Directives 90/385/EEC and 93/42/EEC MEDICAL DEVICES. Clinical Evaluation Report Presentation guide

Transcription

1 Directives 90/385/EEC and 93/42/EEC MEDICAL DEVICES Clinical Evaluatin Reprt Presentatin guide The elements f the clinical evaluatin reprt are recrds f the prcess that the manufacturer applies t the identificatin, selectin, appraisal and critical analysis f clinical data in rder t meet the applicable essential requirements f medical devices Directives. The purpse f this guide, intended t manufacturers f medical devices, is t specify the different elements t be included in the clinical evaluatin reprt, which is part f the design dssier and technical file within the frame f CE marking prcedures fr medical devices, whatever the class f the medical device is. Guide fr the presentatin f clinical evaluatin reprt page 1/17

2 Clinical Evaluatin Reprt Presentatin guide I REFERENCE DOCUMENTS ORIGIN REFERENCE TITLE FRANCE Eurpean Unin Eurpean Unin CEN ISO Cde de la Santé Publique (Public Health Cde) Directives 90/385/EEC (Annex 7) 93/42/EEC (Annex X) 2007/47/EC Annex II.4 / III MEDDEV rev.4 MEDDEV rev.2 NF EN ISO (2016) Active implantable medical devices Medical devices EC cnceptin r type examinatin Evaluatin f clinical data : a guide fr manufacturers and ntified bdies Guidelines n pst market clinical fllw-up Medical devices Quality management systems Requirements fr regulatry purpses CEN ISO NF EN ISO (2013) Medical devices Applicatin f risk management t medical devices. CEN ISO NF EN ISO (2012) Clinical investigatin f medical devices fr human subjects GHTF SG5/N1R8 (2007) Clinical Evidence Key definitins and cncepts GHTF SG5/N2R8 (2007) Clinical Evaluatin Table A: reference dcuments NOTE French transpsitin laws are available in the Jurnal Officiel de la République Française (Official gazette f the French Republic). Eurpean Directives are available in the Official Jurnal f the Eurpean Unin. MEDDEV guidelines are available n the website f the Eurpean Cmmissin. Standards are available at AFNOR GHTF (Glbal Harmnizatin Task Frce) guidelines are available n the fllwing website: Guide fr the presentatin f clinical evaluatin reprt page 2/17

3 Clinical Evaluatin Reprt Presentatin guide II Definitins Bias: bias is a systematic deviatin f an utcme measure frm its true value, leading t either an verestimatin r underestimatin f a treatment s effect. It can riginate frm, fr example, the way patients are allcated t treatment, the way treatment utcmes are measured and interpreted, and the way data are recrded and reprted. [Adapted frm GHTF SG5/N2R8:2007] Clinical data: the safety and/r perfrmance infrmatin that is generated frm the clinical use f a device. Clinical data are surced frm: - clinical investigatin(s) f the device cncerned; r - clinical investigatin(s) r ther studies reprted in the scientific literature, f a similar device fr which equivalence t the device in questin can be demnstrated; r - published and/r unpublished reprts n ther clinical experience f either the device in questin r a similar device fr which equivalence t the device in questin can be demnstrated. [derived frm Article 1.2.k MDD and Art. 1.2.k AIMDD] Clinical evaluatin: a methdlgically sund nging prcedure t cllect, appraise and analyse clinical data pertaining t a medical device and t evaluate whether there is sufficient clinical evidence t cnfirm cmpliance with relevant essential requirements fr safety and perfrmance when using the device accrding t the manufacturer s Instructins fr Use. Nte: In exceptinal cases where an instructin fr use is nt required, the cllectin, analysis and assessment are cnducted taking int accunt generally recgnised mdalities f use. Clinical evidence: the clinical data and the clinical evaluatin reprt pertaining t a medical device. [GHTF SG5/N2R8:2007] Clinical investigatin: systematic investigatin in ne r mre human subjects, undertaken t assess the safety r perfrmance f a medical device. Nte: 'clinical trial' r ' clinical study' are synnymus with ' clinical investigatin'. [EN ISO 14155:2011] Equivalent device: a device fr which equivalence t the device in questin can be demnstrated. (See the explanatin in this guidance dcument, sectin IV) Feasibility study: a clinical investigatin that is cmmnly used t capture preliminary infrmatin n a medical device (at an early stage f prduct design) t adequately plan further steps f device develpment, including needs fr design mdificatins r parameters fr a pivtal study. [MEDDEV 2.7/2 revisin 2] Clinical perfrmance: behaviur f a medical device r respnse f the subject(s) t that medical device in relatin t its intended use, when crrectly applied t apprpriate subject(s). [EN ISO 14155:2011] Clinical safety: freedm frm unacceptable clinical risks, when using the device accrding t the manufacturer s Instructins fr Use. [MEDDEV 2.7/2 revisin 2] Guide fr the presentatin f clinical evaluatin reprt page 3/17

4 Clinical Evaluatin Reprt Presentatin guide Nte: In exceptinal cases where an instructin fr use is nt required, the cllectin, analysis and assessment are cnducted taking int accunt generally recgnised mdalities f use. Clinical use: use f a medical device in r n living human subjects. Nte: Includes use f a medical device that des nt have direct patient cntact. Intended purpse: the use fr which the device is intended accrding t the data supplied by the manufacturer n the labelling, in the instructins and/r in prmtinal materials. [MDD Art. 1.2.g, AIMDD Art. 1.2.f] PMCF plan: the dcumented, practive, rganised methds and prcedures set up by the manufacturer t cllect clinical data based n the use f a CE-marked device crrespnding t a particular design dssier r n the use f a grup f medical devices belnging t the same subcategry r generic device grup as defined in Directive 93/42/EEC. The bjective is t cnfirm clinical perfrmance and safety thrughut the expected lifetime f the medical device, the acceptability f identified risks and t detect emerging risks n the basis f factual evidence. [MEDDEV 2.12/2 rev.2] PMCF study: a study carried ut fllwing the CE marking f a device and intended t answer specific questins relating t clinical safety r perfrmance (i.e. residual risks) f a device when used in accrdance with its apprved labelling. [MEDDEV 2.12/2 rev.2] Sufficient clinical evidence: an amunt and quality f clinical evidence t guarantee the scientific validity f the cnclusins. III Principles f clinical evaluatin III.1) What is a clinical evaluatin? Clinical evaluatin is a methdlgically sund nging prcedure t cllect, appraise and analyse clinical data pertaining t a medical device and t analyse whether there is sufficient clinical evidence t cnfirm cmpliance with relevant essential requirements fr safety and perfrmance when using the device accrding t the manufacturer s instructins fr use. The requirements fr clinical evaluatin apply t all classes f medical devices. The evaluatin shuld be apprpriate t the device under evaluatin, its specific prperties, and its intended purpse. Cnfrmity t the Essential Requirements can nly be assumed when the fllwing items are aligned with each ther: 1. the infrmatin materials supplied by the manufacturer (the labelling, instructins fr use, available prmtinal materials, including accmpanying dcuments freseen by the manufacturer), 2. the clinical evaluatin (the device descriptin used fr the clinical evaluatin) 3. the available clinical data (such as results f Clinical Investigatins, publicatins, PMS studies, etc.), 4. the risk management file Guide fr the presentatin f clinical evaluatin reprt page 4/17

5 Clinical Evaluatin Reprt Presentatin guide 5. the usability demnstratin III.2) When clinical evaluatin is t be perfrmed? Clinical evaluatin is cnducted thrughut the life cycle f a medical device, as an nging prcess. Usually, it is first perfrmed during the develpment f a medical device in rder t identify data that need t be generated fr market access. Clinical evaluatin is mandatry fr initial CE-marking and it must be actively updated thereafter. As reminder, it addresses the sectin f the ISO standard, current versin. III.2.a) During device develpment Typically, manufacturers carry ut clinical evaluatins t: 1. define needs regarding clinical safety and clinical perfrmance f the device; 2. in case f pssible equivalence t an existing device, evaluate if there are clinical data available and determine equivalence; 3. carry ut a gap analysis and define which data still need t be generated with the device under evaluatin, whether clinical investigatins are necessary and if s, t define the study design. III.2.b) Clinical evaluatin fr initial CE-marking Clinical evaluatin is required t be carried ut fr the cnfrmity assessment prcess leading t the CE-marking and placing n the market f a medical device. The purpse is t: 1. dcument that there is sufficient clinical evidence t demnstrate cnfrmity with the Essential Requirements cvering clinical perfrmance and clinical safety; 2. identify aspects that need t be addressed systematically during pst-market surveillance (PMS), e.g. in pst market clinical fllw-up studies (PMCF Studies) required under the medical device directives. Typically, these aspects include estimatin f residual risks and uncertainties r unanswered questins (such as rare cmplicatins, uncertainties regarding lng-term perfrmance, safety under wide-spread use). III.2.c) Updating the CE: frequency and cnsideratin The manufacturer shuld define and justify the frequency at which the clinical evaluatin needs t be actively updated. The clinical evaluatin is actively updated: when the manufacturer receives new infrmatin frm PMS that has the ptential t change the current evaluatin; if n such infrmatin is received, then - at least annually if the device carries significant risks r is nt yet well established; r - every 2 t 5 years if the device is nt expected t carry significant risks and is well established, a justificatin shuld be prvided. Guide fr the presentatin f clinical evaluatin reprt page 5/17

6 Clinical Evaluatin Reprt Presentatin guide When invlvement f ntified bdies is required, updates are usually crdinated with the ntified bdy. Typically, they are aligned with the timetable fr the renewal f the certificates. In accrdance with the Directives, the clinical evaluatin and the clinical evaluatin reprt must be actively updated with data btained frm pst-market surveillance. III.3) Hw is Clinical Evaluatin perfrmed? There are discrete stages in perfrming a clinical evaluatin: Stage 0 - Scpe f clinical evaluatin : It explains the scpe and cntext f the evaluatin, including which prducts/ mdels/ sizes/ settings are cvered by the clinical evaluatin reprt, the technlgy n which the medical device is based, the cnditins f use and the intended purpse f the device; It dcuments any claims made abut the device s clinical perfrmance r clinical safety. Stage 1 - Identificatin f pertinent data : It explains the literature search strategy; It presents the nature and extent f the clinical data and relevant pre-clinical data that have been identified. Stage 2 Appraisal f pertinent data : Its explains the criteria used by the evaluatrs fr appraising data sets; Its summarises the pertinent data sets (methds, results, cnclusins f the authrs); Its evaluates their methdlgical quality, scientific validity, the relevance fr the evaluatin, the weighting attributed t the evidence, and any limitatins; It presents justificatins fr rejecting certain data r dcuments. Stage 3 - Analysis f data : It explains if and hw the referenced infrmatin, such as cnfirmatin f cmpliance with clinical data requirement frm applicable harmnised standards and the clinical data, cnstitute sufficient clinical evidence fr demnstratin f the clinical perfrmance and clinical safety f the device under evaluatin; It explains whether there are adequate data fr all aspects f the intended purpse and fr all prducts/ mdels/ sizes/ settings cvered by the clinical evaluatin. It describes the benefits and risks f the device (their nature, prbability, extent, duratin and frequency); It explains the acceptability f the benefit/risk prfile accrding t current knwledge/ the state f the art in the medical fields cncerned, with reference t applicable standards and guidance dcuments, available medical alternatives, and the analysis and cnclusins f the evaluatrs n fulfilment f all Essential Requirements pertaining t clinical prperties f the device (MDD ER1, ER3, ER6; AIMDD ER1, ER2, ER5); It analyses if there is cnsistency between the clinical data, the infrmatin materials supplied by the manufacturer, the risk management dcumentatin fr the device under evaluatin; whether there is cnsistency between these dcuments and the current knwledge/ the state f the art; It identifies any gaps and discrepancies; Guide fr the presentatin f clinical evaluatin reprt page 6/17

7 Clinical Evaluatin Reprt Presentatin guide It identifies residual risks and uncertainties r unanswered questins (such as rare cmplicatins, uncertainties regarding medium- and lng term perfrmance, safety under wide-spread use) that shuld be further evaluated during PMS, including in PMCF studies. Stage 4: Finalise the clinical evaluatin reprt The clinical evaluatin reprt summarises and draws tgether the evaluatin f all the relevant clinical data dcumented r referenced in ther parts f the technical dcumentatin. The clinical evaluatin reprt and the relevant clinical data cnstitute the clinical evidence fr cnfrmity assessment. III.4) Wh shuld perfrm a Clinical Evaluatin? The clinical evaluatin shuld be cnducted by a suitably qualified individual r a team. The manufacturer shuld take the fllwing aspects int cnsideratin: 1. The manufacturer defines requirements fr the evaluatrs that are in line with the nature f the device under evaluatin and its clinical perfrmance and risks. 2. The manufacturer shuld be able t justify the chice f the evaluatrs thrugh reference t their qualificatins and dcumented experience, and t present a declaratin f interest fr each evaluatr. As a general principle, the evaluatrs shuld pssess knwledge f the fllwing: 1. research methdlgy (including clinical investigatin design and bistatistics); 2. infrmatin management (e.g. scientific backgrund r librarianship qualificatin; experience with relevant databases such as Embase and Medline); 3. regulatry requirements; and 4. medical writing (e.g. pst-graduate experience in a relevant science r in medicine; training and experience in medical writing, systematic review and clinical data appraisal). With respect t the particular device under evaluatin, the evaluatrs shuld in additin have knwledge f: 1. the device technlgy and its applicatin; 2. diagnsis and management f the cnditins fr which the device is intended t be used, knwledge f medical alternatives, treatment standards and technlgy (e.g. specialist clinical expertise in the relevant medical specialty). The evaluatrs shuld have at least the fllwing training and experience in the relevant field: 1. a degree frm higher educatin in the respective field and 5 years f dcumented prfessinal experience; r years f dcumented prfessinal experience if a degree is nt a prerequisite fr a given task, related t the clinical evaluatin. There may be circumstances where the level f evaluatr expertise may be less r different; this shuld be dcumented and duly justified. It is understd that the cmpetences can be shared n a team, knwing that the plan and the reprt need t be signed by all the members f the team. Guide fr the presentatin f clinical evaluatin reprt page 7/17

8 Clinical Evaluatin Reprt Presentatin guide IV Equivalence Clinical, technical and bilgical characteristics shall be taken int cnsideratin fr the demnstratin f equivalence: Clinical: used fr the same clinical cnditin (including when applicable similar severity and stage f disease, same medical indicatin), and used fr the same intended purpse, and used at the same site in the bdy, and used in a similar ppulatin (this may relate t age, gender, anatmy, physilgy, pssibly ther aspects), and nt freseen t deliver significantly different perfrmances (in the relevant critical perfrmances such as the expected clinical effect, the specific intended purpse, the duratin f use, etc.). Technical: be f similar design, and used under the same cnditins f use, and have similar specificatins and prperties (e.g. physicchemical prperties such as type and intensity f energy, tensile strength, viscsity, surface characteristics, wavelength, surface texture, prsity, particle size, nantechnlgy, specific mass, atmic inclusins such as nitrcarburising, xidability), and use similar deplyment methds (if relevant), and have similar principles f peratin and critical perfrmance requirements. Bilgical: Use the same materials r substances in cntact with the same human tissues r bdy fluids. Exceptins can be freseen fr devices in cntact with intact skin and minr cmpnents f devices; in these cases risk analysis results may allw the use f similar materials taking int accunt the rle and nature f the similar material. Different aspects f equivalence and cmpliance t different Essential Requirements can be affected by materials. Evaluatrs shuld cnsider bilgical safety (e.g. in cmpliance t ISO 10993) as well as ther aspects necessary fr a cmprehensive demnstratin f equivalence. A justificatin explaining the situatin shuld be prvided fr any difference. Fr assuming equivalence: equivalence can nly be based n a single device; all three characteristics (clinical, technical, bilgical) need t be fulfilled; similar means that n clinically significant difference in the perfrmance and safety f the device wuld be triggered by the differences between the device under evaluatin and the device presumed t be equivalent; the differences between the device under evaluatin and the device presumed t be equivalent need t be identified, fully disclsed, and evaluated; explanatins shuld be given why the differences are nt expected t significantly affect the clinical perfrmance and clinical safety f the device under evaluatin; the manufacturer shuld investigate if the medical device presumed t be equivalent has been manufactured via a special treatment (e.g. a surface mdificatin, a prcess that mdifies material characteristics); if this is the case, the treatment culd cause differences in respect t technical and bilgical characteristics; this shuld be taken int accunt fr the demnstratin f equivalence and dcumented in the CER; if measurements are pssible, clinically relevant specificatins and prperties shuld be measured bth in the device under evaluatin and the device presumed t be equivalent, and presented in cmparative tabulatins; Guide fr the presentatin f clinical evaluatin reprt page 8/17

9 Clinical Evaluatin Reprt Presentatin guide cmparative drawings r pictures shuld be included in rder t cmpare shapes and sizes f elements that are in cntact with the bdy; the manufacturer is expected t: include the supprting nn-clinical infrmatin (e.g. pre-clinical study reprts) in the technical dcumentatin f the device, and in the clinical evaluatin reprt, summarise the infrmatin and cite its lcatin in the technical dcumentatin; fr the evaluatin f the technical characteristics, devices that achieve the same therapeutic result by different means cannt be cnsidered equivalent; fr the evaluatin f the bilgical characteristics: when a detailed chemical characterisatin f materials in cntact with the bdy is needed, ISO Annex C can be used t shw txiclgical equivalence but this is just a part f the evaluatin f the bilgical criteria; surcing and manufacturing prcedures may adversely affect impurity prfiles; analytical methds chsen t characterise medical devices shuld apprpriately take int cnsideratin knwledge cncerning expected impurity prfiles (tests may have t be repeated when prductin methds r surcing are changed); it may be necessary t shw frm histpathlgical studies that the same hst respnse is achieved in viv in the intended applicatin and the intended duratin f cntact; fr animal tests, differences between species may limit the predictive value f the test; the chice f the test and its predictive value shuld be justified; abrasin, if relevant, and hst respnse t particles may als need t be cnsidered. the nly clinical data that are cnsidered as relevant are the data btained when the equivalent device is a CE-marked medical device used in accrdance with its intended purpse as dcumented in the IFU. Nte: Exceptins can be cnsidered. When the equivalent device is nt a CE-marked device, infrmatin cncerning the regulatry status f the equivalent device and a justificatin fr the use f its data shuld be included in the clinical evaluatin reprt. The justificatin shuld explain if the clinical data is transferrable t the Eurpean ppulatin, and an analysis f any gaps t gd clinical practices (such as ISO 14155) and relevant harmnised standards. Guide fr the presentatin f clinical evaluatin reprt page 9/17

10 Clinical Evaluatin Reprt Presentatin guide V Clinical Evaluatin Reprt Table f cntents 1. Scpe f the clinical evaluatin 2. Clinical backgrund, current knwledge, state f the art Example f cntents 1. Identificatin f devices cvered by this clinical evaluatin reprt, prducts, mdels, sizes, sftware versins, accessries, their prprietary names, cde names assigned during device develpment. 2. Cncise physical and chemical descriptin, including materials. Whether the device incrprated medicinal substances (already n the market r new), tissues, r bld prducts. Mechanical and physicchemical characteristics; thers (such as sterile vs. nn-sterile, radiactivity etc.); picture r drawing f the device. 3. Technlgies used, whether the device is based n a new technlgy, a new clinical applicatin f an existing technlgy, r the result f incremental change f an existing technlgy. Descriptin f innvative aspects f the device. 4. Device grup the device belngs t. Hw the device achieves its intended purpse. Psitining in relatin t available treatment/ management/ diagnstic ptins. 5. Exact descriptin f the intended purpse as described in the device's IFU (In exceptinal cases where an instructin fr use is nt required, describe the generally recgnised mdalities f use), with exact medical indicatins (if applicable) and cntraindicatins; claims made in available prmtinal materials. Name f disease r cnditin, clinical frm, stage, severity, symptms r aspects t be treated/ managed/ diagnsed, target patient ppulatin, target user grup. Intended applicatin f the device, single use/reusable, invasive/nn invasive, implantable, duratin f use r cntact with the bdy, maximum number f repeat applicatins. Identificatin f rgans, tissues r bdy fluids cntacted by the device. Precautins. 6. Claims n clinical perfrmance and clinical safety freseen by the manufacturer. 7. Whether the device is already CE marked, whether it is n the market, since when, in what regins, histry f the device, including date f past mdificatins with reasns and descriptin, sales vlumes. 8. Changes since the last reprt, whether the device has been mdified, identificatin f new prducts, mdels, sizes, sftware, accessries, new intended purpses, new claims, new events related t the device with an impact n clinical evaluatin. Identificatin f the sectins f the clinical evaluatin reprt that are cncerned with the new infrmatin and have been mdified. 9. Other aspects if relevant. 1. Identificatin f medical fields cncerned/ relevant medical cnditins. 2. Brief summary and justificatin f the literature search strategy Guide fr the presentatin f clinical evaluatin reprt page 10/17

11 Clinical Evaluatin Reprt Presentatin guide applied fr retrieval f infrmatin n current knwledge/ the state f the art, including surces used, search questins, search terms, selectin criteria applied t the utput f the search, quality cntrl measures, results, number and type f literature fund t be pertinent. Appraisal criteria used. 3. Applicable standards and guidance dcuments. 4. Descriptin, natural curse and cnsequences f the medical cnditins cncerned. Whether there are different clinical frms, stages and severities f the cnditins. Frequency in the general ppulatin, by age grup, gender, ethnicity, familiar predispsitins, genetic aspects. 5. Descriptin f available therapeutic/ management/ diagnstic ptins, histrical cntext and develpments, summary f advantages and disadvantages f the different ptins, benefit/ risk prfiles and limitatins in relatin t the different clinical frms, stages, and severities f the medical cnditins and in relatin t different target ppulatins. Descriptin f the benefits and risks (nature, extent, prbability, duratin, frequency), acceptability f undesirable side-effects and ther risks (including the nature, severity, prbability and duratin f acceptable harm). 6. Hazards due t substances and technlgies that culd be relevant t the device under evaluatin. The mechanisms f harm, clinical aspects f minimisatin and management f side effects and ther risks. 7. Types f users. Diverging pinins f prfessinals as t the use f the different medical ptins. Unmet medical needs. 3. Device under evaluatin 3.1. Type f evaluatin Whether the clinical evaluatin is based n - scientific literature currently available, and/r - clinical investigatins made - clinical data generated frm risk management activities and the PMS prgrammes r - whether demnstratin f cnfrmity with essential requirements based n clinical data is nt deemed apprpriate. If clinical data is nt deemed apprpriate, adequate justificatin fr any such exclusin has t be given: - The justificatin must be based n the utput f the risk management prcess. - The device/bdy interactin, the intended used and claims f the manufacturer have t be specifically cnsidered. - Adequacy f demnstratin f cnfrmity with the Essential Requirements based n perfrmance evaluatin, bench testing and preclinical evaluatin in the absence f clinical data has t be duly substantiated. - A clinical evaluatin is still required and the abve infrmatin and evidence-based justificatin shuld be presented in the clinical Guide fr the presentatin f clinical evaluatin reprt page 11/17

12 Clinical Evaluatin Reprt Presentatin guide evaluatin reprt 3.2. Clinical data frm literature Brief summary and justificatin f the literature search strategy applied fr retrieval f clinical data, including bjectives, surces used, search questins, search terms, selectin criteria applied t the utput f the search, quality cntrl measures, results, number and type f literature fund t be pertinent Demnstratin f equivalence (nly when equivalence is claimed) 1. Identificatin f the equivalent device and its manufacturer. Exact name, mdels, sizes, sftware versins, accessries, etc. Name f the manufacturer. Relatinship t the device under evaluatin (predecessr/ successr, thers). If the device is nt CE-marked, justificatin fr the use f the data, based n the ther regulatry status. 2. Cmparisn f clinical, bilgical and technical characteristics (see Appendix A1 fr details). Justificatin f equivalence, descriptin f relevant clinical, bilgical and technical characteristics that affect clinical prperties f the device, differences between the intended purpse f the device under evaluatin and the equivalent device (indicatins, cntraindicatins, precautins, target patient grups, target users, mde f applicatin, duratin f use/ number f reapplicatins, thers), type f device-bdy interactin. Chice, justificatin and validity f parameters and mdels fr nnclinical determinatin f characteristics. 3. Identificatin f pre-clinical studies carried ut and literature used, cncise summaries f studies and literature (methds, results, cnclusins f the authrs), evaluatin f the methdlgical quality f the study r dcument, the scientific validity f the infrmatin. 4. Cmparative tabulatins fr the device under evaluatin versus the equivalent device shwing parameters relevant t the evaluatin f the three characteristics. Cmparative drawings r pictures f the device and the equivalent device shwing the elements in cntact with the bdy. 5. Identificatin f differences, evaluatin if differences are expected r nt t influence the clinical perfrmance and clinical safety f the device, reasns fr assumptins made. 6. Cnclusins cncerning equivalence. Whether the cmparisn carried ut cvers all prducts/ mdels/ sizes/ settings/ accessries and the entire intended purpse f the device under evaluatin, r nly certain prducts/ mdels/ sizes/ settings/ accessries, r selected aspects f the intended purpse, which nes. 7. Cnclusins whether equivalence is demnstrated r nt; it it is demnstrated, cnfirmatin that the differences are nt expected t affect the clinical perfrmance and clinical safety f the device under evaluatin; descriptin f any limitatins and gaps. Identificatin f clinical data generated and held by the manufacturer : Guide fr the presentatin f clinical evaluatin reprt page 12/17

13 Clinical Evaluatin Reprt Presentatin guide 3.4. Clinical data generated and held by the manufacturer - All pre market clinical investigatins - All clinical data generated frm risk management activities and the PMS prgrammes which the manufacturer has implemented in Eurpe and in ther cuntries Summary and appraisal f clinical data Summaries f clinical data generated and held by the manufacturer and f scientific literature fund t be pertinent. Including brief summary f the studies r references (methds, results, cnclusin f the authrs), evaluatin f their methdlgical quality, scientific validity f cntents, relevance t the clinical evaluatin, weighting attributed t the data, cntents used (perfrmance data, safety data, bth) reasns fr rejecting a study r dcument, reasns fr rejecting sme f its cntents. (See annex A6 f MEDDEV dcument) Analysis f the clinical data Requirement n safety (MDD ER1 / AIMDD ER1) Requirement n acceptable benefit/risk prfile (MDD ER1 / AIMDD ER1) Summary f cnfrmity assessment with requirement n safety (MDD ER1 / AIMDD ER1). Analysis whether there are special design features that pse special safety cncerns (e.g. presence f medicinal, human r animal cmpnents) that where identified in the device risk management dcumentatin and that required evaluatin frm a clinical perspective, and whether these have been adequately addressed. Whether the risks identified in the risk management dcumentatin and literature have been adequately addressed. Whether all the hazards and ther clinically relevant infrmatin (e.g. clinical precautins fr reductin f risks, clinical management f risks) have been identified apprpriately. Whether the safety characteristics and intended purpse f the device requires training f the end-user r ther precautins, if users freseen are adequate, if training requirements and ther precautins are described in the IFU. Whether there is full cnsistency between current knwledge/ the state f the art, the available clinical data, the infrmatin materials supplied by the manufacturer, and the risk management dcumentatin fr the device. Summary f cnfrmity assessment with requirement n acceptable benefit/risk prfile (MDD ER1 / AIMDD ER1). Summary f the ttal experience with the device, including estimated numbers and characteristics f patients expsed t the device in clinical investigatins, PMCF, frm ther user experience, and in the market; duratin f fllw-up. Nature, extent/severity, prbability/frequency, duratin f benefits t the patients and f undesirable side-effects and ther risks. Fr each aspect f the intended purpse, whether the benefit/risk prfile including its uncertainties r unanswered questins is cmpatible with a high level f prtectin f health and safety, crrespnding justificatins. Guide fr the presentatin f clinical evaluatin reprt page 13/17

14 Clinical Evaluatin Reprt Presentatin guide Requirement n perfrmance (MDD ER3 / AIMDD ER2) Requirement n acceptability f side-effects (MDD ER6 / AIMDD ER5) Summary f cnfrmity assessment with requirement n perfrmance (MDD ER3 / AIMDD ER2). Descriptin f clinical perfrmance. Fr each intended perfrmance, extent t which evaluatin f benefits is pssible based n available data, limitatins f the data, descriptin f gaps, uncertainties r unanswered questins, and assumptins. Whether available data allws adequate evaluatin f perfrmance, limitatins f the data, gaps, uncertainties r unanswered questins. Whether there is sufficient clinical evidence fr every intended perfrmance. Summary f cnfrmity assessment with requirement n acceptability f undesirable side-effects (MDD ER6 / AIMDD ER5). Whether the data available is f sufficient amunt and quality fr the detectin f undesirable side-effects and their frequency, limitatins f the data, descriptin f gaps, uncertainties r unanswered questins, and assumptins. Whether the undesirable side-effects are acceptable and crrespnding justificatins. 4. Cnclusins Clear statement cncerning cmpliance t Essential requirements. Acceptability f the benefit/risk prfile accrding t current knwledge/ the state f the art in the medical fields cncerned and accrding t available medical alternatives. Suitability f the device, including its IFU, fr the intended users and usability aspects; discrepancies. If there is cnsistency between the clinical data, the infrmatin materials supplied by the manufacturer, the risk management dcumentatin fr the device under evaluatin; discrepancies. 5. Pst market surveillance Descriptin f residual risks and uncertainties r unanswered questins, whether these are acceptable fr CE-marking, hw these shuld be fllwed during PMS (uncertainties regarding medium- and lng term perfrmance, safety under wide-spread use, residual risks such as undesirable side-effects and cmplicatins ccurring at rates belw detectin pssibilities f currently available clinical data, thers). Whether these are already being addressed in nging PMS activities, e.g. in currently nging PMCF studies. Whether new r additinal PMS activities, including PMCF studies, shuld be freseen. 6. Date f the next clinical evaluatin Suggested date, justificatin f the date. 7. Dates and signatures Date f the clinical evaluatin reprt. Statement that the evaluatrs agree with the cntents f the reprt. Dates, names and signatures f the evaluatrs. Final release by the manufacturer. Date, name and signature. 8. Qualificatin f the respnsible evaluatrs CV t be prvided 9. References Infrmatin n declaratins f interests t be prvided Guide fr the presentatin f clinical evaluatin reprt page 14/17

15 Clinical Evaluatin Reprt Presentatin guide VI Dcuments t prvide t LNE / G-MED fr assessment 1. Clinical Evaluatin Plan 2. Clinical Evaluatin Reprt 3. All data used t supprt Clinical Evaluatin 4. Evidence f CE marking f equivalent device(s) r ther valid regulatry status 5. Infrmatin material 6. Evaluatr s qualificatin 7. Evaluatr s cnflict f interest declaratin Guide fr the presentatin f clinical evaluatin reprt page 15/17

16 Clinical Evaluatin Reprt Presentatin guide ANNEX 1 Cntents f the evaluatin file n the usefulness f the drug substance with an ancillary functin cmpared t that f the medical device Purpse: t justify the usefulness f the pharmaclgically active substance incrprated as an ancillary t the medical device taking int accunt the intended use chsen by the manufacturer. File cntents: The evaluatin reprt f usefulness must be dated and signed, and must specify the identificatin and qualificatin f the evaluatr. Mrever, it must cntain the fllwing elements: Cnfirmatin f the status f the prduct Descriptin f the cmbined prduct (physical descriptin, cmpnents, features, technlgy applied ), f the perfrmances claimed, f instructins, target ppulatins, cnditins f use including precautins and restrictins f use. Descriptin f the pharmaclgically active substance added Justificatin f the medical device / medicine cmbinatin Rle f the active substance and its capability t be active in the cmbinatin Capability f the substance t demnstrate its actin n the site treated Perfrmances claimed fr the pharmaclgically active substance as well as the presence f side effects r a device/medicine interactin Perfrmances claimed fr the medical device Instructin manual, labelling and descriptin f the packaging Clinical pharmackinetics data: - nature f the expsure (lcal r systemic) - maximum expsure rate and duratin f expsure - useful dse targeted f the substance n the site treated - studies perfrmed cncerning the maximum acceptable rate taking int accunt ptential risks and individual variability - data n the release f the substance f the medical device : tissue/plasma release, in time and space Preclinical data demnstrating the perfrmances f the drug substance Results f tests n animals (relevance f the chsen mdel, cmbined device test versus device nly test) Clinical data specific t the use f the drug substance (bibligraphical data r clinical investigatin r a cmbinatin f bth) Descriptin f the benefits / risks reprt linked with the ptential risks relating t the presence f the drug substance: - Risks linked t the nature f the drug (new therapeutic effect, uncnventinal rute f administratin, new assay, stability, interactin with the medicine device, difficulty f manufacturing, ) - Risks linked with the actin mde f the drug (lcal r metablic risks, risks linked t the diffusin f the substance at a distance frm the treated site, ) - Risks linked with deleterius effects expected r nt f the drug substance (lcal r afar side effects, risks at medium r lng term, drug interactins, ) Final cnclusin n the need t incrprate the drug substance. Guide fr the presentatin f clinical evaluatin reprt page 16/17

17 Clinical Evaluatin Reprt Presentatin guide ANNEX 2 Degrees f nvelty fr a medical device Breaking technlgy : Device that disrupts technlgies in healthcare and culd replace it definitely. Incremental technlgy: Device including a technlgical breakthrugh in cmparisn t anther device 1. Strng clinical impact: Device which presents a majr interest fr healthcare especially by imprving very statistically the clinical practice, and/r the patient s cnditin, and/r prviding a new diagnstic strategy in a clinical field. Mderate clinical impact: Device which presents a new interest fr healthcare especially by imprving the clinical practice, and/r the patient s cnditin, and/r prviding a diagnstic alternative. Lacking r minr nvelty: Device with n r negligible mdificatin cmpared t a similar device already n the market (like aesthetic mdificatin). 1 Fr IVD devices, a new bilgical test/dsage (f ne r several markers) is an incremental technlgy Guide fr the presentatin f clinical evaluatin reprt page 17/17