MedTech Europe Justification benefit risk analysis

1. Medical Device Regulation:
Requirements on hazardous substances
Training session 4: Justification and benefit-risk
assessment
14 February 2020 (15:00 – 16:00 CET)
Speaker: Whitney Christian, PhD, Medtronic
Introduction: Nathalie Buijs, MedTech Europe

2. 2
Introduction
Nathalie Buijs – MedTech Europe

3. 3
Practical information about this webinar session
• 1 hour: Presentation and Q&A session
• Participants’ lines are muted
• You can use the questions tool to send in your questions to the
speaker
• Please note that this session is being recorded!
• The slides and the link to the recording (presentation without the
Q&A) will be sent to all participants after the webinar

4. 4
MDR hazardous substances: Training sessions
Session Topic Date
1 Introduction / General overview 10 October 2019 (15:00 – 16:00 CEST)
2 Endocrine disruptors 28 October 2019 (15:00 – 16:00 CET)
3 Devices and substances in scope 13 November 2019 (15:00 – 16:00 CET)
4 Justification / Benefit-risk assessment 14 February 2020 (15:00 – 16:00 CET)
5 Labelling of hazardous substances 11 December 2019 (15:00 – 16:00 CET)
All materials (slides & recordings) of previous webinars are available to MedTech
Europe members (Corporate Members and National Associations) on our Regulatory
E-Library under ‘Training material’.

5. 5
MedTech Europe guidance
on MDR Section 10.4.
• Corporate Members and National
Associations can download the guidance
(Version 2.0, July 2019) from our
Regulatory E-Library
• Members of National Associations can
request a copy from their contact at the
National Association Secretariat

6. 7
This series of webinars covers:
• MDR Section 10.4.
• Specific requirements (justification &
labelling) for CMR 1A/1B* and
endocrine- disrupting substances
• Specific categories of devices
To be exhaustive, some information is also
provided on Section 23.4. (s) (precautions
on hazardous substances in the IFU)
* CMR = Carcinogenic, Mutagenic, or Reprotoxic
1A = Known human CMR
1B = Presumed human CMR

7. 8
MDR Annex I, Section 10.4. on Substances: Overview
• 10.4.1. Design and manufacture (devices and substances in scope)
• 10.4.2. Justification / Benefit-risk assessment
• 10.4.3. Guidelines on phthalates
• 10.4.4. Guidelines on other CMR/ED substances
• 10.4.5. Labelling

8. 9
Presentation
Whitney Christian, PhD, Medtronic

9. 10
Presenter: Whitney Christian, PhD
Dr. Whitney Christian has over 17 years of experience as a toxicologist and
currently serves as a Sr. Manager of Toxicology and Biocompatibility at
Medtronic, where he provides toxicology and risk assessment support and
oversees hazardous substances and materials of concern compliance
programs throughout the business. Whitney received a Ph.D. in Molecular
Toxicology from the Department of Environmental Medicine at the University
of Rochester and a B.A. in Biology from Davidson College. He is the Industry
Representative for the Immunology Devices Panel of the Medical Devices
Advisory Committee in FDA's Center for Devices and Radiological Health. He
is also a member of MedTech Europe’s Chemicals Working Group and MDR
Substances Ad Hoc Working Group as well as a member of the AdvaMed
Biocompatibility Sub-Group. Whitney serves as a member of the
Mutagenicity, Carcinogenicity, and Reproductive Toxicity Working Group
(ISO/TC 194/WG 6) within the Association for the Advancement of Medical
Instrumentation. He is a full member of the Society of Toxicology and is a
member of the Metals, Risk Assessment, Regulatory and Safety Evaluation, and
Medical Device & Combination Product Specialty Sections, the latter of which
he is currently the Vice-President.

10. 11
Overview of today’s session
• Justification and benefit-risk assessment of hazardous
substances
• When to perform (Annex I, section 10.4.1)
• General structure (Annex I, section 10.4.2)
a) Hazardous substance
b) Alternatives
c) BRA
• SCHEER BRA guidelines (Annex I, section 10.4.3)
• Phthalate-specific, more detailed structure than section 10.4.2
• Example: DEHP-containing PVC medical device
• SCHEER BRA guidelines: key takeaways
• Phthalate phase-out

11. 12
Requirement of justification / benefit-risk assessment
Annex I, section 10.4.1 (scope)
For more information: Training session 3: Devices and substances in scope, Jean-Marc Abbing, 13 November 2019
• Invasive devices
• Direct/indirect patient contact
• Label and justify presence of
hazardous substance(s) when
content >0.1% w/w
• >1,000 chemicals in scope
• CMRs 1A & 1B
• EDCs
• Chemicals designated in CLP,
REACH, and BPR

12. 13
Structure of justification / benefit-risk assessment
Annex I, section 10.4.2 (general justification)
• Three part justification
a) Analysis of hazardous substance
• Exposure assessment
b) Analysis of alternative
• Can be substance, material, or
design
• Use scientific information
• Consider availability
c) Argument against alternative
• Benefit-risk assessment
• Consider vulnerable populations

13. 14
SCHEER BRA guidelines
Annex I, section 10.4.3 (phthalate-specific justification)
• Phthalate CMR/EDC at >0.1%
w/w
• Justification “shall” be based on
latest relevant scientific committee
guidelines:
• ‘
• Legally binding!

14. 15
Justification for presence of CMR/ED >0.1% w/w
Fork in the road?
Justification for presence of CMR/ED >0.1% w/w
Annex I, section 10.4.2
Phthalate CMR/EDC
Annex I, section 10.4.3:
• SCHEER BRA guidelines
Non-phthalate CMR/EDC
Annex I, section 10.4.4:
• No other guidelines issued
• SCHEER BRA guidelines “may” be
used for other CMR/EDCs
• Not legally binding!
• Different CMR/EDC phase-out?

15. 16
SCHEER BRA guidelines
General recommendations
• Utilize multidisciplinary approach
• Need assistance and knowledge/data from:
• Toxicologist
• Material scientist
• Engineer
• Clinical affairs
• Medical safety
• etc…
• Provide thorough explanation of logic supporting argument w/in
justification
• Purpose of assessment criteria, critique of toxicity data, evaluation of benefits and
risks

16. 17
SCHEER BRA guidelines
Overall structure: three part justification
a) Analysis of phthalate
b) Analysis of alternatives
c) Benefit-risk assessment
a b
c

17. 18
SCHEER BRA guidelines
Part a: three steps
a) Analysis of phthalate CMR/EDC
1. Material characterization
• Identify phthalate (% w/w)
2. Purpose of presence
• Use, functionality, performance
• Benefit
3. Toxicological risk assessment
• Traditional four step process

18. 19
SCHEER BRA guidelines
Part b: four steps
b) Analysis of alternatives
4. Long list of alternatives
• Possible design, substance, or material changes
(exhaustive)
5. Short list of alternatives
• Perform high level process of elimination
• Identify 2-3 candidates to further characterize
6. Characterization of relevant alternatives
• Functionality, performance, etc. (design inputs)
• Additional considerations: technical feasibility,
availability, etc.
7. Toxicological risk assessment
• Traditional four step process

19. 20
SCHEER BRA guidelines
Part c: three steps
c) Benefit-risk assessment
8. Compare/contrast benefit
• Functionality/performance profile of phthalate vs.
alternative
9. Compare/contrast risk
• Failure/toxicity profile of phthalate vs. alternative
10. Benefit-risk assessment
• Qualitative or quantitative
• Depends on available knowledge/data
• Uncertainty analysis

20. 21
SCHEER BRA guidelines
Key structural features of three part justification
a) Analysis of phthalate
• Toxicological risk assessment (consider all relevant endpoints, not just CMR/EDC endpoints)
b) Analysis of alternatives
• Two-tiered approach (long list, then short list)
• Assess characteristics: functional properties, performance, technical feasibility, availability... (be
creative)
• Toxicological risk assessment
c) Benefit-risk assessment
• Compare/contrast phthalate and alternative
• Uncertainty analysis

21. 22
SCHEER BRA guidelines
Example justification: aim and scope
• Aim and scope
• Given that Di-(2-ethylhexyl)phthalate (DEHP), a phthalate plasticizer, is
considered a hazardous substance per Annex 1, Section 10.4.1 of the European
Union Medical Devices Regulation, Regulation (EU) 2017/745, and is present at
>0.1% (w/w) in the devices in scope (see Table 1), a justification for the presence
of DEHP in the devices is required per Annex I, Sections 10.4.2 and 10.4.3 of
Regulation (EU) 2017/745. This document provides the required justification per
the recommendations set forth therein, including the SCHEER guidelines on the
benefit-risk assessment of the presence of phthalates in certain medical devices
covering phthalates which are carcinogenic, mutagenic, toxic to reproduction
(CMR) or have endocrine-disrupting (ED) properties.
[insert Table 1 – devices in scope]

22. 23
SCHEER BRA guidelines
Example justification: part a, step 1
• Description of device and presence of phthalate CMR/EDC
• Device category: external communicating, limited contact (≤24 hours)
• Purpose: blood transfer (≤6 hours) during surgical procedures, single-use
• Composition: medical grade PVC tubing
• Phthalate CMR/EDC: bis(2-ethylhexyl) phthalate (DEHP), CASRN 117-81-7
• Concentration: 30% w/w
• Chemical/physical binding: none (blended)

23. 24
SCHEER BRA guidelines
Example justification: part a, step 2
• Purpose of phthalate CRM/EDC
• Use: soften PVC material
• Functionality: render tubing flexible and bendable during the containment and circulation of blood
at different temperatures, flow rates, or pressures
• Performance: biocompatible per ISO 10993-1:2018 & FDA Guidance on ISO 10993-1; history of safe
clinical use
• Benefits:
• Stabilization of red blood cells, reduction of hemolysis
• Material compatibility for solvent bonding, surface coating, process assembly
• Thermal stability for sterilization, shipping, and storage
• Visual clarity, transparency
• Printable for traceability
• Chemical resistance
• Compatibility with anesthetics, solvents, or disinfectants

24. 25
SCHEER BRA guidelines
Example justification: part a, step 3
• Toxicological risk assessment of phthalate CMR/EDC
• Four step process:

25. 26
Toxicological risk assessment
Dose-response assessment
• Toxicity assessment of DEHP
• Collect toxicity data, safe exposure
limits from the scientific literature
• Consider endpoint, route of exposure,
exposure duration, species, age, etc. in
selection of critical study
• Critical study based on relevance of:
• Endpoint: reproductive is most sensitive
• Route of administration: IV ≈ device use
• Duration of exposure: closest to ≤6 hours
• Species: rat is most sensitive
• Age: neonatal is most sensitive

26. 27
Toxicological risk assessment
Exposure assessment
• Exposure assessment of DEHP (in order of decreasing accuracy)
• Measure exposure
• Data from leachables study under simulated-use conditions
• Flow rate: 4 liter per minute
• Duration: 6 hours
• Temperature: 37 °C
• Circulation fluid: bovine blood
• Estimate exposure
• Use leaching values in scientific literature to calculate an exposure
• Worst-case calculation
• Assume all the DEHP in the material leaches out during product use
0.0334 mg/g of PVC

27. 28
Toxicological risk assessment
Risk characterization
• Risk characterization of DEHP
• Calculate the margin-of-safety
based on data from dose-response
(toxicity) and exposure assessments
• Margin-of-safety >1 considered
safe
• Adult & pregnant female: MOS >1
• Pediatric: MOS <1
• Tubing length reduction results in
MOS>1

28. 29
SCHEER BRA guidelines
Example justification: part b, step 4
• Long list of alternatives
• Explore design, substance, and material alternatives:
Alternatives to
DEHP-containing
PVC
PVC-based material
Non-PVC-based
material
Option 1:
Modification
(coating) of DEHP-
containing PVC
Option 2: DEHP
substitution
(non-phthalate
plasticizer)
Option 3: Material
substitution
(non-PVC material)
design material
substance
Option 1: Design
(surface
modification)
Option 2: Substance
(DEHP substitution)
Option 3: Material
(material
substitution)
• Cortiva coating
• Trillium coating
• Balance coating
• Citrates
• Trimellitates
• Adipates
• Cyclohexane
dicarboxylic acids,
diisononyl ester
• Terephthalates
• Ortho-phthalates
• Vegetable oil
derivatives
• Polyurethane
• Thermoplastic
polyurethane
• Polyolefin
elastomers
• Silicone

29. 30
SCHEER BRA guidelines
Example justification: part b, step 5
• Short list of alternatives
• Define inclusion/exclusion criteria for selection of alternatives to further
characterize
Step Attribute Inclusion/exclusion criteria for alternative
1 Toxicity
• A classified hazardous substance of CMR class 1A or 1B?
• Already on a regulated chemical list?
• Toxicity ≥ than DEHP (consider all endpoints)?
• Have relevant toxicity data?
2
Migration /
Leachability
• Migration ≥ than DEHP?
• Leachability into biological fluids ≥ than DEHP?
3 Functionality
• Meet mechanical requirements of DEHP-plasticized PVC?
• Clear and transparent?
• Have temperature tolerance (≤-40 °C for shipping, ≥121 °C for
sterilization)?
• Have processability for bonding, sealing, surface modification etc.?
• Chemical resistant?
• Biocompatible?
• Stabilize red blood cells?
4 Availability • Commercially available?

30. 31
SCHEER BRA guidelines
Example justification: part b, step 5
• Short list of alternatives
• Select alternatives to further characterize
• Option 1 (coatings) – DEHP content unchanged, but key benefits lost (e.g., reduction of
hemolysis)
• All option 1 alternatives eliminated
• Options 2 & 3 – process of elimination
Current Alternative 1 Alternative 2
DEHP-plasticized
PVC
DINCH-plasticized
PVC
TOTM-plasticized
PVC
12
candidates
2
eliminated by
toxicity
3
eliminated by
migration /
leachability
4
eliminated by
functionality
1
eliminated by
availability
2
candidate
alternatives

31. 32
SCHEER BRA guidelines
Example justification: part b, step 6
• Characterization of
alternatives
• Relative or quantitative
• Consider all possible
characteristics
Characteristic Current Alternative 1 Alternative 2
functionality
&
performance
Clarity +++ +++ ++
Elasticity & tear resistance ++ ++ ++
Cold flexibility ++ +++ +
Temperature resistance & sterilization ++ ++ ++
Material compatibility ++ ++ +++
Manufacturability ++ + +
Biocompatibility +++ +++ +++
etc. etc. etc. etc.
material
&
clinical
benefit
Plasticizer migration (causing stress cracking) ++ ++ +++
Spallation (particulate generation) ++ ++ +++
Plasticizer hazard (potency) ++ +++ +++
Thrombus reduction +++ +++ ++
Platelet and white blood cell preservation ++ ++ ++
Red blood cell preservation (hemolysis reduction) +++ ++ +
Elastic recovery (knotting & blockage reduction) +++ +++ ++
etc. etc. etc. etc.
Legend
Symbol Value
+++ Excellent
++ Good
+ Poor
No change
Increase by +
Decrease by +
Decrease by ++

32. 33
SCHEER BRA guidelines
Example justification: part b, step 7
• Toxicological risk assessment of alternatives (ref. approach in slides 25
– 28) DINCH TOTM

33. 34
SCHEER BRA guidelines
Example justification: part c, steps 8 - 10
• Compare/contrast benefit and risk
• Devise a scoring system for the BRA
• Qualitative, semi-quantitative, or quantitative
• Aim for simple, elegant approach
• Score = probability that characteristic affects benefit/risk x impact of that characteristic on
benefit/risk
Low Medium High
1 2 3
Very unlikely (<10%) 1 1 2 3
Unlikely (10-33%) 2 2 4 6
As likely as not (33-
66%)
3 3 6 9
Likely (66-90%) 4 4 8 12
Very likely (>90%) 5 5 10 15
Impact
Probability

34. 35
Overall benefit
Overall risk
Overall benefit/risk comparison
SCHEER BRA guidelines
Example justification: part c, steps 8 - 10
• Overall benefit-risk assessment

35. 36
SCHEER BRA guidelines
Example justification: part c, uncertainty analysis
• Focus on uncertainty in functional performance, clinical efficacy, and
safety
• Transition from individual uncertainty → combined uncertainty → overall
uncertainty
Category Indicator
Uncertainty value range
Explanation of uncertainty value ranges
Current
Alternative
1
Alternative
2
Functional
performanc
e
Material
characteristic
s
0 – 10% 0 – 10% 0 – 10%
Most information is in technical data sheets; therefore, data on material
characteristics are accurate and reliable for predicting functional
performance
Clinical
efficacy
Clinical use 0 – 10% 10 – 30% 0 – 10%
DEHP PVC (MDT product) and TOTM PVC (reported in scientific
literature) have been used in the clinical use scenario of interest (blood
transfer); DINCH PVC has not been used in the clinical use scenario of
interest
Safety
Exposure
estimate
0 – 10% 10 – 30% 10 – 30%
DEHP exposure measured in a simulated-use study; DINCH and TOTM
exposures were estimated from values in the scientific literature
Toxicity data 10 – 30% 30 – 60% 30 – 60%
More DEHP than DINCH/TOTM toxicity studies in the literature; DEHP
studies are closer to actual use scenario than DINCH/TOTM studies;
DEHP composite uncertainty factor less than DINCH/TOTM composite
uncertainty factors
combined

36. 37
SCHEER BRA guidelines
Example justification: conclusions
• For this device, DEHP-plasticized PVC had better overall benefit and
overall risk values than DINCH- or TOTM-plasticized PVC
• Uncertainty associated with the BRA for DEHP-plasticized PVC was low,
for DINCH-plasticized PVC was high, and for TOTM-plasticized PVC was
medium
• Taken together, the BRA indicates that the current PVC material is more favorable
than either alternative material
• The use of DEHP-plasticized PVC in the final, finished product is
PVC Overall Benefit Overall Risk Difference (Benefit – Risk)
DEHP-plasticized 167 75 92 Percent Decrease
DINCH-plasticized 157 90 67 27%
TOTM-plasticized 139 84 55 40%

37. 38
SCHEER BRA guidelines
Phthalate phase-out
• Weighing benefit and risk
• Four general BRA scenarios
• Phthalate phase-out
• SCHEER’s general opinion: no material change is required if presence of phthalate serves a vital
functional role in the device that no other design, substance, or material can fulfill

38. 39
SCHEER BRA guidelines
Key takeaways
• Justification: leverageable to other devices if equivalency can be demonstrated
• Blanket or industry-wide justifications are possible
• Updating justifications: when new data on alternatives available, new Guidelines
released
• Continuous maintenance of justification needed (no time interval defined)
• Prototypes: implied that prototypes may be needed for analysis of alternatives
• SCHEER: decides what data is needed (e.g., high quality), not how the data is obtained
• Acceptable risk: SCHEER will not define (outside scope); up to manufacturer
• Industry concerned because what is acceptable to manufacturer may not be acceptable to
Notified Body
• Cost: indirectly related to availability; ISO 14971 (says cost is not a factor)
applicable?

39. 40
Acknowledgements
• Medtronic ECT
• Charlene Yuan, PhD
• Trevor Huang, PhD, MBA
• Medtronic GmbH
• Joachim Wilke, PhD, MSc
• Medtronic EMEA
• Jean-Marc Abbing
• Medtronic EHS
• Sheri Prosch
• MedTech Europe
• Nathalie Buijs
• Oliver Bisazza
Contact information
Email: whitney.christian@medtronic.com

40. 41
Questions &
Answers

41. 42
MedTech Europe guidance/support tools
• Guidance on the requirements of
MDR Section 10.4.
• Available for download here
• List of CMR 1A/1B and ED
substances likely to be found in
medical devices
• Available for download here
Members of National Associations (who do not have access to MedTech Europe’s Regulatory E-Library)
can request a copy of both documents from their contact at the National Association Secretariat.

42. 43
Follow-up – 2020

43. 44
Updating our guidance
• Questions collected during these webinar sessions will be used to update
MedTech Europe’s guidance
• Proposed solutions will be discussed by the MDR Substances Ad Hoc
Working Group (next calls of the group on 18 February and 19 February)
• Outcome will be made available to all members (and members of
National Associations) in form of Version 3.0 of the guidance

44. www.medtecheurope.org
Thank you!
n.buijs@medtecheurope.org
For more information, please
contact Nathalie Buijs