1/21/ 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

Yes, it is possible. I broke one myself. 1/21/20183 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.

1/21/ 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

1/21/ 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

 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 1/21/

1/21/ 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

What When & 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 1/21/

 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 1/21/

SCOPE CLINICAL EVALUATION PLAN  Based on essential requirements  Basis for future steps  Both favorable and unfavorable data AspectsBefore CEAfter CE Device description (A3) YES Special performance or safety concerns YES Information for evaluation of equivalence YES Risk management documents YES Medical condition, standards, alternatives YES Data source and type 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 1/21/

ORIGIN OF PERTINENT DATA ManufacturerLiterature Premarket clinical investigationsDevice & Equivalent Risk management activitiesCurrent knowledge PMS programs (global)Standards, guidelines PMCF studiesClinical background PMS reportsPotential clinical hazards Adverse incidentsValidity o equivalence criteria ComplaintsValidity 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 1/21/

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 1/21/ All the relevant documents are now available for pick up. Hand trucks are in the back room.

GENERAL CONSIDERATIONS CRITERIA  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 1/21/

Methodological quality, scientific validity  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 1/21/

Relevance & Weighing evidence  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 1/21/ 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

All Completed studies Results available 1/21/ 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 Literature search strategy Duplicates True subject numbers Study size and power Link results to studies identified in registries

1/21/ 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 A6

1/21/ Number of Studies by Phase over Time (completion date)

1/21/ Number of Studies by Results over Time (completion date) Drugs Devices

1/21/ 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 A9

1/21/ 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 A12

1/21/ 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 Annex C Equivalence with a CE-marked device used in accordance with intended use as stated in IFU

1/21/ 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

1/21/ 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

1/21/ MEDLINE/PubMed EMBASE/Excerpta Medica Cochrane CENTRAL trials register Internet 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

1/21/ 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

1/21/ PRISMA Flow Diagram Defibrillators

1/21/ 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

1/21/ Conformity Assessment (Safety) – MDD ER1 / AIMDD ER1 Electrical hazards EN Usability standards EN and EN 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

1/21/ 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

1/21/ 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

1/21/ 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

1/21/ 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

1/21/ 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