Post on 06-Jul-2018
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Ibim Tariah Ph.D Technical Director, Healthcare Solutions
BSI 2014 Medical Device Mini-Roadshow
Understanding Clinical Equivalence
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• Review Requirements from Directives on Medical Devices
• Examine Definition of Medical Devices • Review EU Commission Guidelines on:
• Clinical Evaluation of Medical Devices (MEDDEV 2.7.1) • Post Market Clinical Follow-up (PMCF) Studies (MEDDEV
2.12/2) • Practical Example
Understanding Clinical Equivalence
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EU Directives on Medical Devices
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EU Directives on Medical Devices
MDD & AIMD modified by Directive 2007/47/EC, effective 21 Mar 2010 • MDD: ER 6a – Demonstration of conformity with the
essential requirements must include a clinical evaluation in accordance with Annex X
• AIMD: ER 5a - Demonstration of conformity with the essential requirements must include a clinical evaluation in accordance with Annex 7
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Annex X (MDD) / Annex 7 (AIMD) • As a general rule, confirmation of conformity with the
requirements concerning the characteristics and performances … must be based on clinical data.
• The clinical evaluation: 1.1.1 either a critical evaluation of the relevant scientific
literature currently available relating to the safety, performance, the design characteristics and the intended purpose of the device, where: o there is demonstration of equivalence of the device with that to which
the data relates and, o the data adequately demonstrate compliance with the relevant
Essential Requirements;
1.1.2 or a critical evaluation of the results of all clinical investigations made;
1.1.3 or a critical evaluation of the combined clinical data provided in 1.1.1 and 1.1.2 above.
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Annex X (MDD) / Annex 7 (AIMD)
Clinical Investigations: •MDD: In the case of implantable devices and devices in Class III clinical investigations shall be performed unless it is duly justified to rely on existing clinical data.
•AIMD: Clinical investigations shall be performed unless it is duly justified to rely on existing clinical data.
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Clinical Evaluations: • Many devices developed by incremental innovation, so they are not completely novel • Often possible to draw on the clinical experience and literature reports of the safety and
performance of equivalent devices to establish the clinical evidence • Requires comprehensive analysis of pre- and post-market clinical data relevant to the intended
use • data specific to the device in question • data relating to devices claimed as equivalent
2013 Medical Device Roadshow
Annex X (MDD) / Annex 7 (AIMD)
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Annex X, Sec 1.1c (MDD) / Annex 7, Sec. 1.2 (AIMD)
CER Updates: •CER must be actively updated with data obtained from the post-market surveillance.
•Where post-market clinical follow-up (PMCF) as part of the post-market surveillance (PMS) plan for the device is not deemed necessary, this must be duly justified and documented.
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Where demonstration of conformity with ERs based on clinical data is not deemed appropriate:
• Adequate justification for any such exclusion has to be given based on risk management output and under consideration of the specifics of the device/body interaction, the clinical performances intended, and the claims of the manufacturer.
• Adequacy of demonstration of conformity with the essential requirements by performance evaluation, bench testing and pre-clinical evaluation alone has to be duly substantiated.
Annex X, Sec 1.1d (MDD) / Annex 7, Sec. 1.5 (AIMD)
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Definition of a Medical Device
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Definition of “Medical Devices”
MDD/AIMD – Article 1 • Formal definition
MEDDEV 2.1/1 • Medical devices are defined as articles which are intended to
be used for a medical purpose • Products intended to have a toiletry or cosmetic purpose are
not medical devices even though they may be used for prevention of a disease.
• Products with a multiple purpose which may be used occasionally in a medical environment are normally not medical devices, unless a specific medical intended purpose is assigned to them.
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EU Commission Guidelines on the Clinical Evaluation of Medical Devices
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MEDDEV 2.7.1
• Reflects positions taken in particular by representatives of National Competent Authorities and Commission Services, Notified Bodies, industry and other interested parties in the MEDICAL DEVICEs sector
• Guidelines not legally binding . . . alternative approach may be possible or appropriate to comply with requirements
• It is anticipated that the guidelines will be followed within the Member States
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Sections: 5. General principles of Clinical Evaluation 6. Sources of data / documentation (Stage 1) 7. Appraisal of clinical data (Stage 2) 8. Analysis of clinical data (Stage 3) 9. The CER 10. Role of the Notified Body (NB)
Appendices: A – E: Sample formats / methodologies F: NB Clinical Evaluation Checklist
MEDDEV 2.7.1 – Key Contents
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Section 5.1 – Scope of CER: • Devices should have the same intended use and will need to be
compared with respect to their technical and biological characteristics. • Intended use relates to the clinical condition being treated, the
severity and stage of disease, the site of application to/in the body and the patient population
• Technical characteristics relate to the design, specifications, physiochemical properties including energy intensity, deployment methods, critical performance requirements, principles of operation and conditions of use
• Biological characteristics relate to biocompatibility of materials in contact with the same body fluids/tissues.
• Characteristics should be similar to extent that there would be no clinically significant difference in the performance and safety of the device.
MEDDEV 2.7.1 – “Equivalent Devices”
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Appx. E, Sec. 4 – Possible format for CER • Clearly state if the clinical data used in the evaluation are
for an equivalent device. • Identify the equivalent device(s) and provide a
justification of the equivalency, cross-referenced to the relevant non-clinical documentation that supports the claim.
Appx. F, Sec. 3.2.3 – NB Checklist • If differences are identified, an assessment must be done
to demonstrate potential significance of differences on safety & performance
MEDDEV 2.7.1 – “Equivalent Devices”
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Appx. F, Sec. 3.2.3 (Footnote) – Meaning of Equivalence • Clinical:
• C1 - same clinical condition or purpose • C2 - same site in the body • C3 - similar population (including age, anatomy, physiology) • C4 - similar relevant critical performance for specific intended use
• Technical: • T1 - similar conditions of use • T2 - similar specifications and properties • T3 - similar design • T4 - similar principles of operation
• Biological: • S1 - same materials in contact with the same tissues or body fluids
MEDDEV 2.7.1 – “Equivalent Devices”
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FDA Predicate Device ≠ MEDDEV 2.7.1 equivalent device
Substantially equivalent predicate device (per FDA): • Device has the same intended use as the predicate; and • Device has the same technological characteristics as the
predicate;
OR
• Device has the same intended use as the predicate; and • Device has different technological characteristics and the
information submitted to FDA; • does not raise new questions of safety and effectiveness; and • demonstrates that the device is at least as safe and effective as
the legally marketed device.
FDA – “Predicate Devices”
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• Equivalence should be substantiated based on a detailed assessment.
• Focus should be on discussing the DIFFERENCES rather than highlighting the SIMILARITIES.
• Some devices have very narrow clinical purposes (such as hip replacements) but others have multiple purposes (such as meshes or dressings or fillers). In these cases, equivalent devices should have the same purposes.
MEDDEV 2.7.1 – “Equivalent Devices”
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Device Equivalence Example
• Are devices which are “EQUIVALENT” to your device available on the market?
• Are clinical data available for these devices?
21
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Clearly Not Equivalent
22
Not equivalent Both fruits but different types
– shape, consistency, taste, edible vs. inedible skin Differences clearly impact function and use
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Clearly Equivalent
Equivalent Same variety, colour, etc.
Can use data from one to assume performance will be the same.
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Equivalence Must be Justified
Both apples Different varieties
– colour, taste, crunch, dessert or cooking? How do the differences impact their function or use?
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Stage 1* Identify clinical data from: • Literature searching & / or • Clinical experience & / or • Clinical Investigation
Stage 2 Appraisal of individual data sets: • Suitability • Contribution of results to demonstration
of performance and safety
Stage 3 Analysis of relevant data: • Strength of overall evidence • Conclusion about performance
and safety
Generate new or add’l clinical data
Produce CER
Is clinical evidence sufficient to be able to
declare conformity with relevant
ERs?
Yes
No
* Conformity to harmonized performance standard may be sufficient to demonstrate compliance to ERs
Figure 1:
http://ec.europa.eu/enterprise/policies/european-standards/harmonised-standards/medical-devices/index_en.htm
MEDDEV 2.7.1 – CER Construction
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Stepwise Approach • Identify potential “equivalent devices” for search strategy
MEDDEV 2.7.1 – “Equivalent Devices” Example:
A C B E D F Subject G • Identify data (CER Stage 1) – Discover clinical data on A, B, C, F, and
unknown device G • Appraise data (CER Stage 2) – Determine device C is not equivalent and data for F is weak (small sample size) • Analyze data (CER Stage 3) – Data from A, B, & G supports safety & performance but gap identified
• Repeat as warranted – Search again on device G • Write CER
• Justify Equivalence on Devices A, B, and G • Write PMS Plan (to include PMCF for subject device)
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• For devices cited in literature
Demonstration of equivalence Example:
Parameter Subject Device
Comparative Devices Potential Clinical Impact of Differences Device A Device B Device G
Picture
Indications
Contraindications
Material
Sizes
Design
Lifetime
Etc.
Key Parameters
Based on expert analysis Source of data should be cited
EQUIVALENT
EQUIVALENT
EQUIVALENT
EQUIVALENT?
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Equivalent Devices – Watch-Outs • Equivalent devices not identified • Equivalent devices not EU medical devices • Improper equivalent devices identified – not equivalent for clinical,
technical, and biological • Piecing equivalent features out of multiple devices • Gaps in demonstration of equivalence – insufficient data / information
• Not all information in public domain • Preclinical data can be used to fill in gaps
• Equivalence argument does not cover key parameters that may impact safety or performance
• Differences from subject device not characterized • Potential clinical impact of differences not discussed • Citations do not identify devices used or other key information
• Manufacturer must demonstrate (i.e. justify) equivalence with the device
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BSI Examples Where Equivalence Argument Has Been Rejected • Devices are judged to be alternate treatments
• Composed of different materials in contact with tissues resulting in different biological response (e.g. biologic vs. synthetic)
• Dissimilar material form (e.g. sheets vs. granules vs. foam) • Dissimilar principles of operation (e.g. stop bleeding by pressure
vs. natural hemostasis vs. included medicinal agent) • Vastly different absorption profiles (e.g. non-absorbable devices
claimed to be equivalent to absorbable ones) • Different clinical uses (e.g. hemostasis vs. aid to wound healing)
• Only clinical data available for equivalent device is for off-label use
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CER Stage 2: Data Appraisal – Merits/Limitations • Suitability – appraise quality and relevance
• characterize merits / limitations • document reasons for exclusions
• Contribution – weigh value by considering confounding influences • underlying medical conditions • concomitant treatment(s) • bias
MEDDEV 2.7.1 – “Equivalent Devices”
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• CER Stage 2: Data Appraisal – Suitability Appx D Example:
MEDDEV 2.7.1 – “Equivalent Devices”
? Weight
?
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MEDDEV 2.7.1 – “Equivalent Devices”
• CER Stage 3: Data Analysis – Sufficiency • If clinical literature is presented for equivalent devices,
• is this clinical data when taken together with the available preclinical data sufficient to demonstrate conformity with ERs covering safety and performance of the device in question under normal conditions of use?
• are there gaps in either the demonstration of compliance with each relevant essential requirement or in the demonstration of equivalence that needs addressing through the means of a specifically designed clinical investigation(s)?
• is the data sufficient to address the clinical hazards identified in the risk analysis?
• If no, a clinical investigation(s) will be needed. The objectives of the clinical investigation(s) should focus on those aspects not sufficiently addressed by the available data.
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EU Commission Guidelines on Post-Market Clinical Follow-up (PMCF) Studies
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MEDDEV 2.12/2 - PMCF Studies
Circumstances that may justify PMCF studies include: • Innovation, unanswered questions on long-term safety and performance,
emergence of new information on safety and performance • High risk design, materials, components, invasiveness, clinical procedures,
anatomical locations, target populations • Severity of disease, unstudied subpopulations, interaction with other
medical products or treatments • Generalizability of pre-market clinical data • Verification of safety and performance when exposed to a larger and more
varied population of users • Risks identified from literature, adverse events, clinical investigations or
PMS • Where CE marking was based on equivalence.
Focus of PMCF Subject Device
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Clinical data from PMCF Studies: • Not intended to replace the pre-market data necessary to demonstrate
conformity with the provisions of the legislation. • Critical to update the clinical evaluation throughout the life-cycle of the
medical device and to ensure the long term safety and performance of devices after their placing on the market.
• The objective is to confirm clinical performance and safety, the acceptability of identified risks, and to detect emerging risks on the basis of factual evidence.
• Provides real world experience obtained in larger, heterogeneous and more complex populations, with a broader (and potentially less experienced) range of end-users than is usually the case with clinical investigations.
MEDDEV 2.12/2 - PMCF Studies
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Clinical data from PMCF Studies: • Most useful for identifying less common but serious device-related
adverse events; providing long term information about safety and performance, including durability data and information about failure modes; and elucidating the end-user “learning curve”.
• Particularly useful source of clinical data for low risk devices that are based on long standing, well-characterised technology and, therefore, unlikely to be the subject of either reporting in the scientific literature or clinical investigation.
MEDDEV 2.12/2 - PMCF Studies
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Practical Example
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Subject Device – Mesh A • Absorbable PLLA knitted mesh • Intended Use: For the repair of hernia, uterovaginal prolapse, and other
fascial deficiencies that require the addition of a reinforcing or bridging material to obtain the desired surgical result.
• 4 Sizes (10 x 15 cm, 15 x 20 cm, 30 x 35 cm, 30 x 50 cm) • Absorption time: 3 years
Assessing Device Equivalence
Potential Equivalent Device – Mesh B • 2 Layer co-knitted Mesh composed of non-absorbable polypropylene (top)
and co-knit of absorbable PLA/PGA copolymer (bottom) • Intended Use: For tissue reinforcement and long-lasting stabilization of
fascial structures of the abdominal wall during open and laparoscopic inguinal hernia repair.
• 4 sizes (10 x 10 cm, 10 x 15 cm, 20 x 20 cm, 20 x 30 cm) • Absorption time (absorbable component): 4 months
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Assessing Device Equivalence
Justification for Device Equivalence: • Meshes A and B have been used successfully in the US for the repair of soft
tissue deficiencies and have been judged to be substantially equivalent. The materials used all have a long history of implant use and biocompatibility per ISO 10993 and the devices are offered in similar size ranges. Each can be fixated with sutures or tacks and maintain sufficient strength past 12 weeks to allow healing to occur. After this time, the presence of the mesh is no longer necessary.
• Adverse event (AE) rates associated with the subject device (per the cited literature) are low (0 – 2%) compared to that for Mesh B (2 – 6%). The AE rates of both meshes compare favorably to non-absorbable Polypropylene meshes (10 – 20%) which have been considered the gold standard for decades. The primary complications include infection, pain, adhesions, recurrence, contracture, erosion, and extrusion.
Did justification substantiate device equivalence?
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Assessing Device Equivalence
Device Equivalence Not Substantiated: • Reference made to devices being “substantially equivalent” (per FDA) rather than
“equivalent” per MEDDEV 2.7.1 • Does not expressly discuss clinical, technical, and biological characteristics that are
important to device or discuss the potential clinical impact of differences. • Clinical Uses that May be Important:
o Device A used in uterovaginal prolapse whereas Device B is not – if data are only available on Device B, this indication would not be covered
• Technical Characteristics that May be Important: o Device A is fully absorbable whereas Device B is only partially absorbable - there are likely to be
differences in performance o Device A is available in much larger sizes than Device B – there might be issues related to size o There is no information on key characteristics such as strength/strength retention, stiffness, pore
size, method of application, etc. o No data (e.g. preclinical studies, risk analyses) were presented to substantiate equivalence
• Biological Characteristics that May be Important: o Device A is not the same material as Device B and is not used in the same tissues. While the
justification states that both materials are compatible to ISO 10993, there is no justification for equivalence. It is unlikely that absorbable and partially absorbable materials could be considered equivalent.
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Questions