INTERNATIONAL Iso STANDARD 14155 Second edition 2011-02-01 Clinical investigati for human subjec' ood clinical practice Investigation clinique itifs médicaux pour sujets humains — Bonnes pratiques cli Reference number ISO 14155:2011(E) @1s0 2011180 14185:2011(6) POF aicalmer “OF may ann encase ceric wih es ing ay mayb rid vw at Tia TDlcas Seer oc eres ow edie etwas on ats oni eo premeg fe rg. edad nc pence slam Penne waroety ent rarssaobes ea Poy The 10 Cena eet ‘Sconce nf we. aco aaderan Adee Sens naar Dts of stu prot ued ei POF Mca bs ne Caer nf ihe ne he POE aon etna tv ut tpt. vey chase cn ena ual eb 190 gerbes. ‘iy snr pct aby to ou peon omy be Com Secor be ze ~S oO & *D o> . By S Qe ‘timed. Ue ents woes opr ot is ubleton may be ree ranma my arya Sac Snccuntat ehcnypccayey sed marti, whet pemason wing Som ee 30 he oes bow \SSermenter boty nie cnny oe ont 50 cn len wetusnoct ‘ : (61802011 - arses180 44185:2011(6) Normative references. 3 Terms and definitions Devise defcioncios Clinical investigation documents and doc Amendments rerrsnecnren ‘Subject identification tog. Source document. [Additional members ofthe investigation ste tar ‘Subject privacy and confdentaty of daa... Document and data contol. 10.2001 W‘Sespension, termination and close-out ofthe clinical investigation... ‘Scopension or premature tormination ofthe clinical investigation. ‘rocedure for suspension or premature termination. rocedure for resuming the clinical Investigation afte Responsilites ofthe sponsor. lineal quality assurance and quaity control ‘ines investigation planning and conduct. Selection of eincal personnel Preparation of documents and materia. Conduct of clinical investigation Mentoring ‘Safety evaluation and reporting. Ciica investigation close-out. ‘Outsourcing of dues and functions. Communication wit regulatory authorities Responsiblliies ofthe principal investigator. General. ‘Qualification of the principal investigsior.. ualieation of vestigation ste. (9180201 eta coed180 14185:2011(€) ‘ieratonal Standard vequres approval by aleast 75% of te me casing vot, Ascension |s craw tothe possibity that some ofthe elements ofthis dooimant may be the subject of patent ‘PISO shal not beheld responsible for entiyng sry patent rights. {50 14155 was prepared by Technical Commitee ISOMTC ‘Ts second exon cancels and replaces the fr 150 16155-1:2003 and the first etion of 150 141552 2008, which nave been technical 2 S & 3 valuation of mecca devices.180 14188:2011(6) Clinical investigation of medical devices for human subjects — clinical practice 1 Scope. we “De rates tard arenes good cna pce fr te 9 reprng Zens mosigenos cared ot horan sats seme e aay Mgrorare ede ates Soyo “De sre fn nts etanercept rvestgtine and woud Scoot st as poste, Svatety te tae oe on be reqronen ot ‘Sosa Pie biersto Sanaa pete gee egrets rot the ight, safety and welt being ofhuman ‘ecsue the sciontiic conduct of the clinica i the crectbty of the cnicalinvesigaton a _setne the responsi of he sponsor ana 258s: ssonsors, investigators, ethics commites,reguator authores and her bodes involve in the Sort assessment of medial at apply tn vitro tag “Standards developed ironed ob apt medal dovens. Users of is tational wa need ‘dlr requrements alo appl fo he svesgatorl Geis) F linen meiaanition ‘ted apples, For undated reference, the latest econ ofthe referenced sents) apples devices — Applicaton o risk management o medica! devices“3 Tamms and definitions, Forte papeuns ofthe Socument the fotowing terms and defintions apo), as apse secs ete ae (Some meet sence use ofan investigaonal medica! device NOTE Tae sete ences assess overs resuing tom ineuticent fore, ee ee aac, croperaton or any matncin of ie vesigaton NOTES as cet ectces any event esting tor uae err oF om tention Iovalgaionat = 32 ‘Some eect = (Sy ness mecca occurence, unintended disease oF injury, cr untoward (retuing abnormal Sesser eras) n snjocs, sre or ther person, whether or ntl investigatoral meds! as NOTE! Tes cotton nes ever reutad oe inerigatonal rh comparator eon Dees oeware which one or more Investigation are kept unaware of the treatment NOTE __ Sagi ining usay eer 18) beng unaware fe weamnentassgrmentis), Double rng SS wes Stee ‘Sha natnesneon.corrland aeeosar bg unaware ofthe Seg as ‘case report forms ore ‘sot pinta, ocuments for each subject on which information to be reported to the Seer the CIP as cineca! investigation ‘Seems rvesigason in one of more human subjects, undertaken to assess the safety or performance of Pesca seve, NOTE “Cintra orci ey ar snarymeus wth "ina! investi 2 (21602011 -Atrparenenes= a tee nen Sees ee sais) ie ratonale, cbecives, design and proposed ralysls, methodology, mentoring, (Sica cers tering of crical investigation RSE Dem pret eypenymans wih “CP However, pte! has many erent meanings, some not a a sem, 2 se cn iter fom cauney Yo eeunoy. Thre, therm CP a used nhs Ses as ‘nical investigation report (Secsmest cescng the design, execution, satstcal anaysis and resus ofa ci as ‘letcal pertormance ‘Setawcur ofa medical device or response ofthe subjects) to that In relation ots ended ‘te nen conecy applied o appropriate subjects) a0 ed ‘Reseal coven therapy (09. sive contro, placebo or no used inthe reference group ina circa eget ant ‘contract research organization co ersen or cxganizaton contracted by the ‘oe or mere of the sponsors cinical ‘mresigatonseisted dies and functors 32 ‘corinating investigator ‘mrestpstor who's appoirted by the sponge to coordinate work ina muticanteclnical vestigation a3 ° (gg mentoring committee ‘Scependent commitee tha mgfBBygtaBlones by the sponsor to assess, at intel, the progress of he SAGE nestgnon be Bp the cial peromence endpants and o recommend the sponsor weer contrac suspend Magi. top te cancel vestigation NOTE caret of "dat saley mn board(OSMB) 0 dst safety nontoring armite (SMC a4 Senation aaree S ntentonaly or unitentonaly, he requirements ofthe CIP 318 dence dei ‘nasaquacy ofa modal device with respect ots identty, quay, dabily, eat, safety or performance NOTE Device detcensisnclade melunchons, ae eras and inaseqate ibn 316 endpoints) (emery) principal inccator(s) used for assessing the primary hypothesis of acral imvestigaton aa endpoints) (secondary cicator(s) used for assessing the secondary hypotheses of a cincal investigation 02011 -Ategna reed 3= 180 14185:2011(E) a St mercencon an aes he seis) the rationale, cbectives, design and proposed analysis, methodology, montring Sess me rece ping ofthe cca vestigation SE eee pomaer is eynoymaus win “CP” Hower, pote his many dfeeré memirgs some ot Sx Sa Sekiten nese cn ar or country to county. Tove, te Jem Ci wsed he SS ‘Sisct venagaton ep rest en exeeton santana andreas ofa a ‘canical performance: Scie a seal device or ropa of ha ste) et In relation © ts intended ‘Soe whe conectyappled io appropriate subject) a0 ‘comparator ‘meses cevce, therapy (e 9. active contro, placebo or not sad inthe reference group ina cincat O@ an ‘contract research organization cro esen crparizaton contracted by the ‘one of more of the sparsor’s clinica! ‘Gresigenoneited aus and functions a2 lavetgator ere y ie sagt coorte wrt a mutcetecncalivesiaten as — Panera cone Bre by he sorte o anon, attra, he progres the anager ne ire cuca poromarcasodpont ands vcormerd spre ELSE pene aly g Sone inca mesbuion nore —— 9 ntentonally or urintertionaly, he requirements ofthe CP even: SSS a ees device win reapect tots Monty, qualty, rab, reabity,stey or perommance: NOTE Deven detsionsas nce maltunatons, us ero, a masequte aetng 316 ‘eeapoints) (Gemary) pina inicater() used for assessing the primary hypothesis of clinical investigation a0 endpoints) ‘ecendary)nsestos) used for assessing the secondary hypotheses of a clinical investigation oss02011-Ategrinees 3| = ‘Ceccencesttncy wns responsibilty tis fo review cinical investigations In orer to protect the ight say ‘See beng ot mamae sabes paricpaing na cine! investigation NOTE Fare eucenes ots nteratena Standart “ats comms” synonymous wih “eee ets SSS Smee cr nettonl eve boar The regan requromegs perarng 10 Sr a teva oy county eran ass. cogel ‘Saase eamenert resuting from the objective, regering the investigational or Detomance bat = used to doscn the clncal vestigation and that can be o [eects ote cancalinessgaton ad statistical calculations NOTE The pematyhypomeis te detrinant ofthe vesiotons joy 0 petermance es DS Fity Vesa fo clnate he sanpe se. Secondary Mp 9 oe” ponte of rsest Salas a0 ‘gependent fot mecve n the conduct fa cial investigation, except fx assigned responses in (Scents arid bas or 2 conti of interest an Informed consent process ‘Sitess by when an noMoUal Is provided iformaton to voluntary paticpate ina cincs! » Eressgaton NOTE tomes cntent is ocumerng by means of or dated lores coneant frm. a2 te ‘nesiton oF ste where the cincal Joa NOTE Ferthe purpose otis remtons on soi eyronyraun win investigation coi! 323 investigational medical device ‘dal device being assessed for safely ina cincal investigation NOTE1 This nsices mevioiglcesabeasy onthe mare, hat ae being evauses for new nando wes, new Fepulaons, new natal dest NOTE? tat arms-rvestisonl mail devin an evesgaonal deve” ae uses ‘iercnangeab| a2 investigator [navel member of he imestigaton ste tean designated and supervised by the principal ivestigtor at [evostgaton ste to perorm cial cinlesrinvestgaton rated procedures or 10 make Imporant clinica ‘rwestigaton elated deosons NOTE An indnidual_ member of the lnvestgaton se team can sino be caled “subimesinstr or ones 4 : 2180204 Alterna180 14158:2011(€) as pose SSewiaion © curent cinicl and non-incal lforation on the investigational mesieal device) speert = Pe cca ewestganon as ‘lagaty authorized representative ‘Sawacal © jude or afer body authorized under applicable law to consent, on Bipat of « prospective ‘Sabet tobe subjects parcipaton inthe cca imestigation az matuncton ‘ize oan ivecigational medical deve to perfor in sccordance with hen used in scence with he nrucone for ee or CP a2 medical device ‘25j seument apparatus, Implement, machine, sppliance, mate, or other simar or Jeeesaee 12) tended bythe manutatee to be used, lone or in ion, fr human beings for one or more of {he specte purpose) of 4) agnosis, prevention, montorng, eatent flseace, 2) iagnesis, montrng, estmert. for, an ry, 3) lnvestgatin, replacement, mosiiatig, or SURpgt ofthe anatomy oof a physiological process, 4) supporing o sustaining if, 1) which does not achive. ‘son In oF on the human body By pharmacological a detnd by naionalrquabons. Fe the purposes of hs nematna agnosie madal aves (oe 150 1385 7008. defion 57 ‘a of overseeing ‘of dines Investgstion and fo ensure that itis conducted, recorded, and ‘eperted ‘he CIP, wrlen procedures, INS Intemational Slander andthe appicadle 3.30 ‘multicentre investigation Sines imvasigation that conducted accoring fo sng CIP and takes place at wo or more investigation Stes as 0 Sra pspoe fr conaicing te cca! avestson 0201s atte roned 5180 14185:20116) 322 Point of enrolment ‘ine stench folowing recrutment, a subject sigs ar dates the informed consent form 333 Driscipal Investigator Preiss persn responsible for conducting he ence investigation at an investigation ste NOTE! a cncatinvestgnion conduc by 3 eam of ius aan nvessgntn to, tho pri! ment: "Srespanaol reas ea Soe teem tonne ot Fandomzation ‘roccos of sssgring subjects to he investoatonal medical device or comparator gs using @n estabisod Fecognzed siatistcal metocology i determin the assignment in oreo 338 reerultment ‘Sbve flrs to entity subjects who may be suitabe fr enrolment into he clinical invesigation 336 ‘erious adverse device effect ‘Sovrse vie effec that has resulted in any ofthe consea cof serious adverse event a7 ‘Serious adverse event ‘soverse event that ) lett death, 1) esto serous deterioration in te heath that ether rested in 4) a estrestening ness or injury 2), apemanentimpaiment Pe oa body function, or 3). inpabent or protnges| 4) medial or surgical ion to prevent ifethreateringlness o nur er permnentimpaiment fo. body stu orb function, ©) esto foetal ia, ‘a congenta abnormality birt defect NOTE Panes recising condon, oF x procedure requred by te CI, wihout seus SBteontonin beat, 3 fous eave eve 338 Source data 2 Tfconation in original records certiled copies of egal ecorcs of nica fring, servation, oF oer Sere rca investgaton. necessary forthe reoanstucion and evaluation of he cinica vestigation 330 Source document rote, optical rslecronie document conning source data [EXAMPLES Moepal aco, labretony noes, den accounabliy recat, photographic egaives, radoaaeh, AMPLES, at Racnaganon at, a he boris and et he mederechicaldeparoeni invoked ee cca Imvegaon 6 ts02011- Alea sone180 14186:2011(€) 340 ‘sponsor idvdval or erganizaon taking responsibly and labilty forthe intistion or implementation of a cinical NOTE When an inveigator rites, mplmenta and whee fal reponilty for he crcl ivesbaton te ‘nvesigatr aco acsoncs hos the sporaarandieierfed ate epemacsnvesigator aa da wo pura na chic ivesnin ou, a ea a ie Be cin ‘serous adverse device effect which by ts rate, incidence, seventy Fas not ben identi inthe ‘Surent vrs of he rik analy report NOTE _Antcsted cones aivrse deve sect (ASADE) & an eet which by nue, iecn,severiy O° ‘ace hae been raed ne Mok asia report Secession pg ore at rr NOTE1 Use ororincues spe, pte, and manta NOTE? Anunaipected pysooin reagan destin te cont ue ee. [180 14971-2007, detinion 2:27) ae, nical investgaton could be unc infvenced by the ee ‘wih partcipaton or of realtor response om refusal to paricipste of agnomy due o matty oF trough mens dsabiy, porsons in stjecs mn emergecy stustonm ste rinery guns, ramless ard hace ieaptie of ghang normed consent Other warble sues ode er ‘ral, members of agg win Rerarciea!stuctre such as onrrety sd auordewin hospi end th sponsor member ote armed oes, th rear kept deteton 44° General Cnial investigations shabe conducted in accordance withthe ethical princpias thet have tel origin nthe Declaration of Hesnk (s8e Reference 8), These prinopes protect the lh, safty and wel-belng of human subjects, whch ae the most important consideration and shall preval over inerests of scence and soca ‘These pices shal be understood, cbeerved, and apd at evry stop in the crcal investigation. (21902011 7180 14155:2011(6) 42. Improper influence or inducement “Tne spentr shall acs improper influence on, or inducement ofthe subject, monitor, any westigato() her paries partcpating of conibutng fo, he cial investigation. | investigators shall avoid improper influence on or inducement of the subject sponser, manitor, otter ‘Suestgateis) or over partes partepating in or contibutng to the circa vestigation 43. Compensation and additional health care Compensating eubece for costs resulting ftom participation in he erica investiga ton) ‘Soy bs sonrcbtate slowed by naona!requatons, bt the compensation shal nat be SBlgyge 3 fb unduly (Ercurage he subjects fo paral. ‘srangemerts for adctional heath care for subjects who suffer from an 0 ‘a8 a recut of partcpanng in he cnical investigation sall be made and documented. eee. C) [A partes invives in the conduct ofthe clinical investigation he responsibity for ts ethical ‘Grabet ms ancondance with thelrespecve ries inthe cinca as commanon nin oie comme OY 451, General tt natonal or regional EC requirements are less sit sof hs intemational Standard, the « sponeor shal eply the requrements of his ternational tothe greatest extent possible, srespecive (any loser regiments, and shal record 452 Ina EC submission e [Asa minimum, the folowing infrmaton ts nal be provided to the EC 9 a, >) or equivalent documentation io need to be provided tothe EC depencing on the efnica investigation requrements 1) sample or dat ORF, Incudng oer data cllecton tools, es requred by the CP, documents related o payments and compensation avalabl fo subjects proposed compensation tothe Inston o principal iwestiator |) documentation related to any confit of terest, nung franca on he part ofan ivestigator |) dance ofthe trical investigation insurance, 8 ‘91802011 Ate oes190 14185:2011(E) 1453. tnformation to be obtained from the EC tor te commencing he crcl invvigton, we sport shat cain ocumartat Oa, SO at com entyeg ne cecum ard anaes o wich he oon wos Nore Tmspereorcninqutbe Eon ir hire dr meat domme et ei So Thvestoatn ste oom wore not pat ofthe weg 1454. Continuing communication withthe ES the folowing infomation shall be provided tothe EC, if required By nti CP er the EC, ihichevarte more stinger: 1) serious adverse evens; 1b) requeats for devatons, and reports of devon, the deviation rts, eat and wee Tas’ ne scene inary ofthe cnkcal investigation Under emergency creumstances, devaions fom the CIP 10 hs, safety and wellbeing of Under emerene Seen aio pa aprova te aren We EC: SU cons She human subj reported othe sponeor and he EC ab ea as possible 9) progress repos, including safety surnmary and 4) amendments o any documents aredy approve NOTE For nonsunetanial changes (0 cminaatve changes, change of mont) Meena ember rena of euros ‘Soiree Necnang of homer nets ot fastest the cna! investgnon cece ee accra EC and, wae SRO. ‘Sitar sctees canbe eticont, apptcable,nolicatins of suspensions or premtire termination 1) appicabl, jetileaton anda )- nical invessgaton eportor ng the clnial investigation afer a suspension 455° Continuing from the EC ‘Ase minimum, ding th onthe folowing information shel be obained in weting fom the EC proto implementa 2) spprovafavou of amendments 0s stated in 4.84.) by approval ott rea %, evaton tat can alec the subject's gts, solely and wet-eing or te ah cue bty of tp circa ewestigaton, es sited n 4.5.4), 8 fon ct suspended cricelinvetigaton, sated in 45.40, appeable 48 Vulnerable populations inca vestigations eal ve anda n wera options oy wen CS 8 AS Sa, Cincy mestaston eel Seren re aaa EC peceaues where epee, ese parade penis or apecmcay 0 anes ream clara at Sood, wine ert vere posse of arect healed Benet toe vUnerabl eps lets0011-Alegnaroanes 9180 14155:2011(6) +47 Informed consent 474 General Informed consent shal be cbtsined in writing tom the subject and the process shal be documented belore ‘ry procedure pene to the cincal svestigaion le appled 10 the subjec. except wen special ‘Sreunetancee deesibes in 4734 spy. “The Informed consent form consists ofan information fom (see 47.4) end an informed cortant signature {rm (sne 478), Thee two form can ether be combine n one document or Sepa ments 41.2. Process of obtaining informed consent “Tne general process or obianing nfrmed consent shalbe documented in th C 2) ensure that the principal invesigstr or hiser auhorzed designee informed consent process, 1) Indude all aspects ofthe clinical investigation that are relevant to the Aecision to participate throughout the cial investigation. ° 2 EES CCST Sip Fig i cae tee ¢) sentra nguge tuner 1) provide ample tie for the subject to read and us 7 Informed consent form and to conser Daricipaton i the clinical investigation, a) include persona dated signatures of he subject andthe pip investigator or an authorized designee ‘responsi for conduc the nfermed eongant process, 1) provide the sutject with 2 copy of he, Jsted ord consent form and any other wien [rlrmaton, 1) stow how informed consent recorded in special rcumstances (see 4.73) where the Subject is unas prove t ‘and 1) eneure important new ifognation to new and exstng subjects throughout the cinical investigation ‘The stove requrements wih respect fo informed consent obtained from a subject's legally auhoraed representative, 473. Special Informed consent 4734 Gane “The provisions gvnin 473.2472 ae uot trata reuabons 472.2 Subject nsdn gal suthorza opesentaives ‘oun prone one etigicn fog srt arene sem) te unconscious ity mental person, renially handespped person In suc eases, he subject shal also be informed bout the deal Investigation wibin ser abaty fo understand. 0 (21902011 -Atrot sane180 16185:2011(€) 4733 Subject unable to read or we Informed consent shall be ottained trough 2 supervised oral process if a subject or lgaly eumanizes {presenta is unable f read or wre. An Independent winess shall be present thoughout the process. ‘The witten informed consent form ard ary ober Information shal be ead slow! ana explained t the prospective subject ox ser logaty authorized representative and, whenever Possible, ether shall sgn and ersonally dat the inermed consent fom. The winess aso signs and personaly dates he normed consert ‘erm atesing tat te information was accurately explained and hat informed consents rely aven, 473.4 Emergency treatments For cinclinvesigatons involving emergency treatments, when pir nto he subjects not Possible Because of the subjec’s medal condo, the informed consent ‘auhorzed Feptesentatve, present shal be requests ‘when itis not possible to obtain por informed consent fom the sub sutjct’ logy authorized ‘epresentatve enotavalble, the subject may sll be ervood i 2 hes been dosed ne Ci asgveninA 35) ‘Arrengements shal be made to inform the subec cr legally authorized rePPésetative, 36 s00n as posite, 8) about the subject inclusion inthe circa 1) sbout a aspects ofthe circa investgaton. Durst seamen eigen centr = “The principal vestigate may ental a subject ring the informed consent of the subject o histor Jogaly autorzod representative ony when he none ove tiles ©) the prospective subject fis the emaxgency contons and is obviously in etresteing stuation; 9, rosuficient cic! benefts age the curently avalabe treatment 0 ten prin a Sgr rin pn mn maser aie oS a. siccaehea os ovoocant insets 2) Description and Burpose: 1). statement that the cinicl investigation invoves research; 2), purpose ofthe crcl investigation; 3) antispated duration ofthe crcl investigation, and extent ofthe involvement and responstbites of ‘ach subject during the cirical investigation 4) description ofthe investgatonal device and comparator. any, (91802011 -Ategheeceved "180 14185:201%€) 5) Gescrpson of at procedures imohing be subject: 1) specs oe cna investigation that are expermental 7) descrpton of the cinical {mention of any 8 and the es oe esanion, eng comparison grou 9 mecaecteede cnt 2 ato - 9 ence sg moma moe ecm ra © ntsettamniatr ts ten pn nM ne ce 2 eA 2, etn 44) deszrnion ot inconveniences, ©) Atemative procesure() 4) Infomation on atemstvetestments ot ay be avaiable to the subject, and tho potential Bonetits and ise +3) Confident: 4) statement confirming thts confide, 2). statement confeming that records subject wi be kept confidential tothe extent alowed bythe aw, 8). statement confiming bat stat regulatory authorities, EC representatives and sponsors represeratves the cinicalinestoation wil hove det access Yo mocicl recoe 4) statement incicatng T@lcinical investigation resuts may be publehed wthout dsccsing the subjects inet NOTE Aa cng perioral data prieton canbe reused a per natenl orginal (9) Compensation: 4) formation sbout provisions for compensation avalable In the event of injury ering tom Paricpeton nthe cineal investigation” 2) Information about adctonal heath care for subjects who sue om an adverse event asa esi of Partpatng inthe cial nvestgaton, * 3) formation on nancial compensation fo partispatin, ¥apocabl, 1) Anticipated expenses, i any, to be bere by the subject fr partating inthe cnical investigation 2 1602014 seen130 14186:20111€) 4: wenn cede i tin como 0) wont gt tee men, 2 eerie ct 9) sme crn qr nt ae 1) Statement inating that, upon subject's approval, the subject’ Subjects partelpaton me cllca rvesigaon 1) Termination: 1) creumstanees under which the swtject's partepation can by the principal investigator, applicable; 2) circumstances under which the sponsor can oO prematurely terminate the clinical be informed ofthe invesigaon 47.5 Informed consent signature “Te informed consent signature form shal conan a) the voluntary agreement 10 participate gg. the Bical inestigaton and folow the investigators inaectons, 1b) a.sttement declaring that refusal of paicpaton incurs no pene forthe subject ©) astatement dectring that time incurs no peri forthe subect 8) a statement wih gare Sheequencos of wihirawal ©) an acknowedgement SG ‘answered ’ aaa bjt o hse legally authorized representative agrees to he use of ton provided and confirmation that all the subjects questons were the subjects rele "orb pupoee of he inca investigation: @) a statement te subject o hiner logalysutorized representative agrees that sponsors rears ‘Jonartes ana €C representatives wil be granted drect access to the 478 Now 1 new infomation becomes avaiable tht can sgncanty aflect a subjects ture heath and medical ce 1 cow nt se provided to te subjects) elected in writ for. relevant, ail affected subjects Sha be asked lo confi ther condnuingiflxmed consent wring, ctsoants Atos joene 8180 16155:201116) 5. Clinical investigation planning 54. General Al paras participating in th conduct ofthe sincl investigation shall be quaiied by education. taining or ‘experience to pertorm tek asks and th shel be documented approprtly (ee 82 1), 52. Risk evaluation Fisk ssocited wth the investigational device shall be estmatod in acoordar ‘conduc a cinical investigation. The risk analysis shal Include refer to an ‘sd avalible unpublhed: medical end scertife data A summary of the (Geniicaton of residual risks, shall be included in he 18. “The decision to embark upon a cna investigation ofa medial device requres Pyne residual isk(s), 08 ‘genie nthe ick analysis, as wall as ik(s) to the subjctascciated wh required by the CIP be balanced agains the antispated benefs fo the subjects. This rik analysis sal also be used as a basis for idnttyingantipated: by er nature, nednce, seventy and outcome Rapemteerpers pes ammemen Gy sais (000 85) and te ice eects characterzed Informed consent frm (500.474). NOTE Ths enables compliance wih any reporing regen and nartopated SADES 5.3. Justification for the design ofthe clinical ir “The stilton forthe design of he cna i YP based on the evaluation of pre-cinica data and he resus of cial evaluation ‘The nic! evaluaton intuces an asses 28 of cinical data concaming safety or perfomance fhe investigational Seice o& simi dy ‘The evaluation shall be relevant fo the intended purpose of he rvestigatonal device jf use. Ths Isa sre acy that sha be Sone wit nigour and objectivity ace fe standards using the penspes of GHTF ical ‘valuation (8 Reference (0). ‘The results of he clinical evaluation 1 0 termine and jetty the optimal dcign ofthe cil Shvesigaton. They shall sso help eitigrBlovant endpoints and confounding factors to be taken nto ‘oneideralon, and serve use choca bt comparator) ‘The circa investigation shal signed to evaluate whether the Investigational device is suable forthe ‘orpoao() and the pop oh ti ended. lt shallbe designed In such @ way as to ensure that fhe resuts iss relevance and scenic valdty and adress the cincal Investigation cbjectves. NOTE The not cei invetiten to meet equity fequrement i erminad by tbe apcable ‘atonal reguaons : 54. Clinical investigation plan (CIP) “The CIP shalintue he information specified in Annex A. “The CIP and al subsequent amendments tothe CIP are agreed upon between the sponser. the coosinatng Investigator and i principal evestigetos, and are racoraoa wih a justifeaon fr each amendment 4180 14188:2011€) 55_ Investigator’ brochure (8) ‘The purpose ofthe IB ic to provide the principal investigator wth suttcient safety or perfomance cata from precincal investgaions or cnical Investigations to justty human exposure to the invesigatonal device Spectiedin be OP “The IB shall be updated throughout the course of the cinical investigation as significant new Infrmaton becomes avalate (eg. 2 sgrifeant change nik, tc) ‘The principal nvesbestrs) shall acknowledge the receipt ofthe IB and all amendments, and shal kop al nformaton consent. ‘The IB shal ncute the nfrmation specie in Annex. 56 Case report forms (CRFs) (ORFs shal be develope to capture he data foreach enroed subjecs retired by the CIP. The CRF shall ai ang ents cr. Seat aaa ES $7 wonton pln ‘The sponsor shall assess the exlent and nature appropriate forthe cca investigation, Inciuding the srategy for source data vert Teonsiceraions such as the objective, ces Complexe, eileal data pln ond endpoints Efe clinical mvectigaion. Resuts ofthis atsexsment ‘Shallbe used to develop @ monitoring plan. 5.8 Investigation site selection orto thw ination of th i quaiicatons of the principal investoatrs) and adequacy ofthe investigation ste() shal ‘ooumented in an invesigation ste selection repo. The ‘asonala or ssactng an fe docenanted NOTE tnvestigaten 18 can be based on per expen of ha sponsor wih the pineal Investigate ie mvestoaten 59. Agreement(s) ‘There shall be an agreefRag between the sponsor end the principal investgators\nvecigation ses) and rvestigters, CROVs) and core laoratores), which defines the esponsbites ‘Al opreements shal be esorded in wring and signed and dated by ‘540 Labelling “The Investigational device the insrctons for use or the packaging shall ndleate thatthe investigational cess excuse foruse Ine ciel investigation, frequfod by national oguation, NOTE G40 180 15223-0,EN 141 and national or gina rpuatos freer ifomaton on baling (1902014 paves 6180 16155:20116) 5.11 Data monitoring committee (DMC) ‘The sponsor sha conser establishing @ DMC pir fo starting the clical investigation. ‘The decison to extabish 2 OMC shall be guided by the rk anal, taking ino account beth the risks associated with the ve of the investigational device andthe ieksassocisted win subjects paipaton nthe ies investgaton ‘The primary function of the OMC shall be desorbed inthe CIP. The responsbotiss of thsNBMC shall be etaled In separate wilen procedures to esabiah the frequency of meetings. han smergenoy ‘tuations and documentaton of such meetings 6 Clinical investigation conduct 64 General ‘The inka investgaton shallbe conducted in accordance wth the CP, ‘The cinical investigation shall not commence unt wetlen spprovaltavour pinion trom the EC and, if requred the revert regulatory autores of be counties where invesbgaton i lang place Mas been received 6.2. Investigation site initiation ‘An ition vist foreach parcipatns investigation ste iy. an investigator meeting shal be Condutes and documented by the sponsor or moniter at ofthe circa rwesigaton(se08.24). ~/log shall be inated identi¥ing names, s,s 5 and designated autherzaton forte ‘rncialinvestgaor and members of th investigation Investigation site monitoring “The conduc of he nea investigation sha according to the monitoring pan (500 8.2.4). In general theres @ need for on-te dng, and ater the linia investigation. However, ‘A aaverse events ented in a tmely manner thoughout the circa Investigation and shal be ‘reported as spected in 8.28 9.8 ‘A adverse events sha be reported in an interim onal report of he cil investigation 642 Device deficiencies A device deficiencies elated to the identity, quality, durabity, reliably, safety or perixmance of an Investigatonl mecical devee shall be Socumented twoughout the clinical Investigation and spprepately managed bythe sponsor. 16 (©1502011 Agta sees180 14155:2011) Device deficiencies tht not esd oan adverse event but ould hae edo a redial occurrence 1) tener sutabe acon has not ben taken, )intewenson had nt been made, oF ©) orcamstances had been es fonunate, ovabereaned es speach 8 2S and 08 5 Cina imvengation documents and documentation YS 6.5.41 Amendments The IB, CIP, CRFs, informed consent form and ater subject ter circa investigaton cccurets shal be amended as needed tvougout te crt 2 jsticaton statement shal be incuded with each amencea secton of © document ents tothe CIP ena be ‘Seed. upon. between the sponsor and. principal investigator raating. Investigate. The “amendments to the CIP ar the subjects informed consent form thal 10, oF approved by, the EC ‘and regdsioy autores, # required (see 45), Tne version eumber and de of emenaments shal be ‘socumentes 6582. Subject identifation tog Each investigation ste shall maintain 2 og of lh \Genticason code inked to thor names, ternatv NOTE Depending onthe crcl imestgaion design, be matane hats everyone wo hasbeen fee-sceere plete nrmar'n ne cna! gato ed in the circa investgation,asigning an jn oF contact information. 853 Source documents Source documents shal be crete by the investigation sito team throughout the clinical investigation 8.8 Additional memt site team New members of he investi may be added trom time to time at new or exting sts. New served by ll partis involve a al tes throughout the cnical investigation gains! urautnorzed acess. and confidentiay of hister information shal be preserved in reports and when ‘The principal investigator or instuton shal provide drect access to source data during and str the crical ‘rvesigaton fr montonng, audits, EC revi and registry auhortyinspectons. As requed, the principal |rwoeigator of inestton thal ebain permission for Sect acoees to source documart for te ject hosptaladmsnsraton and national regustory authors belere starting the cance investigation (1902011 7180 14185:2011(6) 2 68 Document and data control 681 Traceability of documents and data ‘as cocaments and data shal be produced and maintained in a way that assures coral and vaceebiy SETS oie eccurcy of wansatone eval be guaranioed and documented. Al documerts, and Vint rer oe, rsted a cial nversgeton sha be Wertiabl, waceable and appropiate stored {Spronde a compiate Fastory of he cial investigation. “The investigator shal assure the accuracy, completeness, legity and timeness ‘Tponest one GRFs and nat requred rors. Where copies ofthe orginal ou BERER.Grovginal electron source doeumets are retained, these shall be signed and Brine vestigation site team wth a satement ti tus reproduction ofthe org 1 sssnment to a tresimert group is Bindedmasked in any way. shal be @laguarded hrovanout Me Uae? iverdgeton, incudng deta onty and processing. Establshas ‘Sideuimeakedcaial nvestgatons shal be fotowes, 682 Recording of data “The data repre onthe CRF shall be derived from source doc be consistent with these source Geesmenss ond any discrepancies shall be expaines in wring. i specty which data can be SoS Siety in be ones The CRFe shal be sgned and d prinepal investigator or hiner ‘SGrorzed aeegneets). Any change or carecton to data IAF shel be dated nad and SGanes necessary, and shal Rot cbscure the orga ud rat shal maintained); Sipies c bom writen and electronic changes o corectons, ~ 583 Electronic clinical data systems nen lecronicclncal databases or remote electronic Mig deta systems are uted, wien procecures shallbe implemented to 1) etbisn andocuer requirements Oy ata system to receive and process data, alee So mammaire ae ag i mec reecie pes ian ©) ensure that data ‘re documented and that there is no deletion of entered dota {fe meintan an uct ral liga, esta, ® prin investigator or sponsor <> EC. and sponser <> ‘epumory ato (he £6 is nottes, sifer by @fprincpal investgatr or by the soonsor. the suspension or premature fhe sponsor shal infer al cher prince invesigators, for any reason, the spor r prematurely terminates the levestgation at an india Itvesignten ste the sponsor sii inform the reeponsisle regulatory autho) as aporopiate and ensure that temoston was nie Isuspensionor n cours, 1) he sponsor {or providing resources tf he cbligations ftom the CIP and using agreements Bifglowng up the subjects enrled inthe inca vestigation. and ) the princpel investigator or auhorzed deslgnee shal prompt inform the enroted subjects at histor Investgaton st, # appropriate. NOTE The method ond fe tng ofthis conmuncaton wil depend on te cumstances a he pecaves re [Al scutes ited in 7.2 shal algo be conducts, 20 (21602011 te aed180 14185:2011(6) 7.42. Procedure for resuming the clinical investigation after temporary suspension \ien the sponsor concides an anahsis ofthe reason(s) forthe suspension, implements the necessary Steuive actons, and decades to lt the temporary suspension, the sponsor shal inform the princes! ‘be ECs, and, where appropriate equity auborty ofthe rationale and provide them with ‘he relevant data supporting ts deiion NOTE The ual nes of communication sr sponser <> rnc mstgator or sponsrg.> EC, and sponsor <> repuatoy aso Cconcurence eal be obtained fom the ECs and, where appropiate, re he circa ‘svesigaton resumes. if subjects have been informed of the suspension, the principal signee shall Inform them a the reasons for resumen. 7.2. Routine close-out Routine close-out acviios sha be conducted o ensure that he gators records are complete, tr cocumerts needed forthe sponsors fies are retieved, remainng’eicalvestigaion malecas are ‘Saposed of prevousy Kenia esues have been resoved andalipares are notiied. 2) Completing the record includes ensuring tht 9 eC) 1 Seabees a Sad arom EE Gia pgarconnan a ©) documenting ispostion Bt ce ~ Fea aie 1) ther cinicglinvesigaton mates, ‘ater close-out ofthe clinical investigation, a report ofthe cineal evaluation shal be completed n accordance (ith tne eppeabe regulations, ven ihe cineal investigation was terminates prematurely 9) Thocinialinvestgntion report shal bein writen fom, 1) The clnical investigation report shall incude ientifcation of the devioe(s. a description of the Imathodology and cesign ofthe cincal investigation, any deviations fom the CP, dota analysis gether ‘th any statetes and @ clea appracal ofthe asc the clic! investigation (21902011 -Ategereane a130 16155:20116) 19) The cic invesSgaton report shall take into account the data from each investigation ete and fora TSSo‘No mines anal be denbtabe ether fom the onal lnvesigaon report or the pubished resute (6) Where agpcabe, the circa vestigation report shall be made avaiebe fo the coordinating investigator WPS SPSS Svecageors for evew and comment The sponsor shail maintain records confming hat ‘Ze ancl mvesigaton report has been provcod for review. Ia reviewer does not agree wih a or bat Sr ee a ned ond corencge oc ose ore ein y onal patos, be sr an xing a a ea ato incon ta Se <1) Fe ee ee es Re sgasn banc ma i treme teeter no nal ediuien po op Met EC coranany ane vores aes nreentmicn sep natn opt nagar nd nace sian Se 1 gue Me Feeeareh device ceveloprent and medical Westment NOTE? _Ineccodanc win he canal raglan, he eer cay Investigation at wells routs {Sorat mot need be erred ina pubic bene 14 ecumentretention H ‘esr cl npr atin a eae emer f Tppleeble reuatary requremeni(s). They shal tke ever aoodentl or premature desruchon Froese documents The prnbal ivestgator of Wvanser custody of eoords to another ete an dsumort rane ae resiefon MB: te peso" ay. NOTE Aleta sania cna! netgon fe manana por aie fe we Saati Ater ° 8 Responsibilities of the _ 81. clinical quay assurance contol Cuatysesuance and qualty fro princes shall apply to he proceses ofthe cial investgnton. The sponser shal Riricel quality procedures to encure thatthe clinical investigation Is Prod and hat ets are generates, documented, recorded and reported in Eat Standard, the CIP, ary subsequent emercimenis), and ary ther requirements, 1) malian records to dosent he comfance of al parbes kwolved in the cca investigation. 18) imploment and mai )enaure that the auditing requirements of6.11 are met, applicable, and 4, sty and document siontcant exceptions to the requirements ofthis Inerainsl Standart Ciel quality axsurance ad quality contra may be integrated inthe sponsor's vera quality Stem. NOTE Forftherntomaton se 180 1945 2 (21g0201 ats soned180 14188:2011(€) ‘82 Clinical investigation planning and conduct 221. Selection of elinical personne! Preto commencement fhe clinical investigation the sponsor sha 8) define, estabish anc allocate all the roles and responelies related to the circa investigation in one or ‘more writen agreements, 38 defined 5, ) select appropritely qualified principal investigators, as cutinedin 8 ©) lect a cordnatng investigator. appropriate, 2s inthe case of mut 8) receWe dclosures of conti af intrest om pencpal investigators ore requited by ‘Sevens ragulsters. 10) ensure the members ofthe investigation ste eam and thei des Joni) ae identi ina ‘og wih deta, a denen 82, 1) designte or appoint one or mare monters, or chenvise assume the responses ofthe monitors), ‘na 9) ensure documentation of training, experience and cine knowledge for all the relevant par incoved m order to adequaiely conduct he ‘tua Waring, 20 1) theuse ofthe investgntoneldeucts), 2). device accountablty procedures (see 69), 38 ‘ ews merase) 6). the wton informed rocest 38 well a8 other writen information provided to subjects, and 7) sponsors ween Intemational Stender and any appicable regulator requrements; 1h) ensure that ne Invessgatons, all ovesigatos and all ther pares inched are given Instrectons on "assessing and documenting cial and laboratory findings, > ena at gf itor acts of sponer representative.) a th mvestston Stet ged Eo tho GI and te nome consent frm, end fat ese Scvites occu 8a 8 i ep gga ta ey, Toomer Mecca nesta aw earges aagowormpemmamee meme me 1) consider the ees for @ OMC and, appropriate, establish the commit 1822 Preparation of documents and materials Prior conmencement ofthe cncalinvstigatin the sponsor shall 2) prapare the documents, as desebed in Clauses 4, 5 and 8, ard ensure tey ae spproved by the Felovat persons by dated signature: # required, copies shall be provided to all partes involved, and dated signatures obtened as appropate, (0180201 esterases 2180 14185:2011(€) 8) assure the accuracy of he ranelaon, where relevant, ©) graure tet» supey of ivestigaional devies, 2s characterized in 69, is avalabe ne tmely manner for {he cial investigator, investgatonal devices shall ot be made avaiable to the penal Mvestgator unl al requirements fo star the clinical nvesigaton ae met, 2) provide insurance covering the cost of estmert of subject in the event of cinical-nvestgaton elated Ini, in accordance wh the nalenal equation I applcabe, ©) document any nancial arangements between the principal investigator or he te and he ‘sponsor ‘submit any required application(s) to begin the crcl investigation in a given Feguletory authertyies) for review, accoptance of petmission [ae regulatory resumen 9) ensue that ECs spprovalavourable opinion 1 obtained and © that appropiate 1) ensure thet any madcatin(s) require by the EC or registry authorty SRPFaade and documented by the pincpal mmesigator and have gelned the approval ‘pinion of the EC or regustny snr 1823. Conduct of clinical investigation “The sponsor shal be responsible for 8) sccountsbty of investigational devices thoughout tne sigation, >») documenting corespandencs wit all parties inca vestigation, including Ee and regulatory authors, (ensuring thatthe clinical investigations 9 rmontored by determining the extent and nate of mmontorng, cuding the stony ‘verfcaton, Based on conigertions such 2 he ‘objective, design, complenty, sz, ‘and endpoits othe cna! Investigation, ©) reviewing the monitoring up any action(s) required n the monitoring reports) (ee 9508247), ©) taking prompt action to secure co lca investigation requrement, and ‘1 submiting progress reparainctuding safety ummary and devctens, when requested, to all reviewing ECs and he reguatony 8241 Generel ‘The purpose of clnical investigation monitoring is to very thatthe conduct of the cine investigation complies wih the approved CIP, subsequent amendmeni(s), this Intemational Standard, and the appacable ‘equator requrement), 8.242 qualifeations ofthe monitor Montors shal be 2) qualified inte fed of ts Intomatona Standard twough airing and experince as well 38 scientific or ical knowedge Fy (61802011 an ersten180 14155:2011(€) 1b). krowedgestle onthe use ofthe invertgatonal devce(s) and relevent requirements, CIP and iformed ‘consent process (222 47), ©) tained on the sponsor's clinical qually sssurance and qually contol system 8 well as any special procedure for montonng 2 speci cna vestigation. “Traning sabe documented in the sponsors les. 2243 Assessment ofthe investigation site “The montor shal assess each iestigaton se overt thatthe prncpel 2) adequate quaieatons ~ 1) adequate resources, ncsing fais, beats, corer este Nee en 6) accesso an adequate numberof subjects 8244 nition ofthe investigation site “The monitor shall inate each investgatin ste to ensure vestigate and investigation site team 18) have rectved and understod the requrements cP, 2 6 23) helnformed consent form, 4) ORF, 5) te nstucions for use. @ ©) anyten circa ts a8 spronit, 2) have acess to an invetiatons devices, «) nave been vainedin pe use of investigational device, and «re tamar win thélaggonsis of the principal vest, deecibedn louse. NOTE an nvestator meeting cn be conducted nied for aon fo, he ore ton 248 alte monitoring visits “The monitor shal perform routine n-ste montring waits to vest that 4) compliance with he CIP, any subsequent amendments), ths Intemational Standard end regulon, cores entained,devations shell be Gacussed wih the principal invesigao() oF euharzod Uenignee documented and reported to he sponsor, 1b) on authored indus, 2s described in 8.2.1), ae paricating inthe cna investigation ‘othe investigations! device is being used according 10 the CIP or insiructons for use and tat, where the restate sured te he oevic, ks method of use othe CIP, hese are repo tothe sponsor, (21802011 Ades gered 8180 16155:201116) investigation ste resources, incising laboratories, equipment andthe investigation ste team, mein ‘Suequite troupe the Srton of tc orca irvesigation, 12) the pincpal vesigtor continues te have eccess o an adequate number of subjects and imestgational ‘sevees, 1) signed and dated informed consent forms have been cbained from each subject a the point of enrciment toler any cinicakmvestgaon lates procedures are undertaken, 9) source documents and ether circa ivesigation records are sccurale, complete. uno dal stores and ‘marines appropiely. 1h) RFs and quaes are compete, recordin atimely manner, and consistent 8 1) aperopiatecorectons, adatons or deeions are made othe ORFs, na necessary and intaed by the principal investigator or by hisher authoizes designer ior shall not make ‘omectons,acsions or dolstons tothe ORFs, |) a aqveree events and device deficiencies are reported to the spon adverse everts ‘nd devos dates tal could ave ed fo a serious adverse deve repovied othe sponsor ‘wthout unused ete, 1) all carious adverse events and deviations are repetd othe 1) the storage and investigational device aocounabilty followed, 1m) all eter required reports, notfeatons, applications, the investigators Wes and are accuse, compte, investigation, 1) maintenance and calibration of he equipment elvant to the assestment ofthe eSical investigation is ‘Sppopelely performed and documented ‘he traceability process 6 being fand correspondence are maintained egible, dated and gently the cincal 2) euent lboratory normal valves, inthe evestgatars o,f rogues, )_ subject wtherawal has boon "Sanitor shal lus this wih the principal investigate or ‘ater autnorzee designee, subject non-complence wie requreent stated inthe informed consent has been documented; the ‘monte shal seuss his 0) the principal inves igaton ste team are iformed and knowledgeable of a relevant incl ivestigaton, ane *®) any corectve 6, st needed, have been implemented and are efectve. 8246 Closeout act “The montor shal perform close-out aces as deseabed in Cause 7, 8247 Monitoring reports [Ai monioring acivties shal be documented n a writen report to the sponsor [see also 8.2.3] and shal iret 1) the date, vestigation site identfcaton, name ofthe montor and name ofthe principal invesbgator ‘ther indus contacted, and 6 ‘ete0 ant alread190 14155:2091(€) >). & summary of what the montor reviewed and hieher obseratio(s) wih regard tothe completion of Gravois seton toms, sitar nange. fs, dewatons,corlusons, and reeammended acon tobe {aken to secu complance, Aczoyt te mentor pte sey fn le stare wn pr meter NOTE The stove requrereis can ato seiy 10 clicatinvesiatonrestd commogistons) depending on ‘ier obese or atonal roputons. 18.25 Safety evaluation and reporting ‘The sponsor is retponsbe for the dastifisation of adverse ovens and g latuation of the Cine investgaton and shal 2) review tne investigators assessment ofall averse events and 36 document n wing their ‘efoteneee and teiatonship to ne vestigatoral dove; In caggOFOgapretment between the sponsor tnd the principal investigator), he sponsor shal commu Getined inc), d) and e) below, 1). review all device deficiencies end determine and Jn witing whether they could have led 0 2 Serous adverse device eect in case of ‘he sponsor end the. prncpal Ivete he Sport Sal communal at ‘concerned partes, 35 defied in) d) e) eon, 2) report censure the reporing, othe EC by th igalo() of al serous advorse events and ovce defines that could have td To frese device effect F requred by ratonal tegulatons or he CI or by te EC, 6) repor 10 regulatory autores, within the"Riguredlime period, all serous adverse events and device ‘Siclonies tat could have le toa serious alate device effect, equred by national reguisons or tec, ©) report al relevart safety fe c.f extablhed, according to writen procedures, 1) the case of 9 multicentre tion, form al princi! investaatrs in wing of al the on ses (nat have een reported tote sponsor and ensure that oy national reqatone or te CIP ox by the EC, wichever fat be tert fo al the principal wesigalors witn a tme frame isk a defined inthe risk anal por. '9) ensure that the EG he requatory suhories are informed of significant new infomation about the Wy incase device effects and device deficiencies that could have ed to serious adverse even rete re isk aalyls needs fo be updated and assess whsher corrective or pe 0 1826 Clinical im close-out “The sponsor shall 9) ensure al incl ivestigaon ese-ou actives are property conducted as described in Cause 7, 1b) provide a statistical analysis of te deta, produce a linia investigation report and submit for review, as described in 73, and oso 201 atea eaves a150 14185:2011(6) 4) eneure that he cnical investigation repon, whether fora completed or prematurely terminates clinical Irvestgaton is provded tothe EC. partoating ivesbgators and reguatory aus, as equred by ‘atonal regdatons 83. Outsourcing of duties and functions “The sponsor may transfer any o al ofthe dues and functions related tothe cirical investigation, including monterng toon extemal organization (auch as a CRO oF inaual contract, butte ulimalerespensbity forthe quay and integrty ofthe crica westigaton data shal reside wth the sponser. Al urements {hs Inlematonl Standard applying toa sponsor sal also appl tothe extemal og aot ‘rgenizaion assumes the ccl-nvestigaonfleted uses ard functone of he “The spontor shal spect in wing any cinicalnvestgation elated diy or func thebxemal ‘rganizatin, rxanng any cinicalinvesigaton-reaied dites and functions not ps rt, ‘assured by, te external organzation. TET rae ete mere tee procedures atthe enteral orgerizaon. 8.4 Communication with regulatory authorities ‘Te sponsor shal required 2) noty or cota approval fem regulatory auhories In re the eical investigation is Conducted 1). repart onthe progress and status of he nical inv © peroem safety reporting as specified in 825. 9 Responsibilities of the principal i 9.4 General = ‘The ‘ole ofthe principal investigator and manage the day-o-day conduct of the cincal Investigation as wel ae enue the right, salty and wel-bang ofthe subjects involved in the cna vestigation, 1 the sponser contzact an ingiiion to conduct the clinical iavestgatin, the Inston shall appoint ‘sopropmetelyquafied person faethe pincalnvesboatr. 92 Qualification of Investigator ‘Toe pina i 2) be qualified by adult, reining and experience to assume responstilty for he proper conduct of the ‘neal imvestgation in ‘tht nfornational Standars,ewdence of such quaifiatons of the principal investigator and Key members of the Investigation ste tam shal be provided to he sponsor rough uptodate CVs o ther relevant documentation, 1b) be experienced inthe fed of application and trained inthe use of the investigational device under conederaten ©) close potenti! confit of interest, Including facial, thtinerfee wih the conduet ofthe lial Investigation or interpretation of resus, and be knowledgeable wih the method of obtaining inform consent a (21602011 - Ate need180 16158:2011(€) 9.3. Qualification of investigation site ‘The pincal nvestgetorsrallbe able to demonstrate thatthe proposed investigation ste 42) has the required numberof eligible subjects needed within the agreed ecrutmant prod. and )_has one or more qualfedinvesigaors, a qualified investigation site team and adequate facies fr the foreseen duration ofthe cnical investigation 8.4 Communication with the EC ‘The principal investigator shail ) provide the sponsor with copies of any cinicabivestgaton es ins between the cial investigator and te EC, ) comply with the requirements descrbedin 45, ©) bain the writen and dated approvattavourble pinion of the 12 clical investigation before Fectuting subjects and iplemening all subsequent amendments, requred, 4) pero safety reporting we species in 2.8, and ©) prompt report any deviations from the CIP hat salty or wellbeing of the subject or the Scien. itegny of the circa wvestgat ng those ‘which ‘cow ‘under emergency reumtances, required by the EC, CIP or ‘ In prtcuarcrcumstances, the communication wi REC'can be performed by the sponser, party or ful, Inwhich case the sponsr shal keep the infomed )_ ensure compliance regulatory requirements and ethical principles for the process of ©) ensure and documens sppropr ie Vaining ian author2od designee is appointed to conduct the informed of he CP in wrt, 2) conduct he cna! investigation in comptance wth the Ci, (9) create and maintain sours documents thoughout the circa iwestgaton and make thom avaiate 25 ‘equeste curing montonng iss or suds, 8) ensure thatthe investigational deve is used solely by authorized users as specited in 62, and in ‘Scoordance wih he GIP and nations for use, 1) propose tothe sponsor any appropiate modifications of the CIP or investigational device or ofthe use ofthe investigational device, (21802011 -An esd Ey180 141 te) retain tem implenening any modcations tothe CIP without agreement from the sponsor, EC and ‘equator auhorbes, required, |5) document and expan any deviation rom the approved CIP that occured curing the cours of the cic investigation, hy ensure that an adequate investgaton ste team and fois exist and are meinisined and docunentes ‘rng the inca investigation, |) ensue that maintenance and caltraton of the equipment relevant forthe assessment Ble cic! Investigation le aperopnatly performed and documented, where appcabe |) ensure he accuracy, completeness, legit and timeliness ofthe data re rin the ‘CRF and in al rogues repos, i) maintan the devices acceurtabity records, 1) allow and suppor the sponsor perform mortring and aueting acti be accessible tothe monitor and respond to questions during montorng Vs ear cane aloae een » Spovacemnntomnmenants CP ieee “Toe pincpalinvesigator shal 2) provide adequate merical care to a subiga curing and afer @ subjects parcipation in 3 inca! Irvostgaton inthe case of adverse inthe informed conser (se8 47.4 1) infor the subject of the nature na ©) provide the subject wih the Frvestigatona device, when any adverse overs experience, on proper use, handling, storage and retum of the ea by bw subje, ©) tnorm the subject of any new signineifdings occuring dung the clrical investigation, inclusng the ‘ed for adetonal medea gir thal may be equres, ©) provide the subject why procedures for posible emergency situations rele to the nical (rvestigaton, and caary srangements for emergency wealment, cluding, decoding lary marked to incicate thatthe subjects enrolled apatotr cca 4) tf 2ppropate, subjects enolled inthe alncal investigation shal be provided with some means of showing thet peepclon nthe Snes Investigation, together wih identfeation and complance formation for ‘Sroeitant weslment measures (contact acaress and telephone numbers shall be provided), 1) inform, with the subjects approval or when required by national regulations, the subjects personal Dyson about the subjects pariopaton inthe cinal investigation, and 1) make al reasonable eft to ascertain the reason(s) for @ subjects premature withdrawal frm the ‘rica invesigaton whl ty respecting the subjects rights. 0 2190201 Aegs meow180 14155:2011(€) ‘98 Safety reporting “The principal nvestgator si |) recor every acveres event and observed device deficiency together wih an assessment, ) report to the sponsor, wthout unjustified delay, al serious adverse events and devie deficiencies tat ‘ould have ed fo a serous adverse device effec: is information shall be promi Tolowed by ctaied ven reports, a speced inthe CIP, ©) por tothe EC serous edverse events and devi defences that. serous adverse ‘evice effec, required by the national regulations or CIP or by the EC. 1) report to regulon auhories serous adverse events and device could have led to 8 seus adverse device eflec, ax requred bythe national regulations 2 senna nme me = fo the safely reporting @ ¥ SS S (21902011 -at agreed Fa180 16155:201118) z Annex A (normative) Clinical investigation plan (CIP) AAA General ‘AA. Introduction ~ “This annex species the content of @ CIP. Ifthe requted infomation i writen jntaon, for ‘ramp te IB such doeamentaton shal be reference in the CIP and shall on request “The content of @ CIP and any subsequent amendments shal inciude fisted In tis annex, {eth neato fr ach ops ha src sereionty 1.2 Identiteation ofthe clinical investigation plan » OF ©) Version dt oft 8, Summary af the reson history inthe cas of is 6) Versions number and reference number, any, wih fe page number and the ttal number of pages net xs eeai A %) Name and adress ofthe sponsor of Sn NOTE ihe sponsors nt eit (cowies)n whch te cia vestigations 1 be cried et {he are and areas of represen Tess coumes)ean be emured sococng fe rons ot ‘eye! equator A414 Principal investigator Investigator and investigation site(s) 8) Name, adsress,and 1 postion of 1) principal 2) coordinating inves Boor, apoinies 1) Name and odes ofthe ivestgation so) n which te cia imvestgaton wil be conducted ) Name(s) and edres{e) of her inatutonsinvled nthe cna invesigaon “The spandcr shall maintain an updated iat of pn nestgntars,ivesigaton ste, and insutons. Te Tat can be kept separately fom the CIP. The defriive fst shall be provided with the cirical vestigation report (see Annex) 2 (2120201 Att venes10 14156:2011(€) [A:15 Overall synopsis ofthe clinical investigation [A sunmary of overview of te cris! nvestgaton shal incude al the relevant information regarding the Cinza Imeeigaton design such ax munonlexclaon cre, numberof subject, curation cf te cca Irvestgebon.ftow-up,cjecbve(s) and endparts). NOTE ght bo vo fo dude fom chat showing he kay sages of een ivestgen o any her Meteasn han Scone i inc meabgton {A2 Identitication and description of the investigational dev ~\ 12) Summary descrifon ofthe invesigntonal device ands intended pu 1) etas concerning the manuacture ofthe Iwestigstonl devo 1) Name or number ofthe modevype, ncudng sofware jones, I any, to perm fa ‘Senicason 18) Deserpion a8 to how traceaby shel be aeneved during and ator WE circa vestigation, for example by assignment oflot numbers, batch numbers or aria 9) Intended purpose of he investigational devs in the {The populations and inceations for wich the 19) Description of the inesigatonal deve inch ‘us. (Tis shall include detas of ery med ‘oF cies boogicaly active substances) that wil ben contac wt tissues or body human or anal tskues oF ee Serivaives, 1h) Summary ofthe necessary training ans exper to use the investigational device 1) Deserston ofthe space medical gigi procedures Involved inthe use of he investigational device. * ‘A3 Justification for the 1 clinical investigation stueaton for me design Investigation, which shall be based on the concusions of the ‘evaluation, as specie in 3, prise {an evaluation of thffésus of he relevant precinical testingascessment cared out jusity the use of the vesigaona! Sayee m human subjects ana 1) an evaluation that ae relevant to Ue proposed cnical investigation [AA Risks Mfipenefits of the investigational device and clinical investigation 8) Aopated cine! beets 1») Acad adverse device ects ©) Residual ks associated wth the investigate! device, es identified inthe sk ana report 4) Fk associated wi parcipation nthe erica invesbgaton, ©) Possie interactions with concomtant medal testmerts (1902011 atepna rears 3AAS Objectives and hypotheses ofthe clinical investigation 2) Objectives. primary and secondary 1») Hypotheses, primary and secondary, to be accepted or rejected by st inca Investigation. {| Clans and interces perormance of the investigational doves that ae 1) Risks and anticipated adverse device effets that are to be assessed — @ a . coer dtm teres i 1) Deception of te measures to be taken to moma, avoid bas, incuding randomization and indingiasking| ©) Primary and secondary endpoints, wth atonal for hel selection and measurement 6) Methods andtinng for assessing, ego ying variables, ©) Eaulpment 0 be used for assessing tigation variables and arrangements for montoing mmanterance snaealtrston 1) Any procedures forthe epi ‘A. Investigational ) and comparator(s) 2} Descrigon of he exposure nvestgatonal devices) or comparators), used. >) Justetion ot pe chloe of Sarat). ©) List ny ater Reale or medication tobe uted dsing thecal investigation 4) NemberatnvestiatioN devers obo use, together wth jstifiatin 3 Subjects 2) ncn ertariafor subject section 0) Exclusion crtr for subject selection. ©) rior an proedues fr subject wthtranal or dscontnuaton. 4 (01802014 eoes180 14185:2011(€) 8) Pont ot ecient ©) Toa expected duration ofthe cnical investigation 1) Expeced duration ofeach subjects partcipaton 9) Number of subjects required to be incuded inthe cial investigation. 1h) Estimated tie noeded t selects number (i. errlment peo, AS4 Procedures 4) Deseo of al the clnicatnvestgatonrelates procedures that su ng the cinical ‘weston ©) Description of tose actives permed by sponsor monitoring). ©) Any known o foreseeato factors tht may compromise the inca vestigation o the Interpretation of recut AMPLE Fac ieise ebjct baseline chaacetin rection the se of ster medical eves an subject face auch as ag, ganda cr ols fr eesaing ee far he ‘Sncalnvettgnton, for exape by sje saeeson Sa ue 2 Sates faa tn) by ‘The folow-up period during the cinical nvestgati the demonstration of peromance over 8 Pod of tine tfsnt to roprecent a ralte ance of he ivestigatonal device réslow pone co seamen i a in ig el dN le i Cal penne: aes {General cutine ofthe monitoring including access to source data and the extent of source erecta gmerncling seinen MO mci oe AAT eto! contcatons ea MG ae ac al diane we ©) hele o sgnfance ad he power ofthe nia nvestigton, ) expected cropout rates, ©) passfal criteria o be applied othe rests ofthe cca! ivesigation, 1) the provon fr anintrn analy, where aptiabe, citer fr te termination ofthe ical vesigaon on eats! grounds, (91502011 Ate cand a180 14155:2011(€) 1) procedure reporting ry deviations) rom the og! tats lan, 1) the specication of subgroup or analysis, 1) proveoutes atthe into acount athe ca, 1) thetvestmentf ising, unused or spurious dats, icing op ous ana wehrawal, 1) te eseisin of partir ifomaton rom the testing ofthe hypotea, eleanor 1) in mutica clinical investigations, the minimum and maximum rumber of ue for eacnoenve ‘Special reescring and sample size(s) may aply for the eary circa invesigatio(y Wy fest cic investigations) ‘A8 Data management 8) Procedures use fr data review, database clearing, and Issuing an resolving data queries » ee ee cae oa GD ©) er apa flat aesrne, —