This is a controlled document. The master document is posted on the JRCO website and any print-off of this document will be classed as uncontrolled.

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1 This is controlled document. The mster document is posted on the JRCO wesite nd ny print-off of this document will e clssed s uncontrolled. Reserchers nd their tems my print off this document for trining nd reference purposes ut re responsile for regulrly checking the JRCO wesite for more recent versions Joint Reserch Audit SOP SOP Reference: JRCO/SOP/018 Version Numer: 7.0 Effective Dte: 25 Oct 2017 Review y: 25 Oct 2020 Author: Gisel Brreto, Clinicl Trils Mnger Approved y: Gry Roper Dte: 24 Oct 2017 Version Dte Reson for Chnge Version My 2007 Annul review Version Jun 2008 Annul review Version Fe 2010 Formtion of Joint Reserch Office Version Jul 2011 Annul Review Version Nov 2012 Annul Review Version Fe 2015 Scheduled Review Version Aug 2017 Scheduled Review V Oct 2017 Pge 1 of 21

2 Tle of Contents 1. Purpose Pge 3 2. Introduction Pge Audit Requirement Pge Role of the Auditor Pge 4 3. Procedure Pge Auditor Qulifictions Pge Selection Process Pge Studies/Site Selection Pge Smpling Frme Pge Systems Prioritistion Pge Audit Pln Pge Physicl Audit Process Pge Audit Findings Pge Audit Results Pge Finl Audit Progrmme Pge9 3.8 Follow-up ctions Pge Escltion Process nd Conflict Resolution Pge 9 4. References Pge Appendices 5.1 Audit Pln Templte 5.2 Audit Tool Templte 5.3 Audit Report Templte Pge 11 Pge 11 Pge 13 Pge 23 V Oct 2017 Pge 2 of 21

3 1. PURPOSE This SOP descries the udit procedures of the Imperil College Acdemic Helth Science Centre (AHSC) s Joint Reserch (JRCO), cting on ehlf of Imperil College nd Imperil College Helthcre NHS Trust s Sponsor orgnistions. This SOP specificlly descries the processes for selecting those studies for udit tht fll under the Deprtment of Helth Reserch Governnce Frmework for Helth nd Socil Cre 2005 (2 nd Edition) nd/or the Medicines for Humn Use (Clinicl Trils) Regultions 2004 nd susequent mendments; the procedures for crrying out udits; nd reporting udit results to Investigtors. This SOP lso descries the requirements for Investigtors to respond to JRCO udit reports nd implement corrective ctions. Hosted Studies will not e udited y the JRCO ut sponsors will e requested to supply copies of ny udit reports of hosted studies where sitution of risk to ptients sfety, serious non-complince or dt integrity wrrnt it. 2. INTRODUCTION As legl Sponsor orgnistion (n institution tht tkes responsiility for initition, mngement nd/or finncing of clinicl tril), Imperil College AHSC s JRCO, representing Imperil College London nd Imperil College Helthcre NHS Trust, is responsile for uditing reserch prctice nd ssuring dherence to current legisltion nd guidelines s prt of qulity mngement system. As such, it is necessry to udit reserch for which Imperil College AHSC is the led Sponsor ginst the stndrds of the Reserch Governnce Frmework 2005 (2nd Edition) nd the Medicines for Humn Use (Clinicl Trils) Regultions 2004 where pplicle nd ginst the qulity systems of Good Clinicl Prctice intrinsic to the Regultions. This guidnce is to ssist reserchers in understnding the udit process, so tht they re prepred should they volunteer or e selected for internl udit. The purpose of reserch udit is to: Ensure prticipnt nd stff sfety Ensure prticipnt rights, welfre nd well-eing re eing dequtely protected. Evlute tril conduct nd ensure reserchers complince with the protocol, SOPs, GCP nd the regultory requirements nd Trust nd College policy Improve reserch systems nd dt qulity Prepre reserchers for externl udit processes Demonstrte roust reserch processes to externl funders nd industry 2.1 Audit requirement Under the Reserch Governnce Frmework nd the Medicines for Humn Use (Clinicl Trils) Regultions 2004, the Sponsor is responsile for the mngement nd monitoring of study. The JRCO is responsile for uditing reserch on ehlf of Imperil College AHSC. Projects will e udited: On voluntry sis As result of risk grded ssessment (routine udit) If there is suspicion of significnt non-complince to regultion (For-cuse udit) V Oct 2017 Pge 3 of 21

4 A written report on study progression does not constitute udit nd should e sumitted for every study in ddition to udit requirements. For detiled description on the risk ssessment process plese refer to JRCO/SOP/ Role of the uditor It is the uditor s primry role to collect evidence of reserch prctice nd compre it ginst the requirements of Good Clinicl Prctice nd Reserch Governnce. The uditor is responsile for documenting oservtions nd conclusions, sfegurding udit documents, records nd reports, ssessing whether requirements re eing met, nd developing reports incorporting recommendtions for chnge or dherence. 3. PROCEDURE 3.1 Auditor Qulifictions The uditor should e independent to the reserch tem/reserch systems to conduct udits ppropritely. An uditor should e qulified y trining nd experience to conduct udits properly. An uditor s qulifictions should e documented (ICH GCP ). 3.2 Selection Process Studies/sites The selection process should tke into ccount the importnce of the reserch project in respect to regultory sumissions, e.g. is it registrtion tril, the type nd complexity of the study, the perceived level of risk to the prticipnts, the numer of ptients to e enrolled nd ny identified prolem (ICH GCP ). A risk sed smpling frme should e used for selecting studies for uditing. Studies cn lso e selected d hoc, trgeted sed on emerging issues Smpling frme Audits of sponsored studies/sites will follow risk-sed pproch. During the sponsorship process studies will e risk ssessed ccording to JRCO/SOP/009. Studies re ssessed ccording to the risk ssessment tool V4 (this uses common formul sed on severity nd likelihood of risks tht impct on ptient/suject welleing/orgnistion nd integrity of dt) nd divided into 5 risk ctegories/severity: Ctstrophic 5 Mjor 4 Significnt 3 Moderte 2 Low 1 V Oct 2017 Pge 4 of 21

5 Ctegory/severity Definition Risk hs severe Risk hs potentil Risk hs little or no potentil hrm to for serious impct if potentil impct on ptients (volunteers) not mnged ptient sfety nd/or integrity of ppropritely on nd/or integrity of dt ptient sfety nd/or integrity of dt dt Routine udits will e performed to prioritise studies within ctegories 5-4 nd 3-2. A docums report will e run to estlish the smple to e udited. The smple will consist of pproved studies nd it will exclude studies in set-up nd those tht hve recently een udited or inspected. Exmple risk fctors for study/progrmme selection Study popultion (e.g. size, vulnerle sujects, new indictions) Product chrcteristics (e.g. new products or with specific risks) Therpeutic re Durtion of study Applicility of regultions (e.g. interntionl vs non-interntionl) Importnce of study to future mrketing sumission (e.g. study phse, pivotl or supporting study) Level of experience of reserch/clinicl tem Confidence in service providers Numer nd nture of outsourcing ctivities nd ssocited interfces for responsiility Level of complexity of study nd trining requirements (e.g. e-system usge/medicl device requirements) Regionl distriution of sites Exmple risk fctors for site selection Numer of sujects per site Numer of protocol devitions Numer of SUSARs/SAE(s) Known complince issues Other spects relevnt to primry study ojectives Efficcy results from site Numer of discontinued sujects Geogrphic loction Level of experience of investigtors nd/or site Level nd nture of monitoring Dt distriution/nomlies/missing dt Multiple vendors oversight cross sites Use of SMO (lone or in comintion with vendor-selected sites) Systems udit - Prioritistion System udits will include numer of studies. The uditor should conduct specific systems or process udits with regulr frequency s defined in the udit progrmme. The selection process for inclusion in the udit progrmme will e risk-sed. The following fctors will e tken into considertion: The importnce of the system/process to (ut not limited to): o Suject sfety or rights (incl. sfety dt reporting) consent process, DSUR process, Dt monitoring committee, Reference Sfety Informtion mngement nd control o Dt integrity review of primry endpoints, monitoring, fit for purposes ssessment of computer systems nd equipment V Oct 2017 Pge 5 of 21

6 Complince with sponsorship procedures o Complince with GCP nd regultions (inc. emerging issues focused on y regultory uthorities) investigtor s complince/oversight, REC sumission process, mngement of Protocol Amendments Degree of process control (e.g. detiled procedures nd controlled documents, level of qulity control pplied y opertionl group, QC/metrics dt, trining) Complince history (e.g. previous udits or inspection findings) Process stility (e.g. new or updted processes) Time since previous udit 3.3 Audit Pln (See Appendix 5.1) An udit pln will e developed y the JRCO Fcilittors nd/or Reserch Governnce Mngers (RGMs)/Clinicl Tril Mnger, nd greed with the resercher involved prior to eginning the udit. The pln should: Define scope nd ojectives for udit Provide timelines for udit conduct Identify where nd when the udit will tke plce Identify requirements to e udited ginst Identify groups nd res to e udited List documents nd records to e studied List responsile people whose functions will e udited Clrify who will get the finl report nd when it will e redy 3.4 Audit Conduct The process will strt y the Reserch Fcilittor nd/or the RGM, explining the scope nd ojectives of the udit, nd how it will e crried out. Exmples of udit techniques include: Interviewing reserchers Reding documents Reviewing mnuls Studying records Reding reports Anlysing dt Oserving ctivity Exmining conditions Confirming interview evidence Documenting oservtions See Appendix 5.2 for the JRCO Audit Tool Templte. V Oct 2017 Pge 6 of 21

7 3.5 Audit Findings Once the prcticl udit hs een completed the Fcilittor/Reserch Governnce Mnger/Tril Mnger will develop summry nd mke preliminry recommendtions to ssist with reserch conduct. The Fcilittor/Reserch Governnce/Tril Mnger will: List ny gps in complince with ny supporting evidence Cross-reference with regultory requirements Grding of findings Audit findings re grded using the following criteri: Criticl: finding defined s one with the cpcity to directly undermine the integrity of the study. It s wekness of, or non-complince with, control process which, if not resolved, will cuse hrm to ptients or dt integrity nd/or orgnistion reputtion tht requires the immedite notifiction nd ttention of senior mngement nd cler timelines for resolution. For exmple findings: Where evidence exists tht the sfety, welleing, rights or confidentility of study sujects hs een (or hs hd significnt potentil to e) jeoprdised. Where reson hs een found to cst serious dout upon the ccurcy nd/or crediility of study dt. Where pprovl for the study hs not een sought from one or more regultory gency/ody or grnted from one or more regultory gency/ody (e.g. Ethics committee, MHRA) ut the study hs commenced regrdless. Where procedures not covered/included on the consent form re eing performed or where new procedures hve een introduced into the study protocol ut where prticipnts who hd consented prior to their introduction hve not een sked to re-consent. Where following study pprovl, significnt mendments hve een mde to the study protocol or documenttion ut no new request for pprovl hs een sumitted. A comintion of multiple mjor udit findings my result in criticl udit finding (if these re in reltion to the sme process or outcome) even though ech of the findings re not criticl. Mjor: finding defined s one tht compromises the integrity of certin component(s) of the study. Wekness of, or non-complince with, control process which, if not resolved, hs the potentil to cuse hrm to ptients or dt integrity nd/or orgnistion reputtion tht requires the timely notifiction nd further investigtion y senior mngement nd cler timelines for resolution. For exmple: Where there hs een filure to comply with the regultory requirements e.g. filure to ssess nd report SAEs nd/or SUSARs ccurtely nd to the correct odies. Where there hs een significnt unjustified deprture from GCP e.g. filure to provide prticipnts with copy of their consent form or Prticipnt Informtion Sheet. V Oct 2017 Pge 7 of 21

8 A comintion of multiple minor udit findings my result in mjor udit finding (if these re in reltion to the sme process or outcome), even though ech of the findings re not mjor. Other/Minor: Any other findings, defined s those where the integrity of the study is not directly compromised ut which represent n sence of due diligence on ehlf of study stff towrds the conduct of the study. Wekness of, or noncomplince with, control process tht currently cuses no hrm to ptients or dt integrity nd/or orgnistion reputtion tht requires resolution. For exmple findings: Which demonstrte tht no definite document mngement/orgnistion processes re in plce t site / no investigtor site file exists. Where there hs een filure y study stff to inform the relevnt uthorities of mendments to strt nd stop dtes or study specific documents. 3.6 Audit Results Where there re mny res of improvement to develop, the Fcilittor nd/or RGM will rrnge meeting with relevnt reserch stff to discuss the recommendtions or gps in complince. This cn e used to develop solutions to ny prolems identified through the udit. 3.7 Finl Audit Report nd Dissemintion Over the following two weeks from initil udit, the Reserch Fcilittor nd/or RGM/CTM will review the gthered informtion nd compile finl report, which will e forwrded to the Hed of Regultory Complince for review. Once the finl report is pproved it will e disseminted to the Chief/Principl Investigtor, the relevnt NHS Trust R&D office, nd stored in the Imperil College AHSC Joint Reserch. The report will include: The detiled udit pln A review of the evidence collected A discussion of ny conclusions drwn from the udit A list of identified gps in complince An ssessment of how well regultory requirements hve een met Recommendtions for chnge in prctice to conform to regultion 3.8 Follow-up ctions It is the Chief Investigtor s responsiility to ensure ction is tken to correct ny identified gps in regultion complince. If ny dvice or ssistnce is required the Reserch Fcilittor/Reserch Governnce Mnger/Clinicl Trils Mnger will e le to help with this. The Chief Investigtor of the study is expected to respond to the udit report within 1 month nd corrective ctions mde within timely mnner. V Oct 2017 Pge 8 of 21

9 3.9 Escltion process nd conflict resolution In the fce of ny dispute the reports nd findings/grding will e reviewed in ccordnce with the Joint Reserch (JRCO) escltion policy. The elow digrm provides the escltion route: Imperil College London Helthcre NHS Trust Bord nd Imperil College London Bord Fculty Den Fculty Operting Officer ICL Director of Reserch ICL Hed of Regultory Complince Reserch Governnce Mnger/Clinicl Trils Mnger Reserch Fcilittor V Oct 2017 Pge 9 of 21

10 4. REFERENCES Deprtment of Helth Reserch Governnce Frmework for Helth nd Socil Cre 2005 (2 nd Edition). UK Clinicl Trils (Medicines for Humn Use) Regultions 2004; ICH GCP E6 (R2) Nov 2016 GCP uditing Principles nd Prctice y RQA NHS R&D Forum. Distinguishing different types of Monitoring nd Audit, Novemer 2008 JRO UK regultions Complince form (Prt 2), version 1.0 NIHR RSS frmework reserch/reserch-support- Service/RSS%20frmework%20docs/Annex%204%20RSS%20NIHR%20Frmework%20 P08%20Oversee%20study.pdf V Oct 2017 Pge 10 of 21

11 5. APPENDICES 5.1 Appendix 1 Audit Pln JRCO Audit Pln Ojectives The ojective of this udit is to ensure complince with <if IMP study> Medicines for Humn Use (Clinicl Trils) Directive 2004, incorporting mendments (2006) from the EU Directive 2005/28/EC on GCP <if non-imp study> Reserch Governnce Frmework for Helth nd Socil Cre, 2 nd edition. For ll studies, we will e looking for dherence to Good Clinicl Prctice s outlined in the ICH Hrmonised Triprtite Guideline for Good Clinicl Prctice (1996). The finl udit report will document findings ginst these guidelines. Project to e udited Project Title JRCO ref PI Type of study Audit site Dte of udit Clinicl tril IMP Audit ojectives Audit smple Audit methods Essentil documents to e ville during the udit ut not limited to: Protocol Consent form nd Prticipnt Informtion Sheets Ethics pprovls nd correspondence Reserch nd Development pprovl nd correspondence JRCO pprovl nd correspondence Regultory pprovls nd correspondence (eg MHRA, GTAC etc) (IMP study only) Generl Study Correspondence (except Trust, Ethics nd Regultory) Trining documents SOPs Dt mngement Serious Adverse Events Phrmcy/Product-Relted (IMP study only) Monitoring nd Audit documenttion Source dt (ie ptient notes) V Oct 2017 Pge 11 of 21

12 Audit Timeline On the dy, the uditor(s) will introduce themselves nd explin the plnned procedure for the dy. It would e useful if seprte room could e orgnised for the uditors to review the documents. For studies tht hve strted recruiting prticipnts, selection of ptient notes should e mde ville for source dt verifiction s per the uditor s selection. Once the udit is complete, the uditor(s) will riefly go through the findings with the study personnel, nd PI if present. A forml report will e provided within two weeks of the udit, with copies sent to the locl R&D office. A response from the PI to the udit findings should e provided within 1 month of receipt of the udit report. V Oct 2017 Pge 12 of 21

13 5.2 Appendix 2 Audit Tool Section 1: Approvls 1 Ethics Approvl Yes No Comments Is there record of full pprovl from REC? Dte: Ref: c d e f If provisionl pprovl, response fully documented? If the REC specified ny mendments/restrictions/conditions to the protocol, were these done/dhered to? If mendments hve een mde were these notified to the REC/HRA/MHRA/Sponsor where pplicle? HRA pprovl HRA pprovl for ll mendments 2 Sponsor Approvl nd Indemnity Does the project hve JRCO pprovl? Dte: If prticipnts re from insurnce-excluded group, hs wiver een pplied for nd ccepted? 3 R&D Approvl Does the project hve R&D pprovl (Cpcity nd Cpility Confirmtion (CCC))? If Trust pprovl ws suject to modifictions eing mde to the reserch design nd protocol, were these mendments mde prior to the project strting? 4 MHRA Approvl Hs full CTA pprovl een received from ech Competent Authority in ech prticipting country? Dte: Dte: EudrCT numer received EudrCT: 5 CAG nd other regultory pprovls not mentioned ove If pplicle, does the study hve pproprite pprovl? CTA ref: Joint Reserch V Oct 2017 Pge 13 of 21

14 6 GTAC Does the study hve GTAC pprovl? Hve SSAs een received for ech ctive locl site? c Flgging project for integrting virl vector studies? 7 JRCO Approvl Does the project hve JRCO pprovl? If JRCO pprovl ws suject to modifictions eing mde to the PIS nd protocol, were these mendments mde prior to the project strting? Section 2: Protocol nd PIS 8 Protocol c Is the finl version of the protocol in the relevnt study file*? Are ll mendments clerly indicted, superseded nd notified to REC/HRA/MHRA where pplicle? Is protocol eing followed ccurtely? 9 PIS, consent nd GP letters c d e f Is the PIS on heded pper with version numer? Is the consent form on heded pper with version numer? Do the PIS nd consent version numers nd dtes mtch? Is consent form in use the ethiclly pproved version? Is there full record of ll reserch prticipnts written informed consent? Hve prticipnts nd resercher completed consent correctly? Yes No Comments V Oct 2017 Pge 14 of 21

15 g h i j k l Is the consent form signed y prticipnt nd resercher on sme, or close dtes (within reson)? Are the consent forms dted y prticipnts nd resercher post pprovls (i.e. ethics/hra, R&D, sponsor, MHRA)? Is copy of the PIS nd consent kept in the ptient notes? Are consented prticipnts eligile? Does the consent form include permission to inform GP? Hs the GP een informed of prticipnt s tking prt in study? m n o p Hs copy of the PIS een given to the reserch prticipnts? Are the consent forms kept in secure loction? Is there full record of ll reserch prticipnts written informed consent? Section 3: Study Conduct 10 Dt Protection If study involves trnsfer of dt to 3 rd prty, is there specific consent? c d e g Are the pper records stored in locked filing cinet? Are electronic files stored on pssword protected computer? If ptient detils re stored on Imperil-networked computers re they nonymised? Does the project meet the Dt Protection Act? If ptients record re ccessed without consent is there pprovl from ECC? 11 Procedures Hve individul study procedures een written? (e.g.: SAE s, Yes No Comments V Oct 2017 Pge 15 of 21

16 tissue, consent, rnd/reg, dt mngement) Is there current study delegtion log? 12 Annul Reports Hve nnul progress reports een sent to REC, Sponsor nd MHRA? 13 Trining c d Do memers of the reserch tem hve individul trining folder Cn they demonstrte knowledge of GCP? Is there current study delegtion log? Are ll study tem memers informed of study nd procedures? 14 IMP studies c d e Is drug ccountility form eing completed (i.e. receipts, dispense, returns re controlled nd documented)? Storge, lelling nd disposl of IMP per Phrmcy instructions? Study listed on pulic Dtse prior to entry of first ptient? EudrCT numer received Hs full CTA pprovl een received from ech Competent Authority in ech prticipnt country? 15 Sfety Reporting c d e Is there record of ll AE s, SAE s nd SUSARs rising during the reserch? Hve nnul DSURs een sent to REC, Sponsor nd MHRA (if pplicle) Hve SUSARS undergone expedited reporting? In protocol, is there list of expected events? Evidence of continued review of sfety of IMP? 16 Tissue studies V Oct 2017 Pge 16 of 21

17 c d e f g h i Is the tissue from recognised tissue nk or hs project-specific ethics pprovl? If tissue is eing stored post ethics-pproved project, is this eing consented to? If tissue is eing stored post ethics-pproved project, is this covered under n pproprite licence from HTA? If genetic nlysis is tking plce, is there pproprite consent? Is the tissue eing used for more thn 1 project? Is the stored tissue nonymised or pseudononymised? Hs the study een logged with the DI for the cmpus? Is there n identified QA person? Is procedure in plce for trcing smples ck to the donor? 17 Steering Committee/Dt Monitoring Does the study hve TSC or DMC? If yes, proof of meetings (minutes) 18 Source Dt Verifiction* *complete monitoring form Does the dt recorded in the CRFs mtch tht recorded in the Source Documents? If there re discrepncies etween the CRFs nd the source dt, hve these een explined nd signed for? *ISF/TMF or other study file s relevnt The ove detils recorded on (<dte>) re correct nd ccurte to the est of my knowledge. Signture of Auditor. Print Nme: V Oct 2017 Pge 17 of 21

18 5.3 Appendix 3 Audit Findings Templte Audit Report Contents Prt A: Visit Detils Prt B: Introduction Prt C: Responses Prt D: Findings Grding of findings Prt E: Comments nd Oservtions Visit findings Prt F: Summry Prt A: Visit Detils Project title JRCO ref PI Type of study Site udited Dte of udit Personnel Present JRCO: Contct detils: Joint Reserch, Acdemic Helth Science Centre, Imperil College London nd Imperil College Helthcre NHS Trust, Room 221, Level 2, Medicl School Building, Norfolk Plce, London, W2 1PG Tel: Emil: Site Stff: Contct detils: V Oct 2017 Pge 18 of 21

19 Prt B: Introduction The purpose of this report is to document the results of the JRCO udit of the ove study nd detil ny findings identified y JRCO stff during the course of the visit. Study findings re divided into three grdes ccording to their seriousness: Criticl, Mjor nd Minor; definition of ech cn e found in section D. You re required to provide the JRCO with response within 1 month of receipt of this report. This response should detil the ctions tht hve een tken to remedy ech of the findings. In the cse of Criticl findings the JRCO my require tht the PI provide evidence tht the recommended ctions hve een tken nd my dditionlly conduct further monitoring visits to re-ssess the site. Findings listed in this report my include references to ICH-GCP (Interntionl Conference on Hrmonistion Good Clinicl Prctice) guideline, the Medicines for Humn Use (Clinicl Trils) Regultions 2004 (SI:1031) incorporting mendments on GCP (SI:1928), Dt Protection Act 1998, the Reserch Governnce Frmework for Helth nd Socil Cre, 2 nd edition. Plese note tht this list is not exhustive. Prt C: Responses Responses should e mde in writing to the JRCO t the ddress ove nd should e sent within 1 month of receipt of this report. Ech finding detiled in this report is numered; the response should list ech finding identified nd detil the ctions tht hve een/will e tken to ddress them. The response should e dted nd should e signed y the Principl Investigtor (PI) for this study. Should the PI or ny memer of site stff feel tht the findings of the visit documented in this report do not ccurtely represent the conduct of the study they my request further consulttion with the JRCO. This request should e mde in writing to the JRCO within two weeks of receipt of this report. The request will need to e signed y the PI, should stte the reson for request nd e directed to those JRCO stff who conducted the originl visit. Upon receipt of the request for consulttion the primry ction of the JRCO will e to confirm receipt nd to schedule meeting etween the PI/site stff nd those memers of the JRCO who conducted the initil visit. The purpose of this meeting will e to discuss the findings of the visit nd scertin where the differences of opinion lie with the im of ultimtely resolving these differences. Prt D: Findings Grding of findings Audit findings re grded using the following criteri: Criticl: A finding defined s one with the cpcity to directly undermine the integrity of the entire study. It s wekness of, or non-complince with, control process which, if not resolved, will cuse hrm to ptients or dt integrity nd/or orgnistion reputtion tht requires the immedite notifiction nd ttention of senior mngement nd cler timelines for resolution. For exmple findings: Where evidence exists tht the sfety, welleing, rights or confidentility of study sujects hs een (or hs hd significnt potentil to e) jeoprdised. Where reson hs een found to cst serious dout upon the ccurcy nd/or crediility of study dt Where pprovl for the study hs not een sought from one or more regultory gency/ody or grnted from one or more regultory gency/ody (e.g. Ethics committee, MHRA) ut the study hs commenced regrdless. Where procedures not covered/included on the consent form re eing performed or where new procedures hve een introduced into the study protocol ut where prticipnts who hd consented prior to their introduction hve not een sked to re-consent. Where following study pprovl, significnt mendments hve een mde to the study protocol or documenttion ut no new request for pprovl hs een sumitted. A comintion of multiple mjor udit findings my result in criticl systemic udit finding even though ech of the findings re not criticl. V Oct 2017 Pge 19 of 21

20 Mjor: finding defined s one tht compromises the integrity of certin component(s) of the study. Wekness of, or non-complince with, control process which, if not resolved, hs the potentil to cuse hrm to ptients or dt integrity nd/or orgnistion reputtion tht requires the timely notifiction nd further investigtion y senior mngement nd cler timelines for resolution. For exmple: Where there hs een filure to comply with the regultory requirements e.g. filure to ssess nd report SAEs nd/or SUSARs ccurtely nd to the correct odies. Where there hs een significnt unjustified deprture from GCP e.g. filure to provide prticipnts with copy of their consent form or Prticipnt Informtion Sheet. A comintion of multiple minor udit findings my result in mjor systemic udit finding, even though ech of the finding re not mjor Minor: Any other findings, defined s those where the integrity of the study is not directly compromised ut which represent n sence of due diligence on ehlf of study stff towrds the conduct of the study. Wekness of, or non-complince with, control process tht currently cuses no hrm to ptients or dt integrity nd/or orgnistion reputtion tht requires resolution. For exmple findings: Which demonstrte tht no definite document mngement/orgnistion processes re in plce t site / no investigtor site file exists. Where there hs een filure y study stff to inform the relevnt uthorities of mendments to strt nd stop dtes or study specific documents. Prt E: Comments nd Oservtions Audit findings During uditing, stff from the JRCO identified findings; of these hve een grded s Criticl, hve een grded s Mjor nd hve een grded s Minor findings. 1. Grde: Criticl Relevnt Guideline(s): Description: Recommended ctions: 2. Grde: Mjor Relevnt Guideline(s): Description: Recommended ctions: Prt F: Summry We will need you to reply to this report within 1 month of receipt nd inform us of wht ctions hve een tken to ddress the findings listed ove. If you hve ny queries plese do not hesitte to contct the JRCO. The ove detils recorded on knowledge. re correct nd ccurte to the est of my V Oct 2017 Pge 20 of 21

21 Signture of Auditor(s). Print Nme: V Oct 2017 Pge 21 of 21