where appropriate, installation of the device
Investigators
A list of investigators and an example of the agreement that they have entered into to
comply with their obligations
Certication of Investigator Agreements
Certication that the list of investigators is complete, that they have signed the agreement
and new investigators must also sign the agreement before participating
IRB Information
A list of names and address of chairpersons of Institutional Review Boards (IRBs) that have
been asked to review the investigation
Other Institutions
The names and addresses of other institutions that may be involved in part of the inves-
tigation but are not identied under the IRB listing e.g. institutions that may perform
supporting analytical testing
Device Charges
Proposed nancial charges for devices that will not be provided free
Environmental Assessment
Certicate of exclusion from environmental assessment or assessment report as applicable
Labelling of Devices
Figure 10.5 Documentation to be provided with an IDE application.
preserve life or well-being, or developmental changes and alterations to protocols
that do not signicantly change the validity or safety of the investigations. These
should be notied to the FDA, ve days in advance of developmental or protocol
amendments and ve days after an emergency change. An overview of the proce-
dures available for the investigation of devices is shown in Figure 10.7.
10.3.4 Labelling of Devices for Investigational Use
Devices intended for clinical investigations must bear thefollowing statement on the
labelling: ‘CAUTION--Investigational device. Limited by Federal (or United States)
law to investigational use’. Devicesintended solely for researchon or with laboratory
animals should be labelled with ‘CAUTION--Device for investigational use in labo-
ratory animals or other tests that do not involve human subjects’. In vitro diagnostic
reagents for eld trial studies should bear the statement ‘For Investigational Use
Only. The performance characteristics of this product have not been established’. If
the reagent is intended for an earlier stage laboratory investigation, then the label
should state ‘For Research Use Only. Not for use in diagnostic procedures’.
230 10 Authorisation of Medical Devices
Purpose
Device description and intended use and objectives and duration of investigation
Protocol
Methodology to be used to conduct and analyse the study
Risk analysis
Risks identied from riskanalysis measures to minimise and controlrisks and information
on subject selection
Description of the device
A description of each signicant component/ingredient of the device and its function and
how it might change during the investigation
Monitoring Procedures
A description of the procedures that will be used to monitor the study
Labelling
Consent Materials
Copies of forms and informational materialsusedto obtain informed consent from subjects
IRB Information
Lists of names and addresses of chairpersons of IRB’s that will review the investigations
Other institutions
A list of other institutions that may be involved in part of the investigation without IRB
oversight
Additional Records and Reports
A description of any additional records or reports that may be maintained above those
legally required
Figure 10.6 Required content of an Investigational Plan.
10.4 Placing of Devices on the Market in the EU
Before a device can be legally placed on the market in Europe, it must go through an
appropriate conformity assessment process to establish that it meets all the general
safety and performance requirements of the applicable regulation. This enables the
manufacturer to make a formal declaration of conformity and apply the CE mark
of conformity to the device. The manufacturer, or an authorised representative (EC
Rep), who takes on the responsibilities imposed by the regulations on behalf of the
manufacturer, must be established in the EU.
10.4.1 Designation of Notified Bodies
As Notied Bodies play a pivotal role in certication of all but low-risk medical
devices the new regulations place greater emphasis on how Notied Bodies are des-
ignated for the tasks that they are deemed competent to perform. Part of the reason-
ing behind this is that, once a Notied Body has been designated by the Member
State in which it is established, it can deliver its designated assessment services
to enterprises in any Member State or third country that require the involvement
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10.4 Placing of Devices on the Market in the EU 231
Yes
No
No
Yes
Reject Approve
Device
investigation
Exempted?
Expedited
IRB review
IDE
regulations
apply
Significant
risk?
IRB
approves study
Submit an IDE
application
FDA
30 days
review
FDA
decision
IRB
approves study
Respond to
FDA
questions
Conduct
investigation
Conduct
investigation
Conduct
investigation
Figure 10.7 Decision tree for conducting investigations of medical devices in the US.
of a Notied Body to establish conformity with EU legal requirements. Thus, to
ensure consistency of standards across the EU, an assessment team for review of
an application for Notied Body status must include three experts, one representing
the Commission and two drawn from a panel nominated by the Members States,
excluding the state where the applicant is established. The Competent Authority of
the Member State of the applicant will lead the on-site assessment conducted by the
assessment team, prepare draft reports and conduct any necessary follow-up with
the applicant. However, thedesignation decision may onlybe issued by the authority
on foot of a favourable opinion from the assessment team and the recommendation
of the Medical Device Coordination Group (MDGC) and it remains possible for the
Commission or any other Member State to raise justied objections. The details of
the designation are published on a NANDO database, an IT system that holds infor-
mation on all Notied Bodies established under various EU regulations. The main
232 10 Authorisation of Medical Devices
Applicant submits an application for designation to the Competent Authority of the Member
State where they are established
Competent Authority checks that the application is complete, and prepares a preliminary
assessment report
30 days
Validated application and preliminary assessment report sent to Commission who
immediately forward the assessment report to the MDCG
The Commission, in conjunction with the MDCG appoint a joint assessment team
14 days
Joint assessment team review the application documentation
Joint assessment team together with Competent Authority conduct site inspections at all
relevant sites
90 days
Competent Authority issue report to applicant identifying any non-conformances that require
corrective action
Applicant prepares a corrective action plan to address non-conformances
When corrective and preventive actions have been appropriately addressed, the Competent
Authority prepares a final assessment report and, if applicable, the draft designation to the
Commission, MDCG and joint assessment team
Joint assessment team provide a final opinion to the Commission who forward it to the MDGC
21 days
MDCG provide a recommendation as regards designation to the Competent Authority
42 days
Member state notifies the Commission and all Member States of its decision to designate the
applicant via NANDO
28 days
Window for other Member States to raise objections
14 days
Commission issue Identification Number to Notified Body and publicly list on NANDO
Figure 10.8 Outline of the main steps in the designation process for Notified Bodies.
steps in the process and specied timelines are outlined in Figure 10.8. Once desig-
nated, a Notied Body will be subject to ongoing monitoring that includes an annual
review and observations of personnel conducting quality audits.
10.4.2 Conformity Assessment Procedures
Dierent conformity assessment options are available depending on the type of
device and the level of associated risk. For low-risk devices (Class 1 and A), the
manufacturer can make a declaration of conformity based solely on self-assessment
without the need for involvement of a Notied Body. For all other devices Notied
Bodies are required to perform one or more of the certication tasks outlined
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10.4 Placing of Devices on the Market in the EU 233
Table 10.2 Certification activities of Notified Bodies.
Quality systems certification Device certification
Quality management system certicate
Certication based on auditing against a
quality management system standard for
design, production and nal inspection
(i.e. ISO 13485)
EU technical documentation
assessment certicate
Certication based on examination of the
design dossier vs. standards/general safety
and performance requirements (paperwork
review + verication testing of Class D IVDs)
EU quality assurance certicate/EU
production quality assurance certicate
Certication based on auditing against a
quality system standard for production and
nal inspection (i.e. ISO 13485 – design
control)
EU Type-examination Certicate
Certication of design based on testing of
physical samples vs. standards/general
safety and performance requirements
EU product verication certicate
Certication of individual production
batches based on testing of all or samples of
the batch vs. standards/acceptance criteria
in Table 10.2. HIV, hepatitis and blood grouping tests represent the highest risk
devices, as they are critical to ensuring the safety of blood and blood products.
For example, a defective HIV test device could result in widespread infection in
an unsuspecting population, whereas the detrimental eects of a Class III device
failure will just be conned to the individuals treated by the device. At this end of
the risk spectrum, Notied Bodies are required to verify the applied quality system,
the specic device design, and the nal testing of individual batches. The various
options that may be applied to dierent categories of device are summarised in
Figure 10.9.
The purpose of all the conformity assessment procedures is to ensure that
the device as designed and as subsequently manufactured will meet the general
safety and performance requirements. For most devices where Notied Body
involvement is required, the manufacturer may choose between the strategies of
relying on the application of appropriate quality systems or independent testing to
demonstrate this.
10.4.2.1 Conformity Assessment Based on a Quality Management System
and Assessment of Technical Documentation
This is the preferred option for high-risk devices, where the development of the
device has been subject to design controls. The manufacturer must lodge an appli-
cation with a Notied Body to have their quality management system and technical
documentation relating to the device assessed accompanied by information on the
quality system and the relevant technical les.
The Notied Body will conduct on-site audits of the quality management system
to verify that it conforms with requirements. For Classes III, IIb, IIa, C and D devices
the quality system must be routinely audited at least once a year and in addition be
234 10 Authorisation of Medical Devices
Medical Devices Regulation 2017/745 In Vitro Diagnostic Medical Devices
Regulation 2017/746
Class III
EU Technical Documentation Assessment
Certification (specific device)
and
Quality Management System Certification
(Annex IX)
Or
EU Type-examination Certification (Annex X)
+
EU Quality Assurance Certification (Annex XI)
or
EU Product Verification Certification (Annex XI)
Class D
EU Technical Documentation Assessment
Certification (specific device)
and
Quality Management System Certification
(Annex IX)
+
Independent batch verification
Or
EU Type-examination Certification (Annex X)
+
EU Quality Assurance Certification (Annex XI)
+
Independent batch verification
Class IIb
EU Technical Documentation Assessment
Certification (group representative device /
specific implantable device)
and
Quality Management System Certification
(Annex IX)
Or
EU Type-examination Certification (Annex X)
+
EU Product Verification Certification (Annex XI)
Or
EU Product Verification Certification (Annex XI)
Class C
EU Technical Documentation Assessment
Certification (group representative device)
and
Quality Management System Certification
(Annex IX)
Or
EU Type-examination Certification (Annex X)
+
EU Production Quality Assurance Certification
(Annex XI)
Class IIa
EU Technical Documentation Assessment
Certification (category representative device)
and
Quality Management System Certification
(Annex IX)
Or
Technical documentation (Annexes II and III)
+
EU Quality Assurance Certification (Annex XI)
or
EU Product Verification Certification (Annex XI)
Class B
EU Technical Documentation Assessment
Certification (category representative device)
and
Quality Management System Certification
(Annex IX)
Class I
EU Declaration of Conformity based on technical
documentation (Annexes II and III)
Class A
EU Declaration of Conformity based on technical
documentation (Annexes II and III)
R
i
s
k
Figure 10.9 Conformity assessment options available to manufacturers for different types
of device.
subjected to one unannounced inspection every ve years. The regulations do not
contain surveillance requirements for other classes of devices, but the norm is that
quality systems are inspected annually by the certifying body.
In the case of Classes III, IIb implantable (except for sutures, staples, dental
llings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and
connectors) and D the assessment of technical documentation must be based on
the dossier for the device in question. For other Class IIb and Class C devices, the
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