Clinical evaluation: Supporting medical device product life-cycle. Applicable Standards

SUPPORTING MEDICAL
DEVICE PRODUCT LIFE-CYCLE
Applicable Standards
6/DEC/2022
ARETE-ZOE, LLC 2022 - Clinical Evaluation -
Applicable Standards 1
CLINICAL EVALUATION

Clinical Evaluation: Applicable Standards
• MDR 2017/745 – Article 61
• MDR 2017/745 - Annex XIV
• MDR 2017/745 - Annex I
• MDCG 2020-5, MDCG 2020 -6, MDCG 2020-13
• MDCG 2020-7, MDCG 2020 -8
• MEDDEV 2.7/1 Rev4, MEDDEV 2.12/2 rev2, MEDDEV 2.7/4 Rev. 4
• IMDRF MDCE WG/N56 FINAL:2019
• IMDRF MDCE WG/N55 FINAL:2019
• Biological evaluation – ISO 10993-1, ISO 10993 -18
• Clinical Investigations – ISO 14155
• Information supplied - ISO 15223-1:5/2017
• Risk management – ISO 14971:6/2020 , ISO/TR 24971:2020
• Quality Management System – ISO 13485:ed2:12/2016
ARETE-ZOE, LLC 2022 - Clinical Evaluation - Applicable Standards 6/DEC/2022 2

CLINICAL EVALUATION
MDR 2017/745 Article 61
MDR 2017/745, Annex XIV, Part A

Clinical Evaluation
• Confirmation of conformity with GSPR
requirements (Annex I)
• Acceptability of Side-effects
• Benefit-risk- ratio (Sec. 1 and 8 of Annex I)
• Clinical data providing sufficient clinical
evidence (incl. PMS – Annex III)
MDR 2017/745, Article 61

Clinical Evaluation Procedure
Scientific literature on the safety, performance, design
characteristics and intended purpose of the device where:
—demonstrated the device under evaluation is equivalent for
the intended purpose (Section 3 of Annex XIV)
— the data demonstrate compliance with GSPR requirements;
Clinical investigations performed under Articles 62 to 80,
any acts adopted pursuant to Article 81, and Annex XV
Consideration of currently available alternative treatment
options for that purpose.

High-risk devices
• Option to consult an expert panel for Class III
and certain Class IIb (Article 106)
• Clinical investigation must be performed for
Class III Implantable devices (exceptions exist)

Conformity with GSPR
• Demonstration of conformity with GSPR requirements
based on clinical data is not deemed appropriate
• Justification shall be based on the results of risk
management and the specifics of the device, intended
clinical performance and claims.
• Manufacturer shall duly substantiate why it considers
non-clinical testing methods alone to be adequate.

Clinical evaluation shall be thorough and objective and
take into account both favorable and unfavorable data.
Its depth and extent shall be proportionate and
appropriate to the nature, classification, intended
purpose and risks of the device in question, as well as
to the manufacturer's claims in respect of the device.
MDR 2017/745, Annex XIV, Part A, Paragraph 2

The results of the clinical evaluation and the clinical
evidence on which it is based shall be documented in a
CLINICAL EVALUATION REPORT which shall support the
assessment of the conformity of the device.
Clinical evidence and non-clinical data shall
demonstrate CONFORMITY WITH GSPR REQUIREMENTS and
be part of the technical documentation.
Both favorable and unfavorable data must be
considered.
MDR 2017/745, Annex XIV, Part A, Paragraph 4

CLINICAL EVALUATION PLAN
ANNEX XIV – Part A

Clinical Evaluation Plan
• Identification of GSPR requirements that require clinical data
• Intended purpose
• Target groups, indications, contra-indications
• Intended clinical benefits with relevant clinical outcome
parameters
• Methods of examination of clinical safety with reference to the
determination of residual risks and side-effects
• Specify parameters of acceptability of the benefit -risk ratio
for each indication and intended purpose
• Address benefit-risk issues relating to specific components
(pharmaceutical, non-viable animal or human tissues)
6/DEC/2022 ARETE-ZOE, LLC 2022 - Clinical Evaluation - Ap p licab le Stand ard s 11

Clinical development plan
• Progression from exploratory investigations, first-in-
man studies, feasibility and pilot studies, to
confirmatory investigations
• PMCF Plan
• Define milestones and acceptance criteria

Clinical data
• Identify available clinical data
• Identify any gaps in clinical evidence through a
systematic scientific literature review
• Appraise all relevant clinical data for suitability for
establishing the safety and performance of the device
• Generate data through clinical investigations or PMCF
• Define additional clinical data necessary to address
outstanding issues
• Analyze all relevant clinical data in order to reach
conclusions about the safety and clinical performance of
the device including its clinical benefits.

GSPR REQUIREMENTS
ANNEX I

ANNEX I – Chapter I
General requirements
• Devices shall achieve the performance intended by
their manufacturer
• Shall be designed and manufactured to be suitable for
intended purpose during normal conditions of use
• Shall be safe and effective
• Any risks constitute acceptable risks when weighed
against the benefits, considering state of the art.
• Reduce risks as far as possible without adversely
affecting the benefit-risk ratio

General Requirements
Manufacturers shall establish, implement, document and maintain a
risk management system.
• Continuous process throughout the entire lifecycle of a device
• Establish and document risk management plan for each device
• Identify and analyze the known and foreseeable hazards
• Evaluate risks during intended use and foreseeable misuse
• Evaluate the impact of information from production phase (PMS)
• Amend risk control measures through design, protection
measures, information for users, training to users

General Requirements
• Manufacturers shall inform users of any residual risks
• Reduce risks of human error
• Reduce risks related to ergonomic features ( design)
• Consider users' technical knowledge, experience, education,
training and use environment
• Characteristics and performance of the device shall not be
adversely affected during normal use or transport
• Acceptable side effects and foreseeable risks
• No risk / max. acceptable risk for devices w/o medical purpose

Chemical, physical and biological properties:
• Choice of materials in regards to toxicity, compatibility,
flammability, mechanical and surface properties,
chemical and physical specifications
• Designed, manufactured and packaged to minimize risk
posed by contaminants and residues
• Designed and manufactured to be used safely with
materials and substances relevant during intended use
ANNEX I – Chapter II

Design and manufacture of devices:
Reduce risk of debris, particles and degradation products
Special requirements for invasive devices and those used to
administer and transport medicines:
• Carcinogenic, mutagenic, reprotoxic: Reg.(EC) 1272/2008
• Endocrine disruptors: Reg. (EC) 1907/2006, Reg. (EU) 528 /2012
• Phthalates
• Nanomaterials
• Labeling requirements on these substances

Infection and microbial contamination:
• Design and manufacture shall eliminate risk of infection
(safe handling, microbial leakage, contamination)
• Facilitate safe cleaning, disinfection, sterilization
• Sterile devices shall be designed, manufactured, labeled,
and packaged to remain sterile
• Drug-device combinations – drug component shall comply
with Directive 2001/83/EC

Devices with materials of biological origin:
• Donation, procurement and testing of the tissues and
cells shall be done in accordance with
Directive 2004/23/EC
• Traceability: Directives 2004/23/EC and 2002/98/EC
• Tissues or cells of animal origin: Reg.(EU) No 722/2012
• Non-viable biological substances: safe for patients and
users, appropriate sourcing, inactivation, disposal

Special types of devices
• Devices used in combination with other devices
• Devices with diagnostic or measuring function -
Directive 80/181/EEC
• Radiation emitting devices - Directive 2013/59/Euratom
• Electronic programmable systems (software)
• Active devices
• Active implantable devices
• Devices supplying energy or substances

Protection against the risks posed by lay persons
• Devices for use by lay persons shall be designed and
manufactured appropriately considering users’ skill level
• Instructions /training appropriate for lay person
• Device can be used safely and accurately by the intended user
• Reduce the risk from unintended cuts and pricks
• Reduce the risk of handling error and result interpretation
• Lay person can verify that the device will perform as intended
• User is warned in case of failure

Protection against the risks posed by lay persons
• Devices for use by lay persons shall be designed and
manufactured appropriately considering users’ skill level
• Instructions /training appropriate for lay person
• Device can be used safely and accurately by the intended user
• Reduce the risk from unintended cuts and pricks
• Reduce the risk of handling error and result interpretation
• Lay person can verify that the device will perform as intended
• User is warned in case of device failure

Information supplied with the device
• WHAT: Device identification, manufacturer, relevant
safety and performance information
• WHERE: on the device, packaging, IFU, website
• HOW: appropriate to device and user
• LABELS: human readable, RFID, barcode
• IFU not required for Class I and IIa
• A single copy for multiple users when agreed
• Electronic format, Reg.(EU) No 207/2012
• Residual risks must be communicated
• Internationally recognized CS symbols
ANNEX I – Chapter III

Information on the label
• Name or trade name of the device
• Device identification, intended purpose
• Manufacturer's name and address, authorized representative
• An indication that the device contains a medicinal substance, human
blood or plasma derivative, human tissues or cells, animal tissues or
cells
• Lot number, serial number, UDI carrier
• Time limit for using or implanting the device safely, date of
manufacture
• Storage and /or handling condition
• Sterile state and the sterilization method
• Warnings or precautions
• Single use, reprocessing (total and remaining cycles)
• Custom-made device
• Medical device / ‘exclusively for clinical investigation’
• Substances, combinations of substances, overall composition

Sterile packaging
• Indication the packaging is sterile
• Declaration that the device sterile
• Method of sterilization
• Name and address of the manufacturer
• Description of the device
• ‘exclusively for clinical investigations’
• ‘custom-made device’
• Month and year of manufacture
• Time limit for using or implanting the device safely
• What to do if the sterile packaging is damaged

Instructions for Use
• Intended purpose, indications, contra-indications, target
groups, users
• Clinical benefits, performance of the device
• Residual risks, contra-indications, undesirable side-effects
• Special facilities, training, qualifications required
• Maintenance, cleaning, disinfection, sterilization, reuse, re -
sterilization
• Appropriate combinations of devices and equipment
• Warnings, precautions, contra-indications, limitations of use
• Infection, microbial and physical hazards
• When to consult a healthcare professional
• Date of issue
• Where to report serious incidents

Instructions for Use
• Sterilization, assembly, calibration
• Radiation: characteristics of radiation, protection of
patients /users
• Information for patients if implanted device
• Links to Summary of Safety and Clinical Performance (SSCP)
• Software compatibility and requirements
• Degree of accuracy for devices with a measuring function

DEMONSTRATION OF EQUIVALENCE
ANNEX XIV, Part A
MDCG 2020-5

A clinical evaluation may be based on clinical data relating to a
device for which equivalence to the device in question can be
demonstrated:
• Technical: similar design, similar conditions of use, has similar
specifications and properties, similar deployment methods,
similar principles of operation and critical performance
requirements.
• Biological: the same materials in contact with the same human
tissues or body fluids for a similar kind and duration of contact;
similar release characteristics
• Clinical: the same clinical condition or purpose, the same body
site, similar population, the same kind of user, similar relevant
critical performance.
Demonstration of Equivalence

• No clinically significant difference in the safety
and clinical performance of the device.
• Proper scientific justification.
• Manufacturers have sufficient levels of access to
the data relating to devices with which they are
claiming equivalence
Demonstration of Equivalence

• Covers demonstration of equivalence
• Highlights differences MEDDEV 2.7/1 rev. 4 vs. MDR
• Use of data from similar device
• Clinical data identification
• Equivalence table – technical, biological and
clinical characteristics
MDCG 2020-05
MDCG 2020-5: EQUIVALENCE

CLINICAL DATA
MEDDEV 2.7/1 Rev4
IMDRF MDCE WG/N56 FINAL:2019

• Device description
• Specific concerns
• Info needed to demonstrate equivalence
• Risk management documents
• State of the Art and clinical background
• Data generated and held by the manufacturer
• Literature
• Changes – design, materials, information
• Updates from PMS
MEDDEV 2.7/1 Rev4
SCOPE DEFINITION

• Premarket clinical investigations
• Clinical data from RM and PMS activities
• PMCF studies
• PMS reports
• Literature
• Incidents, complaints
• FSCAs, recalls
• Preclinical studies
IDENTIFICATION OF PERTINENT DATA
Data held by manufacturer
MEDDEV 2.7/1 Rev4

• Device under evaluation or equivalent device
• SOTA – benchmark devices, guidelines and
standards, clinical background
→ identify potential clinical hazards
→ validity of surrogate endpoints
• Sources (MEDDEV, App. 4)
• Literature search and review protocol
• Literature search report
IDENTIFICATION OF PERTINENT DATA
Literature
MEDDEV 2.7/1 Rev4

• Comparability of Device (App. A)
• Literature search report format (App. B)
• PRISM flowchart (App. C)
• Data from different jurisdictions – demographics, clinical
practice, social factors regional diseases (App. D)
• Criteria for methodological and scientific validity (App. E)
• Appraisal (App. F)
LITERATURE SEARCH PROTOCOL & REPORT

Criteria
• Methodological quality and scientific validity
• Relevance of the dataset
• Weighting the contribution of each data set
The criteria adopted should reflect the nature,
history and intended clinical use of the device.
Appraisal plan should be documented in the
clinical evaluation report.
APPRAISAL OF PERTINENT DATA
MEDDEV 2.7/1 Rev4

APPRAISAL: SUITABILITY CRITERIA

APPRAISAL: DATA CONTRIBUTION

SAFETY
• RM and IFU must be consistent with clinical data available
BENEFIT:RISK PROFILE
• Evaluation of the description of the intended purpose
• Benefits to patient
• Quantification of benefit to patient
• Clinical risks of the device
• Acceptability of benefit:risk profile
PERFORMANCE
• The device achieves intended performance under normal conditions of use
• Sufficient clinical evidence exists
UNDESIRABLE SIDE EFFECTS
• Must be acceptable compared to benefits
ANALYSIS OF PERTINENT DATA
MEDDEV 2.7/1 Rev4, Appendix 7

PERFORMANCE
• Identify relevant datasets and demonstrate how they support
performance characteristics
SAFETY
• Describe total experience including numbers
• Specify any training required for end user
LABELING
• Labeling consistent with the clinical data available?
ANALYSIS OF PERTINENT DATA

• Conclusions reached about the safety, clinical performance
and/or effectiveness of the medical device from the
evaluation, with respect to the intended use of the device.
• Risks identified addressed by the clinical data?
• For each proposed clinical indication: clinical evidence
demonstrates conformity with relevant Essential Principles
- safety, clinical performance /effectiveness and the risks,
benefit:risk
CONCLUSIONS

1 General details
2 Description of the medical device and its intended application
3 Intended therapeutic and/or diagnostic indications and claims
4 Context of the evaluation and choice of clinical data types
5 Summary of the clinical data and appraisal
6 Data analysis
6.1 Performance
6.2 Safety
6.3 Product labeling
7 Conclusion
WRITING A REPORT

CLINICAL EVALUATION UPDATE

LIFECYCLE MANAGEMENT
6/DEC/2022 48
Product launch
PMS Plan
PSUR
RM ISO 14971
CER
MDR 2017/745 Article 61 (12)
MEDDEV 2.7.1 Rev. 4
83.3 Annex III 1.1B
CAPAs
Changes
Vigilance
(own product)
PMCF
MDCG 2020-7, MDCG 2020-8
Literature
MDR 2017/745
MEDDEV 2.7/4 rev.4
PMCF Studies
MEDDEV 2.12/2
Vigilance databases
(equivalent and similar)
Complaints, Feedback
(own product)
PMS & PMCF

POST-MARKET SURVEILLANCE
Annex III 1.1

• Update the benefit-risk determination (Chapter I, Annex I)
• Update design /manufacturing information, IFU and labelling
• Update the clinical evaluation
• Update the SSCP (Article 32)
• Identify needs for FSCA
• Improve usability, performance and safety of the device
• Contribute to the post-market surveillance of other devices
• Detect and report trends (Article 88)
POST-MARKET SURVEILLANCE SYSTEM
PMS shall be used to

• Serious incidents
• PSURs, FSCAs
• Non-serious incidents, undesirable side-effects
• Trend reporting
• Relevant specialized or technical literature
• Databases and registers
• Feedback and complaints from users, distributors
• Publicly available information about similar devices
POST-MARKET SURVEILLANCE PLAN
Collection and utilization of information:

• Correct characterization of the performance of the devices
• Comparison between the device and similar products
• Effective and appropriate assessment of the collected data
• Continuous reassessment of benefit:risk using suitable indicators
and threshold values
• Effective investigation of complaints and market-related experience
• Management of Article 88 events subject to the trend report
• Effective communication with competent authorities, notified
bodies, economic operators and users
• Procedures in Articles 83 (PMS), 84 (PMS Plan) and 86 (PSUR)
• Identify and initiate appropriate measures (CAPA, FSCA)
• Tools to trace and identify devices where CAPAs apply
• PMCF plan or justification why no PMCF applies
POST-MARKET SURVEILLANCE SYSTEM
PMS process shall achieve

POST-MARKET CLINICAL FOLLOW-UP
ANNEX XIV, Part B
MDCG 2020-7 (Plan)
MDCG 2020-8 (Report)
MEDDEV 2.12/2 rev 2

PMCF plan specifies methods for collecting and evaluating
clinical data:
• Confirm safety and performance through device lifecycle
• Identify new side-effects
• Monitor known side-effects and contraindications
• Identify and analyze emergent risks
• Ensure continued acceptability of benefit-risk ratio
• Identify possible systematic misuse or off-label use
PMCF PLAN
ANNEX XIV – Part B

General methods and procedures: gathering of clinical experience,
feedback from users, literature, other sources of clinical data
Evaluation of suitable registers or PMCF studies
Rationale for the appropriateness of PMCF methods
Reference to the clinical evaluation report and the risk management file
Specific objectives to be addressed by the PMCF
Evaluation of clinical data relating to equivalent or similar devices
Adequately justified time schedule
Analyze findings, document results in a PMCF report (part of CER)
Consider conclusions in clinical evaluation and risk management file
PMCF PLAN
ANNEX XIV – Part B

Section A. Manufacturer contact details
Section B. Medical Device description and specification
Section C. Activities related to PMCF - general and specific
methods and procedures
Section D. Reference to the relevant parts of the technical
documentation
Section E. Evaluation of clinical data relating to equivalent or
similar devices
Section F. Reference to any applicable common
specification(s), harmonized standard(s) or applicable
guidance document(s)
Section G. – Estimated date of the PMCF evaluation report
MDCG 2020-7 (PLAN)

GENERAL
• Screening of literature
• Survey from patients /users
• Survey from health professionals
• Complaints, vigilance
SPECIFIC
• Device registry – own and similar
• National public registries
• PMCF studies – summary, design, sample size, endpoints,
inclusion /exclusion
• RWD/RWE analyses
Activities related to PMCF:
MDCG 2020-7 (PLAN)

• Manufacturer contact details
• Medical Device description and specification
• Results of PMCF activities
• Evaluation of clinical data reg. equivalent or similar devices
• Impact of the results on the technical documentation
• Reference to any common specification(s), harmonized standard(s)
or guidance document(s) applied
• Conclusions
PMCF REPORT
MDCG 2020-8 (REPORT)

• Innovation
• Significant changes to the products or its intended use
• High product-related risk
• High-risk anatomical locations, target populations, severity of disease
• Ability to generalize clinical investigation results
• Long-term safety and performance
• Results from any previous clinical investigation
• Previously unstudied subpopulations
• Continued validation throughout the expected life of the product
• Risks identified from the literature for similar marketed devices
• Interaction with other medical products or treatments
• Larger and more varied population of clinical users
• Emergence of new information on safety or performance
• Where CE marking was based on equivalence
PMCF STUDIES ARE JUSTIFIED:
MEDDEV 2.12/2

PMCF studies may not be required when the
medium/long-term safety and clinical
performance are already known from previous
use of the device or where other appropriate
post-market surveillance activities would provide
sufficient data to address the risks.
PMCF STUDIES NOT REQUIRED:
MEDDEV 2.12/2

OTHER CONSIDERATIONS
MDCG 2020-6

• IMDRF MDCE WG/N55 FINAL:2019 – Clinical Evidence – Key
definitions and concepts
• MDCG 2020-6 - Clinical evidence needed for legacy devices
• MEDDEV 2.7/1 rev.4 – Clinical Investigations
• ISO 10993-1 - Biological evaluation
• ISO 14155 - Clinical Investigations
• ISO 15223-1:5/2017 - Information supplied
• ISO 14971:6/2020 - Risk management
• ISO 13485:ed2:12/2016 - Quality Management System
OTHER STANDARDS TO CONSIDER

CLINICAL EVALUATION CHECKLIST
MDCG 2020-13

MDCG 2020-13: TEMPLATE CEAR
ARETE-ZOE, LLC 2022 - Clinical Evaluation - Ap p licab le
Stand ard s 6/DEC/2022 64

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6/DEC/2022 65
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