Presentation by Michael imhoff about the upcoming Medical Device Regulation (MDR) in the EU. Includeds compliance with the General Safety and Performance Requirements. Demonstration of conformity with the general safety and performance requirements in clinical evaluation. Clinical evaluation with evidence for safety and performance of the medical device. Assessment of side effects and the acceptability of the risk-benefit-ratio, based on clinical data. MDR is not a health technology assessment for payers. Results of the clinical evaluation should be documented in a clinical evaluation report (CER).

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1MDR Challenges – Clinical Evaluation
The New Regulatory Challenges in Europe
The Clinical Evaluation of Your Devices
Michael Imhoff, MD PhD
Senior Advisor
Boston MedTech Advisors

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2MDR Challenges – Clinical Evaluation
Overview
• The Medical Device Regulation (MDR) requests the
compliance with the General Safety and Performance
Requirements in Annex I.
• Demonstration of conformity with the general safety
and performance requirements shall include a clinical
evaluation
• The clinical evaluation shall give evidence for safety
and performance of the medical device, and an
assessment of side effects and the acceptability of the
risk-benefit-ratio, based on clinical data.
• This is not a health technology assessment for payers.
• The results of the clinical evaluation are documented
in a clinical evaluation report (CER).

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3MDR Challenges – Clinical Evaluation
MDR and MEDDEV 2.7/1
• MDR: What is a clinical evaluation (5 pages)
• MEDDEV 2.7/1 Rev 4: How to do a clinical
evaluation (65 pages)
• Guidance document (legally not binding, but …)
• Compliance with Essential Requirements
(MDD),
General Safety and Performance Requirements
(MDR)
• Acceptable risk (benefit-risk analysis)
• Safety – freedom from not acceptable side
effects
• Intended performance

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4MDR Challenges – Clinical Evaluation
Requirements
• Clinical evaluation along the total product life cycle as
a continuous process
• Strong emphasis on clinical benefit from all medical
devices
• Performance, benefit, safety, risk minimization require
clinical evidence
• Comprehensive (exhaustive) clinical data required
• Very strict requirements for equivalence
(MEDDEV < MDR)
• CER defines requirements for PMS and PMCF
• Excessive requirements for the qualification of authors
• Frequent updates required

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5MDR Challenges – Clinical Evaluation

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6MDR Challenges – Clinical Evaluation
General Principles
• Clinical evaluation during development of a medical
device
• The clinical evaluation process begins with the start
of development
• Definition of the need for clinical data for safety and
performance
• Gap analysis  (new) data from clinical studies
• CER requested for the initial conformity assessment
(CE mark), active updates thereafter
• Clinical evaluation for the initial CE mark:
• Sufficient evidence for compliance with GSPRs
(ERs)
• Identification of need for PMS/PMCF

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7MDR Challenges – Clinical Evaluation
Equivalence
• All relevant aspects of equivalence must be shown in
ONE medical device!
• Partial equivalence from different products not acceptable
• Only CE-marked devices
• Detailed comparison on the level of development and
production details
• Clinical properties (application, intended use, operation
mode, etc.)
• Technical properties (incl. production process)
• Biological properties (e.g. materials in contact with patient)
• For implants and class III de facto only products from own
production (vs. competitor devices)
• In general, equivalence is only accepted for effectively identical
devices
• Data from “similar” devices may be used to define the state of
the art (and for extended safety assessment)

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8MDR Challenges – Clinical Evaluation
Equivalence
• MDR Article 61 (5):
• A manufacturer of a device demonstrated to be equivalent
to an already marketed device not manufactured by him,
may also rely on paragraph 4 in order not to perform a
clinical investigation provided that the following conditions
are fulfilled in addition to what is required in that
paragraph:
• the two manufacturers have a contract in place that
explicitly allows the manufacturer of the second
device full access to the technical documentation
on an ongoing basis, and
• the original clinical evaluation has been performed
in compliance with the requirements of this
Regulation,
• and the manufacturer of the second device provides clear
evidence thereof to the notified body.

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9MDR Challenges – Clinical Evaluation
Risk-Benefit Analysis
• Increasing emphasis on risk-benefit analysis
Note: Benefit does not equal performance!
• Assessment of patient benefit from device
• Quantification of patient benefit
• Assessment of clinical risks from device
• Assessment of the acceptability of the risk-benefit
profile
• Changes in medical alternatives have to be
considered
• Results of the risk-benefit analysis may change
over time!

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10MDR Challenges – Clinical Evaluation
Risk-Benefit Analysis
• Requirements of MEDDEV/MDR for the clinical
evaluation
• Assessment of risks
• Assessment of risk-benefit ratio
• Assessment of (not acceptable) side effects
• These are core competences of risk management!
• Risk management should be done at only ONE
place in the tech file
Close coordination between RM and CER

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11MDR Challenges – Clinical Evaluation
Clinical Data
• All clinical data from within and outside the EU:
• Clinical trials and studies
• PMS data
• Register data/studies
• Field safety corrective actions (FDA, competent
authorities)
• MAUDE, MHRA, SwissMedic, BfArM, etc.
• Data from all countries where the device is
marketed
• Clinical data from the literature
• Systematic analysis of all retrieved information

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12MDR Challenges – Clinical Evaluation
Literature
• Systematic literature searches
• Both for state of the art as well as for the actual medical
device
• MEDLINE alone not sufficient (explicit statement)
• Additional databases required (e.g., EMBASE)
• Unpublished data, as available
• Literature searches:
• Description of the state of the art, medical alternatives
• Description of performance, safety and benefit of the
evaluated device and (if claimed) equivalent products
• Data from similar devices for state of the art and
extended safety assessment
• Separate search protocols and results reports

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13MDR Challenges – Clinical Evaluation
Literature
• Appraisal of each publication ( appraisal plan)
• Relevance for clinical use according to
intended use
• Methodological quality
• Determination of the level of evidence
• Systematic assessment for the clinical
evaluation
• Appraisal plan and results in an appendix to the
CER
• Literature assessment as in a systematic review
• Explicit recommendations for the appraisal
scheme

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14MDR Challenges – Clinical Evaluation
Clinical Investigations
• If gaps are present that cannot be addressed by other
means, clinical investigations should be planned and
carried out.
• Implants and high-risk devices, those based on
technologies where there is little or no experience, and
those that extend the intended purpose of an existing
technology (i.e. a new clinical use) are most likely to
require clinical investigation data.
• Clinical investigations may also be required for other
devices, including for devices in class I and class IIa, and
for class IIb devices that are not implantable.
• Gaps become wider due to the increased requirements for
equivalence
• Further aggravation due to changes in classification rules in
MDR

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15MDR Challenges – Clinical Evaluation
Example 1 – Vascular Implant (class III)
• Large patient population,
established therapeutic
principles
• State of the Art / medical
alternatives:
• Numerous recent
guidelines
• Many meta-analyses with
moderate to very high
quality
• Direct competitor (5 years
longer in market)
• Large RCT
• Long-term follow-up
• One RCT with own product
• < 2 years follow-up
• Unambiguous risk-benefit
analysis
• Very low complaint rate, no
serious adverse events
• Equivalence to competitor
claimed
• Equivalence not accepted by NB
• Minor structural differences
(clinically not relevant)
• No access to technical
documentation
• Status after two years
• Certificate not renewed
• New clinical studies
requested
• Large register study, or
• New RCT with long-term
follow-up (5+ years)

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16MDR Challenges – Clinical Evaluation
Example 2 – Patient Monitoring (class IIb)
• Numerous products in
market
• Established technology
for the last 50+ years
• Universal use (no
specific patient
populations)
• State of the art / medical
alternatives
• Guidelines very
general
• Systematic studies
only in special
patient populations
• Performance and safety
comprehensively defined
in industry standards
• Clinical benefit
• Clinical benefit results
only from medical
action triggered by
monitoring!
• Example:
Perioperative pulse
oximetry  outcome
benefit cannot be
shown
• Risk-benefit analysis
unclear (and not really
appropriate)

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17MDR Challenges – Clinical Evaluation
Example 3 – Documentation SW (class IIa)
• Alternative to paper-based
patient records
• Established application for
2,000+ years
• Universal use (every
patient), indispensible
• State of the art / medical
alternatives:
• Documentation legally
required, in guidelines
requested
• Method of technical
implementation not
required/regulated
• Clinical benefit
• Without documentation
no consistent patient
care
• No clinical studies into
the benefit of
documenation
• Clinical risks
• Decision making
influenced by
missing/erroneous data
(technical risk)
• Literature search de
facto not feasible
• Risk-benefit analysis not
feasible and not
meaningful

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18MDR Challenges – Clinical Evaluation
Updates of Clinical Evaluations
• Whenever new relevant information from PMS
• At least annually, if the device carries significant risks or is
not yet well established; or
• Every 2 to 5 years, if the device is not expected to carry
significant risks and is well established, a justification
should be provided.
• Translation:
• Class III: at least annually
• Class IIb implants, drug administration: annually
• Class IIb: every 2 years (PMS annually)
• Class IIa: every 2-5 years (PMS every 2 years)
• Class I: every 5 years (PMS when necessary)
• If the evidence for the product changes (e.g, by new
medical alternatives) it may need to be taken off the market

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19MDR Challenges – Clinical Evaluation
Authors – Requirements
• Knowledge of the technology and application of
the device
• Knowledge of scientific work
• Knowledge of the design of clinical investigations
• Knowledge in biostatistics
• Knowledge of the disease to be treated/diagnosed
with respective clinical experience
• Experience in use of databases and in medical
writing
• Regulatory knowledge
 A team of authors and contributors required!

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20MDR Challenges – Clinical Evaluation
Authors – Example
• Vascular implant class III
• Main author
• MD, board certified surgeon and intensivist
• PhD in medical informatics and statistics
• Internal reviewer
• MD, board certified vascular surgeon
• Literature searches
• External specialist team
• EMBASE database expert
• PMS Data
• Internal complaint management team
• Close coordination with RM team

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21MDR Challenges – Clinical Evaluation
Clinical Evaluation
• Clinical evaluation along the entire product life
cycle
• Strong emphasis on clinical benefit for all medical
devices
• Stricter requirements for equivalence
• Separate data searches and analyses for state of
the art and the actual product
• Massively increased requirements for data
analysis (esp. literature appraisal)
• More clinical data required
• More clinical studies needed

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22MDR Challenges – Clinical Evaluation
Clinical Evaluation
• More emphasis on PMS and PMCF
• More frequent updates required
• Strong focus on implants
• The lower the risk class the higher the incremental
effort
• Extreme requirements for author qualifications
• MEDDEV and MDR overlap with other guidance
documents and standards (e.g., RM, PMS, clinical
studies)
• The MDR does not define the requirements for
clinical evaluations in any detail

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23MDR Challenges – Clinical Evaluation
Thank You!
Contact information:
Boston MedTech Advisors, Inc.
990 Washington Street
Dedham, MA 02026
Ph. +1.781.407.0900
Tannenschlag 32
D-23568 Lübeck
Germany
Ph. +49.451.707698.0
mimhoff@bmtadvisors.com