MEDDEV 2.7/1 revision 4 (June 2016) Section 6a of Annex I to DIR 93/42/EEC Section 5a of Annex I to DIR 90/385/EEC (both amended by DIR 2007/47/EC)

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Section 6a of Annex I to DIR 93/42/EEC
Section 5a of Annex I to DIR 90/385/EEC
(both amended by DIR 2007/47/EC)
Essential Requirements
Annex X to DIR 93/42/EEC
Annex 7 to DIR 90/385/EEC
The Depth and Extent of Clinical
Evaluations should be flexible and
appropriate to the intended Purpose
and Risks of the device
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3. Yes, it is possible. I broke one myself.
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Male mandible after surgery
Very badly aggravated female
All materials left in situ
following your encounter with
an aggravated female have to
be appropriately tested and
safe to use.
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Not legally binding
Common practice
Subject to change
DIR 90/385/EEC (AIMD)
DIR 90/42/EEC (MD)
REG 722/2012 (animal origin)
REG 920/2013 (notified bodies)
ISO 14155:2011 MD GCP
ISO 14971:2012 MD RM
MEDDEV series
Manual on borderline & classification
NBOG BDP series
GHTF SG5 guidance
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AIMDD – Active Implantable Medical Device Directive
CEAR – Clinical Evaluation Assessment Report
CER – Clinical Evaluation Report
ER – Essential Requirement
IFU – Instructions for Use
MDD – Medical Device Directive
PMS – Post Market Surveillance
PMCF – Post Market Clinical Follow-Up
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6.  Adverse Event - any untoward medical occurrence in subjects, users or other persons, related or not
 Bias – systematic deviation of an outcome measure from its true value
 Clinical data – safety/performance information generated from clinical use
 Clinical evaluation - methodologically sound collection, analysis and appraisal of clinical data
 Clinical evidence - clinical data and clinical evaluation report
 Clinical investigation (clinical study) – systematic investigation in one or more human subjects
 Clinical Investigation Plan – rationale, objectives, design, proposed analysis, methodology
 Clinical performance – behavior of device or subject’s response in relation to intended use
 Device registry - organized data collection system under normal conditions of use
 Clinical safety - freedom from unacceptable clinical risks
 Clinical use – use in living humans
 Equivalent device – a device for which equivalence can be demonstrated
 Feasibility study - preliminary investigation needed to plan future investigation
 Hazard – potential source of harm
 Hazard due to substances and technologies – products that share the same technologies
 Incident – malfunction or deterioration of device, inadequacy in IFU which might lead to death
 Information materials supplied by the manufacturer - Labeling, IFU, promo materials
 Intended purpose – intended use in the labelling, IFU and promotional materials
 Investigator - Individual member of the investigation site team
 PMCF plan – organized collection of clinical data based on the use of a CE-marked device
 PMCF study – a study on a CE-marked device used in accordance with IFU
 Risk – probability and severity of occurrence of harm
 Risk management – systematic application of policies, procedures and practices to analyzing, evaluating,
evaluating, controlling and monitoring risk
 Serious adverse event – death, life-threatening illness/injury, permanent impairment, hospitalization,
 Sufficient clinical evidence – amount and quality of evidence that guarantees scientific validity
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Stage 0
Scope, Plan
Sec. 4, A3
Stage 1
Identification of pertinent data
Sec. 8, A4-A5
Stage 2
Appraisal of
pertinent data
Sec.9, A6
Stage 3
Analysis of clinical data
Sec.10, A7-A8
Stage 4
CER+PMS/PMCF plan
Sec. 11, A9-A10
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8. WhatWhen&Why
 Methodologically sound
 Collection, appraisal & analysis of clinical data
 Benefits & risks
 CER is a part of the technical documentation
› Conformity to the Essential Requirements
› Intended purpose
› Clinical performance
› Measures for risk avoidance
› Usability
› Suitability of IFU
 Mandatory for initial CE-marking
› Define safety/performance needs
› Equivalence
› Gap analysis
 Post-market surveillance
› Conformity with Essential Requirements
› Identify need for PMCF studies
› Active updates throughout the device life cycle
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9.  Suitably qualified individual or team
 Manufacturer should justify the choice of evaluator
 Documented qualification and experience
› Research methodology
› Information management
› Regulatory requirements
› Medical writing
› Device technology
› Clinical expertise
› A relevant degree + 5 years experience or 10 years relevant experience
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10. SCOPECLINICALEVALUATIONPLAN
 Based on essential requirements
 Basis for future steps
 Both favorable and unfavorable data
Aspects Before
CE
After CE
Device description (A3) YES YES
Special performance or safety concerns YES YES
Information for evaluation of equivalence YES
Risk management documents YES YES
Medical condition, standards, alternatives YES YES
Data source and type YES YES
Changes to design, materials, manufacturing YES
Specific new clinical concerns YES
PMS: new clinical data, performance, risks,
benefits, hazards, claims, treatment standards
Both the device and its equivalent
YES
PMS planning needs YES
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11. ORIGINOFPERTINENTDATA
Manufacturer Literature
Premarket clinical investigations Device & Equivalent
Risk management activities Current knowledge
PMS programs (global) Standards, guidelines
PMCF studies Clinical background
PMS reports Potential clinical hazards
Adverse incidents Validity o equivalence criteria
Complaints Validity of surrogate endpoints
Explanted devices analysis Objective search strategy (A4)
User reports (custom use device,
compassionate use)
Literature search and review
protocol (A5)
FSCAs Appraisal of clinical data (A6)
PMS literature Literature search report
Relevant pre clinical studies Verification of search methods
and results
Full texts required
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12. All data generated and held
by the manufacturer
Complete disclosure of data
to the evaluators
Europe & other countries
Clinical studies & use data
All datasets shall be
documented in CER
SUMMARY
APPRAISAL
ANALYSIS
REFERENCES
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All the relevant documents are now
available for pick up. Hand trucks are
in the back room.
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13. GENERALCONSIDERATIONSCRITERIA
 Determine data value:
› Methodological quality
› Relevance
› Weight contribution of the data to Evaluation
 Systematic and unbiased appraisal
APPRAISAL PLAN
 Methodological quality
 Scientific validity
 Relevance
 Weighing contribution
 Qualitative & quantitative appraisal
 Appraisal documented in CER
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14. Methodologicalquality,scientificvalidity
 Apply the pre-defined criteria
 Full text publications, full datasets
 Document the appraisal process
 Confounding influences
 Bias, random error, disclosure, misinterpretation
 Study design: sample size, power, endpoints, controls,
randomization/blinding, incl./excl. criteria, follow-up, reliability of
methods, SAE reporting, missing data
 IRB/EC approvals, regulatory approvals
 Clinical investigation plan: amendments, changes
 Case report forms, monitoring, audit records
 SAE reports, intermediate report
 Clinical investigations outside the EU
 Gap analysis
 Ethical and regulatory standards: ISO 14155, DoH, GCP
 Vigilance data: information about outcomes, registries, case series
and patient dossiers
 Statistical methods, exclusions, report quality
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15. Relevance&Weighingevidence
 Pivotal data
› Device under investigation or equivalent
 Other data
› Current knowledge / state of the art
› Hazard identification
› Validity of equivalence criteria
› Validity of surrogate endpoints
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Device under evaluation | Equivalent | Benchmark | Other
 To what extent are the data representative
 Aspects covered (i.e. performance, safety, claims)
 Intended purpose
 Model, size, setting
 User group, patient demographics
 Medical indication, severity of condition
 Duration of use
Appropriate standard for weighing evidence
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16. AllCompletedstudiesResultsavailable
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Defibrillators
302 Completed
Suspended
Terminated
Withdrawn
70
Study results
available
Literature search
strategy
Duplicates
True subject numbers
Study size and power
Link results to studies
identified in registries
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Qualitative or quantitative
Consistency of results from pivotal datasets
Exclude data w/o scientific validity (A6)
Determine performance with Essential Requirements
Adequacy of pre-clinical testing
Risks to patients, users and other persons
Benefits to patients
Performance, usability, design, IFU
Gaps in evidence
Consistency in documents
 Determine additional needs
 PMCF needs
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A6

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Number of Studies by Phase over Time (completion date)
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Number of Studies by Results over Time (completion date)
Drugs Drugs Devices
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• Documents clinical evaluation and its output
• Sufficient detail of understanding by the reader
• Outline of all stages of the evaluation process
• Scope and context
• Document claims
• Literature search strategy
• Nature and extent of clinical data
• Relevant preclinical data
• Criteria for appraisal of datasets
• Summaries and Appraisal of datasets
• Justification for exclusions
• Explanation how the evidence is sufficient
• Description of benefits and risks
• Analysis of consistency
• Identification of gaps, discrepancies and residual risks
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A9

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Detailed recommendations in Appendix 12
Notified Bodies Operations Group (NBOG) guidance
• Section 6a of Annex I MDD
• Section 5a of Annex 1 AIMDD
The demonstration of conformity with the Essential requirements
must include a clinical evaluation in accordance with
• Annex X of DIR 93/42/EEC
• or Annex 7 AIMDD
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A12

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Annex X of DIR 93/42/EEC or Annex 7 AIMDD
CLINICAL
TECHNICAL
BIOLOGICAL
Based on a single device
Include supporting non-clinical information
Chemical characterization of materials: ISO 10993-18 Annex C
Equivalence with a CE-marked device used in accordance with
intended use as stated in IFU
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The need for clinical investigations
depends on the ability of existing data to
adequately address the benefit/risk profile,
claims and side effects.
Implants and high-risk devices are most
likely to require clinical investigations
Special attention:
New claims
New design features
New intended purpose
Seriousness of risks
Invasiveness
Duration of use
Medicinal substances
Animal tissues
Medical alternatives
Newly recognized risks
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• Name, model, sizes, components, software, accessories
• Device group
• Device under development/CE-marked
• Device currently on the market in Europe
• Intended purpose
• General description
• Medical needs
• Equivalent device
• Intended performance
• Predecessors
• Label, IFU, promo materials
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MEDLINE/PubMed
EMBASE/Excerpta Medica
Cochrane CENTRAL trials register
Internet
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• Applicable standards
• FSCAs
• Implant registries
• Systematic review databases
• Expert documents produced by professional organizations
• HTA reviews and meta-analyses
• ICTRP and ClinicalTrials.gov
• Non-published data
• Referenced literature from reviews

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• Review of current knowledge
• Considered together with clinical investigations
• The device under evaluation, equivalent, benchmark, other and medical
alternatives
Systematic search and review methods:
• PICO
• PRISMA
• MOOSE
• Cochrane Handbook
Background
Objective
Methods
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PRISMA Flow Diagram
Defibrillators

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Lack of information on elementary aspects
Lack of statistical significance
Improper statistical methods
Lack of adequate controls
Significant differences between results from publications
Improper collection of SAE
Misinterpretation by authors
Illegal activities
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Conformity Assessment (Safety) – MDD ER1 / AIMDD ER1
Electrical hazards EN 60601-1
Usability standards EN 62366 and EN 60601-1-6
Conformity Assessment (Benefit/Risk) – MDD ER1 / AIMDD ER1
Description of the intended purpose
Evaluation of benefits to patients
Quantification of benefit to patients
Evaluation of clinical risks of devices
PMS – expect under-reporting
Acceptability of benefit/risk profile
Comparison with alternative treatment options
Conformity Assessment (Performance) – MDD ER3 / AIMDD ER2
Conformity Assessment (Side Effects) – MDD ER6 / AIMDD ER5
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Breakthrough products
Medical conditions that are life-threatening or cause permanent
impairment to bodily functions and for which medical
alternatives are insufficient or carry significant risks
Subsequent products
PMCF studies
Rapidly evolving evidence
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Summary
Scope
Clinical background, current knowledge, state of the art
Device under evaluation
Type of evaluation
Demonstration of equivalence
Clinical data generated by manufacturer
Clinical data from literature
Summary and appraisal of clinical data
Analysis of the clinical data: safety, R/M, performance, side effects
Conclusions
Date of the next evaluation
Dates and signatures
Qualifications of the responsible evaluators
References
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• Level of detail and readability
• All clinical data mentioned and summarized?
• Demonstration of equivalence
• PMS/PMCF data included?
• Updated current knowledge / state of the art
• All models, sizes and settings included
• Conformity to each ER clearly stated
• Consistency of submitted documents
• Residual risks identified and addressed
• Date
• Evaluator’s professional credentials, CV and DOI
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Employment by the manufacturer
Family financial interests
Ownership/shareholding
Grants sponsored by manufacturer
Benefits, travelling, hospitality
Interests in connection with manufacturing of the device
Interests in intellectual property, affected by outcome of the evaluation
Other interests affected by the evaluation
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AUDIT
DESIGN DOSSIER
Procedures to address CER review
Reference to guidance and checklists from NBOG
Examination of a design dossier
Clinical Evaluation Assessment Report (CEAR)
Clinical data from an equivalent device
Review of technical documentation of representative samples
NB specific procedures
Suitable resources, clinical competence
Review
Document opinion and rationale
Document result of the assessment
Preserve confidentiality
Clearly identify how data are identified and reviewed
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