Understanding Clinical Equivalence

Transcription

1 Understanding Clinical Equivalence BSI 2014 Medical Device Mini-Roadshow Ibim Tariah Ph.D Technical Director, Healthcare Solutions 1

2 Understanding Clinical Equivalence 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 2

3 EU Directives on Medical Devices 3

4 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 4

5 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: 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 o there is demonstration of equivalence of the device with that to which the data relates and, the data adequately demonstrate compliance with the relevant Essential Requirements; or a critical evaluation of the results of all clinical investigations made; or a critical evaluation of the combined clinical data provided in and above. 5

6 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. 6

7 Annex X (MDD) / Annex 7 (AIMD) 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 7

8 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. 8

9 Annex X, Sec 1.1d (MDD) / Annex 7, Sec. 1.5 (AIMD) 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. 9

10 Definition of a Medical Device 10

11 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. 11

12 EU Commission Guidelines on the Clinical Evaluation of Medical Devices 12

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14 MEDDEV 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 14

15 MEDDEV Key Contents 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 15

16 MEDDEV Equivalent Devices 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. 16

17 MEDDEV Equivalent Devices 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 NB Checklist If differences are identified, an assessment must be done to demonstrate potential significance of differences on safety & performance 17

18 MEDDEV Equivalent Devices Appx. F, Sec (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 18

19 FDA Predicate Devices FDA Predicate Device MEDDEV 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. 19

20 MEDDEV Equivalent Devices 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. 20

21 Device Equivalence Example Are devices which are EQUIVALENT to your device available on the market? Are clinical data available for these devices? 21 21

22 Clearly Not Equivalent Not equivalent Both fruits but different types shape, consistency, taste, edible vs. inedible skin Differences clearly impact function and use 22 22

23 Clearly Equivalent Equivalent Same variety, colour, etc. Can use data from one to assume performance will be the same. 23

24 Equivalence Must be Justified Both apples Different varieties colour, taste, crunch, dessert or cooking? How do the differences impact their function or use? 24

25 MEDDEV CER Construction Figure 1: 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 Generate new or add l clinical data No Is clinical evidence sufficient to be able to declare conformity with relevant ERs? Stage 3 Analysis of relevant data: Strength of overall evidence Conclusion about performance and safety Yes Produce CER * Conformity to harmonized performance standard may be sufficient to demonstrate compliance to ERs 25

26 MEDDEV Equivalent Devices Example: Stepwise Approach Identify potential equivalent devices for search strategy Subject A B C D 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) E F G 26

27 Demonstration of equivalence Example: For devices cited in literature Parameter Subject Device Device A Comparative Devices Device B Device G Potential Clinical Impact of Differences Picture Indications Contraindications Material Sizes Design Lifetime Etc. E Q U I V A L E N T E Q U I V A L E N T E Q U I V A L E N T EQUIVALENT? Key Parameters Source of data should be cited Based on expert analysis 27

28 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 28

29 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 29

30 MEDDEV Equivalent Devices 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 30

31 MEDDEV Equivalent Devices Appx D Example: CER Stage 2: Data Appraisal Suitability Weight?? 31

32 MEDDEV 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. 32

33 EU Commission Guidelines on Post-Market Clinical Follow-up (PMCF) Studies 33

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35 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 35

36 MEDDEV 2.12/2 - PMCF Studies 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. 36

37 MEDDEV 2.12/2 - PMCF Studies 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. 37

38 Practical Example 38

39 Assessing Device Equivalence 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 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 39

40 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 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? 40

41 Assessing Device Equivalence Device Equivalence Not Substantiated: Reference made to devices being substantially equivalent (per FDA) rather than equivalent per MEDDEV 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. 41

42 Questions 42

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