Interactive Technologies

1. Interactive Technologies At the Forefront of IVR & Web Technology for Clinical Studies

2. Menu 2. Service Portfolio 1. Interactive Technologies Overview 3. Drug Management 4. ePro 5. System Delivery & Support 6. Appendix

3. Interactive Technologies Overview « Menu

4. Interactive Technologies Service Portfolio Three Integrated Applications ICOWEB Reporting application that summarizes study data for clients, Investigators and other partners in the trial ICOPHONE Interactive Technologies’ branded IVRS platform. ICOPhone has a dual platform that allows for both IVRS (telephone) or IWRS (web) data access ePro Electronic Patient Reported Outcomes (ePRO) application that allows subjects to enter diary or questionnaire data via the web or telephone « Menu

5. ICON Divisional Structure Central Laboratories Clinical Research Medical Imaging Development Solutions « Menu

6. ICON Clinical Research Structure and Services « Menu

7. Marlow, UK • Project Support • Business Development • Dublin, Ireland • Project Management • Project Support • Chicago, IL • Project Management • Project Support • North Wales, Philadelphia • Project Management • Project Support • Biostatistics • Finance • Business Development and Proposals • Contracts • North Carolina, PA • Project Management • Project Support • Business Development • Houston, Texas (HQ) • Quality Operations • Quality Management • Technical Services • Project Support and Maintenance • Project Management • Help Desk • Quality Assurance • Chennai, India • Project Support and Maintenance • Help Desk • Technical Services Interactive Technologies Operations 300 dedicated staff worldwide « Menu

8. Marlow, UK • Project Support • Business Development • Dublin, Ireland • Project Management • Project Support • Chicago, IL • Project Management • Project Support • North Wales, Philadelphia • Project Management • Project Support • Biostatistics • North Carolina, PA • Project Management • Project Support • Houston, Texas (HQ) • Quality Operations • Quality Management • Technical Services • Project Support and Maintenance • Project Management • Help Desk • Quality Assurance • Chennai, India • Project Support and Maintenance • Help Desk • Technical Services Interactive Technologies Operations 300 dedicated staff worldwide « Menu

9. Marlow, UK • Project Support • Dublin, Ireland • Project Management • Project Support • Chicago, IL • Project Management • Project Support • North Wales, Philadelphia • Project Management • Project Support • Biostatistics • North Carolina, PA • Project Management • Project Support • Houston, Texas (HQ) • Quality Operations • Quality Management • Technical Services • Project Support and Maintenance • Project Management • Help Desk • Quality Assurance • Chennai, India • Project Support and Maintenance • Help Desk • Technical Services Interactive Technologies Operations 300 dedicated staff worldwide « Menu

10. Interactive Technologies: Experience Profile • Client Experience: XX Studies • List therapeutic areas • Total: XXX studies implemented worldwide (300+ active) • - Multi-Lingual Support 65+ languages • - Complex Study Support • - Adaptive Randomization • - Global Trial Support • * (includes Minimization, Biased Coin, Dose Titration, etc.) « Menu

11. Validation Reliability Capacity • Two fully redundant systems • Full data back-up (nightly/7days a week) • Tailored study specific procedures • Full system validation on each project • Routine quality control reports • 21 CFR 11 Compliant • Regularly monitored phone lines • 138 simultaneous calls - <20% capacity • ICOPhone  105,000+ calls monthly System Guarantees « Menu

12. Service Portfolio « Menu

13. System Features and Benefits ICOPhone is ICON Clinical Research’s branded IVR/IWR system « Menu

14. Data Management and Integration • CTMS: IMPACT, TrialWorks, ICOTrial • EDC: Medidata Rave, PhaseForward Inform, OC RDC • Clinical Supply: Fisher, Aptuit, Almac, Catalent, Xerimis • Formats: Text file, XML, ASCII, CDISC, SAS • Methods: sFTP (secured file transfer protocol), Cyclone CTMS EDC Lab Systems « Menu

15. Data Management and Integration • Can integrate directly with other clinical trial applications (CTMS, EDC, Lab Systems, etc.) • Real-time program information across study management tools • Experienced in multiple data transfer formats – e.g., ASCII, XML, SAS, CDISC, etc. • Can transfer any information collected in the IVR system Benefits: « Menu

16. Site Activation Site Deactivation Emergency Unblinding Sponsor- Data Management Commonly Used System Modules: • Benefits: • System provides a simple option for enabling and disabling the sites • Sponsors can modify site parameters through site flags or caps • Sponsors can receive alerts, reports and notifications when events occur « Menu

17. Site – Data Management • Commonly Used System Modules: • Subject Screening • Subject Randomization • Subject Discontinuation • Emergency Unblinding • Subject Resupply promotes Efficiency ensuresSafety • Benefits: • Screening helps determine if subject meet eligibility criteria • Randomization helps maintaining balance in treatment arms while maintaining the blind • Discontinuation helps Sponsors key metrics • Emergency unblinding expedites the Sponsor notification and reporting process easy Access to data « Menu

18. Services Offered – Biostatistics Randomization services List Specification Guidance Drug Supply Management Subject and Pack List Generation Complex and client specific randomization schemes Logistics of how randomization list is used in the IVR Adaptive trial design and logistics of implementation of these complex trial designs Within the (sponsor) team and the technology Bid defense (Business Development) « Menu

19. Services Offered – Biostatistics Dynamic randomization services Presentations and publications for reference Development of dynamic algorithm Development of customized reports Response adaptive randomization services Other randomizations based on what is known at baseline Randomization based on combining information from subject responses (Primary efficacy endpoint) Can be stand alone or covariate baseline hybrid Covariate baseline Known stratification factors Mostly phase II dose ranging studies Consultation on ePRO Which psychometric tool to select How to best capture patient responses electronically « Menu

20. Services Offered – Biostatistics Consultation on ways to facilitate data integration Lab data EDC IVR/IWR services Consultation and design work for specialized statistical data reports on the web Interim analyses Adaptive trial design Consultation on electronic clinical supplies management Customized to protocol and dependant on triggers, expiry, supply availability, number and location of site and stratification « Menu

21. Consultation on designing longitudinal studies Clinical trials or epidemiological studies Knowledge of SAS programming and Data sets  Data Integration Data base structures Client specific randomization EDC and data management Consultation on establishing patient registries Services Offered – Biostatistics « Menu

22. Biostatistics - Randomization List Generation Independent biostatistics team within Interactive Technologies: Interactive Technologies Biostatistician and SAS programmer assigned to every project Support the generation of many subject and pack randomization list designs including: Replacement strategy Re-randomization Multiple stratification factors Multiple drug ratios Latin square « Menu

23. Biostatistics - Randomization List Generation Randomization list specifications captured in separate documents Requirements documents are separate from main system requirements in order to: Capture randomization list requirements in greater detail Maintain the study blind May contain additional logical rules Approval of test and live subject/pack randomization Lists Unblinded statistical services available Approval of test and live randomization lists Approval of list generation documentation Confirmation of successful IVR system load « Menu

24. Biostatistics – Adaptive Randomization • Statistical consultation is available for the management of mis-randomizations that have a higher consequence in an adaptive randomization. • ICON’s service regarding adaptive randomization also includes the development of customized web reports, available in real time to unblinded staff members. These three customized web reports: • Track the randomization events for individual subjects • Show the cumulative balance within strata by treatment groups • Show the impact of special cases on the randomizations « Menu

25. Biostatistics – Adaptive Randomization • Eva Miller, Ph.D., Director, Biostatistics, Interactive Technologies, works with the project statistician to delineate the adaptive randomization algorithm in scientific terms such that the algorithm can be appended to the protocol. • The specification of the adaptive randomization algorithm must meet regulatory standards of replicability: • given a particular set of randomization counts, a probability value, and the logic of the algorithm, there can be one and only one treatment assignment per subject. • Following the algorithm specification, the client can provide simulations for “black box” testing or ICON Clinical Research can provide simulations for the client statistician’s review. « Menu

26. Drug Management « Menu

27. Drug Supply Management • System Modules and Capabilities: • Automated drug ordering • Replace Kit Module • Resupply Expiration Tracking • Visit Projection • Inventory Tracking • Benefits: • Comprehensive Inventory Management • Allows for a study to start with a minimum of packaged drug « Menu

28. Drug Supply Management System selects the appropriate kit based on site inventory and study randomization scheme System sends resupply drug order to depot to resupply dispensed kits Study Coordinator calls System for subject resupply visit Sponsor can monitor site and study levels via alerts and web reports « Menu

29. Drug Management Goal • ICON’s typical drug management scheme utilizes an algorithm that is successful in: • Minimizing the number of shipments created • Minimizing amount of drug wastage « Menu

30. Site Drug Management Scheme – Visit Schedule • A pre-defined visit schedule is needed for each treatment arm • User defines visit schedule • Expected visit day is defined for each visit • System uses visit schedule to ‘project’ when drug is needed at the site for each patient • Flexible enough for titrations • Start and Stop Visits are configurable within the system • Start visit: when projection starts for a subject i.e. enrollment or randomization visit • Stop visit: when project ends for a subject. « Menu

31. Site Drug Management Scheme – Short Window / Projected Need • Short Window • timeframe used to determine the number of each kit type that will be allocated to active subjects at the site, that is to be included in the calculation of the Projected Need • Used to identify ‘if’ a shipment needs to be sent • Flag driven and defined in User Requirements • Projected Need for each kit type • [(# of kits needed for each active subject to be supplied at all visits within the short projection window + trigger level value) - (# kits in transit + # kits available at the site + # kits pending at the site)] • If projected need for any kit type >/= 0 then shipment needs to be generated « Menu

32. Site Drug Management Scheme – Long Window / Quantity to Ship 2. Long Window • timeframe used to determine the number of each kit type that will be allocated to active subjects at the site, that is to be included in the calculation of the Quantity to Ship • Used to identify how much to send in a shipment • Flag driven and found in User Requirements • Quantity to Ship • Identified for each kit type • [(# of kits needed for each active subject to be supplied at all visits within the LONG projection window + ‘RESUPPLY up to’ value) - (# kits in transit + # kits available at the site + # kits pending at the site) ] « Menu

33. Site Drug Management Scheme – Short Window / Projected Need • Projected Need for each kit type Short Window • Timeframe used to determine the number of each kit type that will be allocated to active subjects at the site, that is to be included in the calculation of the Projected Need • Used to identify ‘if’ a shipment needs to be sent • Flag driven and defined in User Requirements • [(# of kits needed for each active subject to be supplied at all visits within the short projection window + trigger level value) - (# kits in transit + # kits available at the site + # kits pending at the site)] • If projected need for any kit type >/= 0 then shipment needs to be generated Phase II: « Menu

34. Site Drug Management Scheme – Long Window / Quantity to Ship Quantity to Ship Long Window • Timeframe used to determine the number of each kit type that will be allocated to active subjects at the site, that is to be included in the calculation of the Quantity to Ship • Used to identify how much to send in a shipment • Flag driven and found in User Requirements • [(# of Identified for each kit type • [(# of kits needed for each active subject to be supplied at all visits within the LONG projection window + ‘RESUPPLY up to’ value) - (# kits in transit + # kits available at the site + # kits pending at the site) ] Phase II: « Menu

35. Site Drug Management Scheme – Long Window / Quantity to Ship 2. Long Window • timeframe used to determine the number of each kit type that will be allocated to active subjects at the site, that is to be included in the calculation of the Quantity to Ship • Used to identify how much to send in a shipment • Flag driven and found in User Requirements • Quantity to Ship • Identified for each kit type • [(# of kits needed for each active subject to be supplied at all visits within the LONG projection window + ‘RESUPPLY up to’ value) - (# kits in transit + # kits available at the site + # kits pending at the site) ] « Menu

36. Depot Drug Management • Most xxx (Client Specific) studies include: • a depot to depot shipment request IWR module. • Drug can only be moved from a main depot to a sub depot • Ability to handle depot to depot drug management via trigger and re-supply values • Values are flag driven and can be updated. « Menu

37. ePRO « Menu

38. Subject Data Management (ePro) • Benefits: • Eliminates data entry costs • Increases subject compliance • Reminder calls & alerts • Higher data quality • Can be delivered via IVRS / IWRS • Supports Multiple Languages What is ePro? ICON’s proprietary electronic patient reported outcomes (ePRO) application ePro stores data in database Sponsors can receive alerts or can view data via reports in real time Subject enters diary into application « Menu

39. ePro Logic • Eligibility calculations • Ability to determine if/when a patient should advance (screening => randomization) • Adaptive branching • Ability to ask different questions based on patient responses • Forced order • Patient must answer each question before continuing « Menu

40. ePro Benefits • Reduces time & cost of data entry (forces data entry confirmation) • Increased patient compliance • Increased data quality • No paper or device for patients to lose • System can enforce time window improving accuracy of data « Menu

41. System Demonstration Access Details • Phone: 800-594-4977 • Web: icophone.iconplc.com • Demo User ID: 10000 • Demo Pin: 9999 « Menu

42. ICOWeb - System Reports Standard Reports • Study at a Glance • Shipment History • Site Inventory • Visit Summary • Site Status • Depot Inventory • Screening • Enrollment/Randomization • Discontinuation • Web-based, Real-time • Ability to be exported to Excel, data filtered • Standard and custom reports available Reporting « Menu

43. System Delivery and Support « Menu

44. 4 WEEKS 4 WEEKS 2-3 WEEKS +1 WEEK UAT TESTING 1 WEEK INTERACTIVE TECHNOLOGIES Phase 1 Business Development BD Gate Plan Gate Phase 2 Planning Phase 3 Development Dev Gate Phase 4 Validation SOL Gate Phase 5 Installation Phase 6 Maintenance Retire Gate System Delivery Lifecycle Phase 7 Retirement « Menu

45. Estimated Timelines « Menu

46. Group Manager Project Implementation Client Manager Business Analyst Assistant Project Manager Technical Analyst Validation Specialist Programmer/ Developer Project Team Structure – Development Phase Vice President Project Operations Project Manager Project Implementation « Menu

47. Group Manager Project Support Client Manager Project Lead (if applicable) Call Center Project Support Analyst(s) Project Team Structure – Maintenance Phase Vice President Project Operations Project Manager Support Services « Menu

48. Communication Path Business Development Vice President Global Data & Technical Services Vice President Project Operations Client Management Group Manager Project Manager « Menu

49. User Acceptance Testing (UAT) • System will be made available for testing prior to implementation • Testing will be supported by the project team • Changes and/or defects are reported, tracked and corrected • Upon acceptance, system is formally validated and installed « Menu

50. System Support: Call Center / Help Desk • Available 24/7/365 • Staffed by ICON employees • E-mail access & toll-free phone • Direct access from system by pressing “0” • 140 languages supported • Trained on technical components of system per protocol • Calls routinely reviewed for quality • Data change procedures « Menu