1. Cardialysis Company profile

2. Content Cardialysis overview European Cardiovascular Research Institute (ECRI) Clinical trial services Complete suite of services Independent core laboratory Experience Clinical event adjudication Experience Selection of current clinical trials Track record Summary 2 3. Cardialysis overview Cardialysis Services: Full services Contract Research Organization Regulatory submission and regulatory affairs services Fully integrated imaging core lab Over 31 years of Cardiovascular expertise Global reach European focused with ability to conduct global clinical trials Staff 140+ employees, less than 5% turnover in staff per year Expertise In-house subject matter expertise in cardiovascular area Track record 250+ Cardiovascular trials managed to date Thought leaders Strong academic network 3 4. Cardialysis profile Cardialysis is an independent CRO Based in Rotterdam, the Netherlands Founded in 1983 as spin-off from thorax center of the Erasmus MC Started as Holter monitoring company - cardiovascular expertise Large expertise in Cardiovascular clinical trials: 250+ trials Phase I Collaboration with department experimental cardiology Erasmus MC Phase II IV, investigator sponsored trials & registries Experience with trials for submission to regulatory authorities Quality assured by performing trials according to Current FDA / EMA / Japanese GCP / ICH guidelines ISO 14155 standard 4 5. Regular company audits No critical or major findings Dutch health authorities audit in 2006 No critical findings Conclusion: No need for re-inspection On average 6 sponsor audits per year for: Compliance with ICH-GCP Compliance with ISO14155 European and FDA regulatory requirements Conclusion: No critical or major findings in 2014 5 6. Staff Office F&C, HR, FS, secretariat Statistics & Data Management M. Bressers Core Laboratory R. Pawar Board of Management P.J.A. Bruijs G.A. van Es ICT R. Stadhouders Operations & Program Management P.P. Kint QA J. Pranger Program Management G. Rude Organogram Cardialysis CRA, Safety & Site Management Department M. Mol Project Management M. Mol Medical Affairs H. Garcia Garcia Business Development T. Smits Strategy & Business Development I.P.E.M. Kuit Project Implementation & Oversight 6 7. European monitoring network The network of monitors is easily increased within countries and expanded to other countries in Western and Eastern Europe depending on sponsor requirements All freelancers are trained and work according to the Cardialysis SOPs The BeNeLux countries are monitored by our in-house CRAs 7 8. Cardialysis profile II High-quality CRO services in cardiology A complete suite of services for pharma & device trials Opinion-leader expertise and strong academic network Therapeutic focus: Acute Coronary Syndromes, Atherosclerosis, Coronary Artery Disease, Diabetes Mellitus, Electrophysiology, Heart Failure, Hypertension, Restenosis, Stable Angina Pectoris Investigator network of >1,200 cardiology sites Network of free lance monitors in Western & Eastern Europe Global reach via preferred partners Independent in-house cardiovascular core laboratory 8 9. Thought leader expertise Prof Patrick Serruys (Imperial College, London & Emeritus Professor Erasmus MC, Rotterdam) Prof Karl-Heinz Kuck (Asklepios; Hamburg) Prof Stefan Windecker (Bern University; Bern) Prof John Camm (St Georges Hospital; London) Dr Robert-Jan van Geuns (Erasmus MC; Rotterdam) Prof Gabriel Steg (Bichat-Claude Bernard Hospital Center; Paris) Dr Marco Valgimigli (Erasmus MC; Rotterdam) Dr Nicolas van Mieghem (Erasmus MC; Rotterdam) Dr Arie-Pieter Kappetein (Erasmus MC; Rotterdam) Prof Freek Verheugt (Onze Lieve Vrouwe Gasthuis) Prof Jan Tijssen (Academic Medical Centre Amsterdam) 9 10. Investigator network of >1200 sites Europe: 800 cardiovascular sites 10 11. Academic Research Consortium (ARC) Harmonization of clinical endpoints 4 Academic Research Organizations joining forces: Boston Harvard Clinical Research Institute Durham Duke Clinical Research Institute New York Cardiovascular Research Foundation Rotterdam Cardialysis Cooperating with the FDA , clinicians and relevant clinical societies Completed: Percutaneous Valve ARC I & II Bleeding complications ARC Initiatives: Atrial Fibrillation ARC peripheral intervention ARC Bioresorbable Vascular Scaffolds ARC Antiplatelet therapy ARC 11 12. Vulnerable Patient Meeting Annual Boutique meeting hosted by Cardialysis Participation by invitation only; 75 100 attendees Faculty of thought leaders, regulators, industry experts & decision makers Expert in depth discussion regarding vulnerable patients Updates on the progress of technologies Scientific Board of Directors Prof. Patrick W. Serruys - Imperial College London, UK Prof. Gregg W. Stone - Columbia University Medical Center, USA Prof. Wolfgang Koenig - Ulm University, Germany Prof. Amir Lerman - Mayo Clinic, USA Prof. Ton van der Steen - Erasmus MC, The Netherlands Dr. Hector Garca-Garca - Cardialysis, The Netherlands 12 13. European Cardiovascular Research Institute Platform for investigator sponsored trials ECRI is an organisational structure that: Acts as intermediate between thought leaders and supporting industry Acts as sponsor for investigator sponsored trials Controls the clinical research project(s) Has no intention to make profit Current trials: ECRI 1 GLOBAL LEADERS ECRI 2 SYNTAX II ECRI 3 ABSORB STEMI; the TROFI II study ECRI 5 DESSOLVE III 13 14. Complete suite of services Trial design Site selection & contracting Regulatory submission Clinical monitoring & site management Project management Data management Statistical analysis Safety monitoring & reporting Core laboratory Clinical event adjudication services 14 15. Core laboratory services Independent & continuous focus quality Techniques are validated to and in compliance with the latest regulatory and industry standards ISO 14155: 2011 (GCP) GCLP endorsed by WHO: 2009 FDA 21 CFR part 11: electronic records; electronic signature Test runs and training of sites Feedback to the site with regards to quality Continuous training of core lab analysts Less than 5% turnover in core lab staff High quality data with minimum inter & intra observer variability Quality assurance and quality control Reproducibility protocols including phantom analysis 15 16. Core laboratory services Supervising cardiologists Supervision of core laboratory activities by experts in the field Cardialysis in-house supervising cardiologists: Dr Hector Garcia-Garcia Consultant interventional cardiologist specialised in invasive cardiovascular imaging Main research topics are intravascular imaging and coronary atherosclerosis Dr Osama Soliman Consultant cardiologist specialised in non-invasive cardiovascular imaging He serves on the editorial board of the Journal of the American Society of Echocardiography Dr Yoshinobu Onuma Consultant interventional cardiologist specialised in invasive cardiovascular imaging Leading expert in the field of bioresorbable scaffolds 16 17. Non-invasive modalities High quality output Echocardiography: CPA, 2D & 3D, TDI, TEE & TTE 12-lead ECG, Holter, Implantable loop recorder & ECG event monitoring Exercise tolerance test: treadmill & stress echo Cardiac Magnetic Resonance Imaging MultiSlice Computed Tomography 17 18. Invasive modalities High quality output Invasive modalities: Angiography Quantitative Coronary Angiography (QCA) Syntax Score (Qualitative Angiography) Bifurcation analysis LV-analysis Quantitative Vessel Analysis (QVA) Invasive modalities: Sound-based modalities Intravascular Ultrasound (IVUS, gray scale) Virtual Histology (VH, Volcano) iMap (Boston Scientific) IVUS Palpography Invasive modalities: Light-based modalities Optical Coherence Tomography (OCT) Near-Infrared Spectroscopy (NIR) 18 19. Core laboratory services AG Mednet for e-transfer A specialized, electronic image data capture (EIDC) and submission network. 21 CFR Part 11 Compliant Fully managed network guarantees delivery of images and ancillary data 500+ global clinical trials since October 2008 in all therapeutic areas 26,000+ users in more than 12,000 investigator sites in 87 countries 80% or better adoption and utilization on average. 100% on many trials Average 75% reduction in queries when compared to all other methods. Experience with all modalities, DICOM and non-DICOM. No file size limitations. 19 20. Core laboratory services Track-Record Since 1983, Cardialysis has provided core lab services for 150+ trials including landmark trials such as, BENESTENT, SYNTAX, LEADERS, ABSORB-STEMI & EUROPA Non-Invasive core lab Cardialysis has extensive experience: Successfully completed >1 million datasets of non-invasive imaging modalities including ECGs, ambulatory monitoring tracings, device ECG, Echo, MRI and MSCT in trials such as, ECHO IRIS, ADVANCE, PROTECT, SOFA, RESPOND, MORE CRT-MPP & HORRACLES Invasive core lab Cardialysis has extensive experience: Successfully completed >1 million datasets of intravascular imaging modalities such as QCA, IVUS, VH and OCT in trials such as, BENESTENT, RAVEL, LEADERS, ABSORB II, RESOLUTE & IBIS II 20 21. Clinical event adjudication FDA perspective: independence is critical 21 22. Clinical event adjudication Save time and costs, easy to use Clinical event adjudication at Cardialysis Large adjudicator network Fully trained to (Cardialysis) procedures Highly configurable web based system Adjudication according to FDA & EMA guidelines & ARC initiatives Advantages sponsor Swift recruitment of event committee Smooth and quick clinical event adjudication processes and work-flow Harmonization and consistency of data review 22 23. Web based event adjudication Efficiency from the web Why choose for web CEC? Whomever Wherever Whatever Rapid response time Advantages to our customers Reduced cost less paperwork, less travelling Client in full control highly configurable system Convenience all documentation on-line, instant adjudication results Teleconference + WebCEC 23 24. Clinical event adjudication Track record Experience in clinical event adjudication services: Total number of CEC activities: 91 trials Current number of CEC activities: 25 trials Largest trial: 6,878 event triggers Global, with emphasis on Europe 24 25. Track record Experience from A to Z in cardiology Cardialysis is currently involved in ~40* trials in various stages Ranging from start-up to finalization Cardialysis has managed >250 trials 50 Pharma trials 200 Device trials Data of >100 trials have been submitted to CA in US, EU and Japan Data of >50 trials have been submitted for gaining CE-mark Experience with DEKRA, TV & BSI *This includes complete trials but also single services for a trial, like core lab or statistical analysis 25 26. Track record Selection of current trials I Transaortic valve implantation 2,500 patients, global Services: protocol, core lab (ECHO & ECG), CEC adjudication & DSMB Hybride surgical ablation 120 patients, Europe Services: monitoring & regulatory submission Bioresorbable scaffold 501 patients, global Services: core lab (OCT, IVUS, MSCT & QCA) & CEC adjudication PCI and DAPT 16,000 patients, global Services: protocol, statistics, data management, monitoring, CEC adjudication, DSMB & core lab Safety & efficacy dose finding trial NOAC 105 patients, Europe Services: Monitoring, data management, CRF, CEC adjudication & DSMB Coronary Artery Disease - Cardiotonic Agent 3,000 patients, global 26 27. Track record Selection of current trials II Risk stratification for ICD implantation 365 patients, Europe Services: monitoring, statistics, protocol, core lab (ECG & ECHO) & data management Heart failure: CRT-D 1,500 patients, global Services: core lab (ECHO, Angio & ECG) Left atrial appendage occlusion 700 patients, Europe Services: CEC adjudication Transaortic valve implantation 1,000 patients, global Services: core lab (ECHO) Bioresorbable Scaffold 190 patients, Europe Services: protocol, statistics, data management, monitoring, CEC adjudication, DSMB & core lab PCI in three-vessel disease (3VD) 450 patients, Europe Services: protocol, statistics, data management, monitoring, CEC adjudication, DSMB & core lab 27 28. Track record Landmark clinical trials I ABSORB (Abbott, Bioresorbable scaffold) Serruys, Lancet 2009;373:897-910 30 patients, 5 sites Europe and New Zealand Services: design, core lab (QCA, IVUS, VH & OCT) & CEC adjudication ABSORB Cohort B (Abbott, Bioresorbable scaffold) Ormiston, Lancet 2008; 371: 899907 Serruys, Lancet 2009; 373: 897910 101 patients, 10 sites Europe and New Zealand Services: core lab (IVUS, VH, OCT, MSCT, Palpography & QCA) APPROACH (GSK, rosiglitazone) Gerstein, Circulation 2010;121:1176-87 672 patients, 92 sites, 19 countries in Europe, US, Asia and South-America Services: core lab (IVUS) BENESTENT (J&J, coronary stent) Serruys, NEJM 1994;331:489-95 520 patients, 28 sites, 9 countries in Europe and South-America Services: design, data management, statistics, Core Lab: QCA, CEC adjudication, monitoring & coordination 28 29. Track record Landmark clinical trials II COMPARE I and II (WESPH, drug eluting stent) Kedhi, Lancet. 2010 Jan 16;375(9710):201-9 Smits, Lancet. 2013 23;381(9867):651-60 Total : 4,500 patients in Europe Services: statistics, CEC adjudication & core lab (Syntax score) EUROPA (Servier, perindopril) Fox, Lancet 2003;362:1-7 13,200 patients, 450 sites, 25 EU countries Services: design, data management, statistics & core Lab (IVUS sub-trial) EXAMINATION (Abbott, bare metal stent & drug eluting stent) Sabate, JACC Cardiovasc Interv. 2014 Jan;7(1):55-63 2,665 pts, 5 sites in Italy and Spain Services: statistics, CRF, data management, CEC adjudication, DSMB & monitoring HELVETICA (Ciba Geigy, hirudin) Serruys, NEJM 1995;333:757-63 1,141 patients, 28 sites, 7 countries in Europe Services: design, core lab (QCA), CEC adjudication & statistics 29 30. Track record Landmark clinical trials III IBIS-2 (GSK, darapladib) Serruys, Circulation 2008;118:1172-82 330 patients, 25 sites, 10 countries in Europe Services: core lab (IVUS, VH & palpography) LEADERS (Biosensors, drug eluting stent) Windecker, Lancet 2008;372:116373 1,707 patients, 10 sites in Europe Services: design, data management, core lab (QCA & Syntax Score), CEC adjudication & statistics LIPS (Novartis, fluvastatine) Serruys, JAMA 2002;287:3215-22 1,677 patients, 77 sites, 10 countries Services: design, data management & statistics PROSPECT - Palpography sub trial (Abbott, stent) Stone, N Engl J Med. 2011 20; 364(3):226-35 350 patients, 40 sites in US and Europe Services: core lab (Palpography) 30 31. Track record Landmark clinical trials IV PURSUIT (Schering-Plough, eptifibatide) Harrington, NEJM 1998;339:436-43 12,500 patients, 351 sites, 18 countries US, Europe and South-America Services: data management & CEC adjudication RAVEL (Cordis, drug eluting stent) Morice, NEJM 2002;346:1173-80 238 patients, 19 sites, 7 countries in Europe and South-America Services: design, data management, core lab (QCA), CEC adjudication & statistics RESOLUTE (Medtronic, drug eluting stent) Serruys, N Engl J Med 2010; 363:136-462 300 patients, 79 sites in Europe Services: protocol, statistics, data management, CEC adjudication & core lab (ECG & QCA) SOFA (WCSF, fish oil) Brouwer, JAMA 2006;295:2613-19 500 patients, 25 sites in Europe Services: data management, monitoring & core lab (ICD & ECG) 31 32. Track record Landmark clinical trials V SYNTAX (Boston Scientific, stent & CABG) Serruys, NEJM 2009;360:961-72 3,075 patients, 86 sites US and Europe Services: design, core lab (QCA & Syntax Score), CEC adjudication & monitoring TWENTE I and II (Dutch Peers, drug eluting stent) Von Birgelen, Lancet. 2014 1; 383(9915):413-23 Von Birgelen, J Am Coll Cardiol. 2012 10; 59(15):1350-61 3,200 patients, 1,000 sites Global Services: CEC adjudication 32 33. Exclusively worked on cardiovascular trials for over 31 years Thought Leader advisory network for trial design in cardiology Integrated cardiovascular core lab and efficient web based CEC system Global reach, covering EU, US, South-America and Australasia One point of contact and full CRO service offering Master Service Agreements with: AtriCure Inc, Abbott Vascular, Boston Scientific, Medtronic, Servier & St Jude Medical Flexible, sponsor focused approach to meet your trial objectives Summary 33