Paths Of The Clinical Evaluation“

„Medical Devices–Paths of the Clinical Evaluation“EndoVESPA MeetingBioRobotics Institute, SSSAPontedera10. February 2016Dr. rer. nat. Timo Weilandnovineon CRO & Consulting Ltd

1Medical device life cycle and approval process2Context of Clinical Evaluation according to guideline 93/42/ECC3MEDDEV 2.7.1: Clinical Evaluation via the literature route4MEDDEV 2.7.1: Clinical Evaluation via clinical investigation2

1Medical device life cycle and approval process2Context of Clinical Evaluation according to guideline 93/42/ECC3MEDDEV 2.7.1: Clinical Evaluation via the literature route4MEDDEV 2.7.1: Clinical Evaluation via clinical investigation3

Medical device life cycle and approval processPhase 1: Product ideaSource:Phase 2:from development tomarket introductionPhase 1:ideaPhase 3:marketintroductionPhase 4:post-marketsurveillanceProduct idea:52 % of the ideasfor new medicaldevices are frommedical doctors(users)Phase 5:Re-audits

Medical device life cycle and approval processPhase 1: R&D and assessment of technical feasibilityPhase 2:from development tomarket introductionPhase 1:ideaPhase 3:marketintroductionPhase 4:post-marketsurveillanceProve of technicalfeasibilityCooperation betweenmedical doctor andengineerPhase 5:Re-audits

Medical device life cycle and approval processIntended use of a medical deviceA product’s intended use is what it is supposed to be used for according to themanufacturer’s specifications, instructions, and other information. The manufacturer defines the intended use / intended purpose as well as the field ofindication The intended purpose decides whether or not a product is a medical device The manufacturer takes responsibility that the medical device fulfils its intendedpurpose and the safety of the patient and user is assure according to the EssentialRequirements

Medical device life cycle and approval processLegal definition „Medical device“ – European legal frameworkA medical device is any (instrument, apparatus, implement, machine, appliance,implant, reagent for in vitro use, software, material or other similar or related article)device, intended by the manufacturer to be used, alone or in combination for thespecific medical purpose(s) of diagnosis of disease or other conditions, or in the cure,mitigation, treatment, or prevention of disease in man.In contrast to drugs, it does not achieve its primary intended action by pharmacological,immunological or metabolic means.

Medical device life cycle and approval processPhase 2: Technical documentation and establishment of quality managementsystem (EN ISO 13485)Phase 2:from development tomarket introductionPhase 3:marketintroductionPhase 1:ideaEstablishment of a qualitymanagement systemto ensure process and productqualityPhase 5:Re-auditsSource: BVMed, 2014Phase 4:post-marketsurveillance

Medical device life cycle and approval processPhase 2: SafetyPhase 1:ideaPhase 3:marketintroductionRisk analysis and riskevaluationComparison of the benefitwith the potential risksEvaluation of thebiocompatibilityPhase 4:post-marketsurveillancePhase 5:Re-auditsQuelle: BVMed, 2014Phase 2:from development tomarket introduction

Medical device life cycle and approval processPhase 2: SafetyPhase 2:from development tomarket introductionPhase 3:marketintroductionPhase 1:ideaTechnical testsaccording tospecific standardsPhase 5:Re-auditsSource: BVMed, 2014Phase 4:post-marketsurveillance

Medical device life cycle and approval processPhase 2: Efficiency/EfficacyPhase 2:from development tomarket introductionPhase 3:marketintroductionPhase 4:post-marketsurveillancePhase 1:ideaClinical evaluationbased on clinical dataPhase 5:Re-audits

Medical device life cycle and approval processPhase 2: Assessment of technical documentation by Notified BodiesPhase 2:from development tomarket introductionPhase 3:marketintroductionPhase 4:post-marketsurveillancePhase 1:ideaNotified bodiescertify safety andefficacyPhase 5:Re-audits

Medical device life cycle and approval processConformity assessment procedureGuarantee of compliance of the medical device in question with the Essential Requirementson safety and efficacy Device description / definition of intended purpose Standard conformity / tests Risk analysis / risk managment report Quality management Clinical evaluationThe technical documentation demonstrates compliance with the Essential Requirements

Medical device life cycle and approval processAnnex I / MDD – Essential requirements Any risks which may be associated with their use constitute acceptable risks whenweighed against the benefits to the patient The devices must achieve the performances intended by the manufacturer During the lifetime of the device, characteristics and performances as indicated by themanufacturer must not be adversely affected Conformity with the essential requirements must be demonstrated by a Clinical Evaluationin accordance with Annex X. .

Medical device life cycle and approval processNotified BodyA Notified Body, in the European Union, is an private enterprise / organization that hasbeen accredited by a Member State to assess whether a product meets certainpreordained standards.Auditing, evaluation and certification: Quality management system Technical documentation / Design dossier Medical device

Medical device life cycle and approval processMilestone: Declaration of conformity – CE markingPhase 2:from development tomarket introductionCE markingPhase 3:marketintroductionPhase 4:post-marketsurveillancePhase 1:ideaPhase 5:Re-auditsProduct ready for commercializationand routine clinical use

Medical device life cycle and approval processCE markThe CE mark is an indication that a product complies with the Essential Requirementsof applicable directives and that it has been proven in a conformity assessment procedureThe CE mark is a mandatory label required for distribution and sale in the EU

1Medical device life cycle and approval process2Context of Clinical Evaluation according to guideline 93/42/ECC3MEDDEV 2.7.1: Clinical Evaluation via the literature route4MEDDEV: 2.7.1: Clinical Evaluation via clinical investigation18

Context of Clinical Evaluation according to guideline 93/42/ECCGuideline 93/42/EEC, appendix X specifies the requirements for the Clinical EvaluationThe Clinical Evaluation is a medical-scientific benefit-risk assessment of a medical deviceor its product family based on clinical data to demonstrate efficacy and safety includingadverse events in regards to the intended use defined by the manufacturer. Risks have to be reasonable in relation to the clinical benefit. The benefits awarded by the manufacturer have to be proven. Features and performance have to comply with the standards throughout theproduct lifespan.

Context of Clinical Evaluation according to guideline 93/42/ECCMEDDEV 2.7.1 is the key document for the clinical evaluation of medical devicesRecommendation of a suitable method for the clinical evaluation via the literature routeAim of the MEDDEV 2.7.1: Assistance for manufacturers concerning the evaluation of clinical data Notified Bodies concerning the assessment of the Clinical Evaluation within theprocedure of conformity assessment

Context of Clinical Evaluation according to guideline 93/42/ECCPaths of the Clinical Evaluation

1Medical device life cycle and approval process2Context of Clinical Evaluation according to guideline 93/42/ECC3MEDDEV 2.7.1: Clinical Evaluation via the literature route4MEDDEV 2.7.1: Clinical Evaluation via clinical investigation22

MEDDEV 2.7.1: Clinical Evaluation via the literature routePaths of the Clinical EvaluationClinical Evaluation on the literature route is possible under the following conditions Clinical experience with the device in question or an equivalent device exists Literature is sufficiently available and accessable Equivalence of products can be plausibly shown No further requirements e.g. hamonized standards for the implementation of clinicalinvestigations

MEDDEV 2.7.1: Clinical Evaluation via the literature routeThe concept of equivalence“Equivalence“ is the similarity of two devices concerning all relevant features withregard to safety and efficacyClinicalTechnicalBiological Indications Design Materials Contraindications Application conditions Biocompatibility Use at the same part of Physical/technicalthe human bodyfunctional principle Patient population Technical performance Clinical mode of operation

MEDDEV 2.7.1: Clinical Evaluation via the literature routeThe concept of equivalence

MEDDEV 2.7.1: Clinical Evaluation via the literature routeThe clinical data are identified, assessed and evaluated until the clinical evidence issufficient to carry out a Clinical EvaluationPhase 1: Identification of clinical data Literature search and/orClinical experience and/orClinical trialPhase 2: Assessment of the data SuitabilityContribution of the results to the evaluationof safety and efficacyGeneration of new oradditional clinical data in case ofknowledge gapsnoClinical evidenceis sufficient fordemonstration ofconformity with therelevant essentialrequirements?Phase 3: Evaluation of all data Overall-evidenceConclusion concerning safety and efficacyyesPreparation of the Clinical Evaluation

MEDDEV 2.7.1: Clinical Evaluation via the literature routeNon-clinical data and properties of the device in question are also evaluated anddiscussed in the Clinical Evaluation Risk analysis / risk management report Proof of biocompatibility (ISO 10993) Design validation and verification (e.g. Stent shortening) Mechanical Tests (z.B. radial strength, stent fracture strength) Technical safety (z.B. electrical IEC 60601-1) Animal experiments

MEDDEV 2.7.1: Clinical Evaluation via the literature routeSafety is defined as freedom from unacceptable risksThe Clinical Evaluation is based upon an integrated summary of clinical data, technicaltest results and risk management dataThe Clinical Evaluation and its outcome shall be documented. This documentation shallbe included and/or fully referenced in the technical documentation of the device.The Clinical Evaluation and its documentation have to be actively updated.

1Medical device life cycle and approval process2Context of Clinical Evaluation according to guideline 93/42/ECC3MEDDEV 2.7.1: Clinical Evaluation via the literature route4MEDDEV 2.7.1: Clinical Evaluation via clinical investigation29

Clinical Evaluation via clinical investigationClinical investigationAny specific study in human subjects undertaken to verify the safety andperformance of a specific medial device under normal conditions of use.The objectives of clinical investigation are: to verify that, under normal conditions of use, the performance of the devicesconform to those referred to in Section 3 of Annex I, and to determine any undesirable side-effects, under normal conditions of use, andassess whether they constitute risks when weighed against the intendedperformance of the device. A clinical investigation generates data on safety and efficacy of a medical devicedestined for conformity assessment procedures

Clinical Evaluation via clinical investigationFollowing NB-MED 2.7/Rec1, a clinical investigation needs to be performed when a completely new device is proposed for the market, whose components, featuresand / or method of action are previously unknown an existing device is modified and the modification might significantly affect theclinical safety and performance a previously established device is proposed for a new indication a device incorporates new materials, previously unknown, coming into contact withthe human body or existing materials applied in a location not previously exposed sothat material, and for which there is no convincing prior clinical experience# the device will be used for a significantly longer time Gaps of knowledge; lack of available clinical data