Embracing Risk in Clinical Trial Monitoring James Streeter Senior Director Life Sciences Product Strategy HSGBU October 2, 2014 Copyright © 2014, Oracle and/or its affiliates. All rights reserved. |

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Copyright © 2014, Oracle and/or its affiliates. All rights reserved. |4 Strategy Life Sciences Healthcare Convergence Accelerate clinical development Support entire drug safety lifecycle Enable clinical data aggregation Power enterprise healthcare analytics Enable provider/payer integration Drive personalized medicine Intersection of clinical trials and clinical care Develop collaboration networks for providers and life sciences companies

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. |5 Oracle delivers advanced transformative value for clinical R&D in a modular, integrated and scalable cloud environment and helps you: Clinical Research and Development Solutions Delivering End-to-End Value Optimize Operations With technology that helps you maximize efficiency across your clinical life cycle Innovate By incorporating genomics, biomarkers and real-world patient data Future-Proof your Business With a platform that evolves and grows with you and the industry Gain Actionable Insights From aggregated clinical and healthcare data

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Risk Based Monitoring Embracing Risk in Clinical Trial Monitoring – Current state of risk-based monitoring – Why sponsors and CRO’s are shifting to comprehensive, real-time analytics – Integrated with trial management Mobility Data from any standards-based EDC system – The technology backbone to effectively conduct a strategic risk-based monitoring program. – KRI’s – Limitations of current eClinical technology – Challenges – Summary

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Risk Based Monitoring Why Monitoring is required? –Patient safety –Eligible patient enrollment –Protocol compliance –Accurate data collection Paradigm shift…a more targeted, centralized, and risk-based approach to Monitoring –Improve resource efficiency –Increase quality of trial conduct and data collected –Maintain or reduce study timelines –Reduce overall study costs An industry that has been risk adverse

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Key Drivers for RSDV through technology – Only 2.4% of critical data is queried on average – Quality focus Site and data Increasing safety – Streamlining drug development Getting more drugs to market to help patients – R&D pipeline Reducing risk for financial investment 10 to 40% cost savings needed over the next 3 to 5 years – Travel cost – Resource cost – Site time

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | RSDV Industry Investments CRO’s and sponsors investing millions to implement RSDV – Standardizing data and processes – Creating KRI’s Operational focused Infancy in what is working and what is not. – Introducing new business process and change management Business Intelligence (BI)tools – Integrating systems and data – platform approach Next focus – Focus on data quality algorithms, not just operational data – Business process management tools – Artificial intelligence

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Industry Initiatives Regulatory drivers – FDA, MHRA, EMA Guidance document on eSource Data Collection Oversight of Clinical Investigation – A Risk-Based Approach to Monitoring Clinical Trials Transformation Initiative (CTTI) – Quality by design (QbD) Transcelerate – Building QbD into trials – Early and ongoing risk assessment – Focus on critical processes and d – Use of risk Indicators through trial

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Risk Based Monitoring Platform from a Technology / platform perspective (Current) Analytic Systems CTMS Monitoring (if separate from CTMS) Paper, EDC / IVRS CDM eTMF Safety / Surveillance Systems

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Risk-Based Monitoring Oracle’s Multi-System Holistic Approach Siebel CTMS Suite Integration & Open Interfaces External 3 rd Party Data, Programs InForm Argus OC/RDC Life Sciences Data Hub Empirica StudyEmpirica TopicsRisk Analysis Argus AnalyticsClinical Development Analytics Customer PortalMobile CRA Clinical Dashboards & Reports ClearTrial Provide continuous monitoring of study and site data Support multiple methodologies for streamlining site monitoring through targeted SDV Single global safety repository ensuring risk monitoring of subject safety Access to historical quantitative and qualitative site and investigator performance; Lower costs leveraging Oracle’s pre- built integrations and open interfaces to enable RBM Plans Extensibility to incorporate data and programs from customer applications in the clinical ecosystem (e.g. EDC, CTMS, Lab, ePro, eTMF, etc.) Over 80% OOTB coverage of risk indicators identified in TransCelerate position paper Incorporating customer specific systems and processes via open interfaces Enabling real-time access to actionable insights for decision making through Mobility Upfront risk based trial planning via ClearTrial

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Siebel CTMS Suite Integration & Open Interfaces External 3 rd Party Data, Programs InForm Argus OC/RDC Life Sciences Data Hub Empirica StudyEmpirica TopicsRisk Analysis Argus AnalyticsClinical Development Analytics Customer PortalMobile CRA Clinical Dashboards & Reports ClearTrial Risk-Based Monitoring Oracle’s Multi-System Holistic Approach Provide continuous monitoring of study and site data Support multiple methodologies for streamlining site monitoring through targeted SDV Single global safety repository ensuring risk monitoring of subject safety Access to historical quantitative and qualitative site and investigator performance; Drive down costs leveraging Oracle’s pre-built integrations and open interfaces to enable RBM Plans Extensibility to incorporate data and programs from customer applications in the clinical ecosystem (e.g. EDC, CTMS, Lab, ePro, eTMF, etc.) Over 80% OOTB coverage of risk indicators identified in TransCelerate position paper Incorporating customer specific systems and processes via open interfaces Enabling real-time access to actionable insights for decision making through Mobility Upfront risk based trial planning via ClearTrial GOAL: Enable Life Sciences customers to deploy Centralized and Risk Based Monitor Strategies By leveraging existing investments and Oracle technology to drive down costs While ensuring data integrity, subject safety and compliance

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Risk Based Monitoring stages Planning – Identify, plan, and prioritize risk of studying the investigational product. Design – Define protocol eligibility criteria, efficacy, and safety risk factors during design; for inclusion in the eCRF edit build, as well as define key protocol deviations anticipated for study. Execution: – Clear direction in the oversight and monitoring of parameters leading up to study endpoints, integrated study level monitoring plan, clear direction on evaluating fraud. Analysis: – Clear definition of data measurement and reporting, defined elements of statistical analysis of protocol endpoints, safety, etc. Disclosure – Publish outcome data, bringing all the above together in the clinical study report (CSR).

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Risk Assessments of investigators, site staff, and sites are key Protocol, a comprehensive risk assessment is essential to ensuring your risk based – Identify the risk factors unique to the investigational product, the program and the protocol. – Define a risk based strategy, Identify the key data, Appropriate performance thresholds, Determine the appropriate monitoring levels for a specific protocol. – Risks of the trial only solves part of the equation. The risks of each individual site. Comprehensive risk assessment that focuses on site risk factors, Set each site up for success by defining a focused risk mitigation strategy. – Benefits of a risk assessment that includes the evaluation of each site improving site selection by stratifying sites based on key risk factors; establishing early mitigation plans for sites with higher risk; determining a site-specific monitoring level (prior to the study start) that is based on actual data; and assigning monitors and site managers appropriately, based on site risk.

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Access to Data We need data at it’s point of origin, original source. – This allows for real time analysis – Still using manual/paper/independent collection rather than central sources for collections – Sites are beginning to have their own EMR, so need ways to communicate with their EMR Collect on a central device that can be attached to their EMR and viewed by CRA remotely Access to their EMR – however, there EMR may not capture data in the form as specifically as we require

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Protocol Deviations Data Entry & Approval Data Cleanliness Follow Up Items Site Visit Frequency Screen Failure Rate Subject Withdrawal Rate TMF Compliance Clinical Supplies SDV Enrollment Rate Subject Visits Out of Window Visit Report Contents Historical Clinical Data Risk Categories & Key risk Indicators SAEs Current Clinical Data Historical Site Performance Historical Investigator Performance

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Key Risk Indicators – Must be in real time – Must be predictive, reliable and sensitive – Must be able to trend over time – Must be able to use data gathered within the study (rates, means, Standard Deviations) until established thresholds can be determined – Thresholds may need to be customized by indication, therapeutic area or study phase – Need to examine source of that data for reliability Deviations self-reported by site not reliable Deviations captured by CRA’s while onsite not in real time or predictive – Need to be able to tap into historical data (site performance on other studies, similar studies, etc)

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | New and Changing Roles Remote/Centralized CRA – Monitors data across sites/subjects – Compares sites or subjects to other sites or subjects – May communicate through onsite CRA or may be primary site contact Data Analyst – Monitors data across the study or a program – Compares study against other studies or subjects against other subjects – Fraud detection – Communication passes through PM or CTM to CRA or site Blurring/Overlapping of Roles – DM and CRA – PVG and CRA

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Challenges to be expected Introduction of data with new risks – EMR and Patient devices Introducing historic data outside of clinical studies Lack of agreement between clients and vendors on the sharing of data – as a result of multiple service providers This isn’t just about data, but about process and roles which are different company to company As a result sharing data means putting differentiators at risk, particularly for vendors Revenue shift in service providers

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | Risk-Based Monitoring Coverage Oracle’s Platform Approach Risk-Based Monitoring by Application OC/RDC & InForm or 3 rd Party OC/RDC & InForm or 3 rd Party Applications Presentation Ad Hoc Analysis Proactive Alerts MS Office Integration Interactive Dashboards iPhone / iPad Integration OBI-EE Clinical Development Analytics Clinical Development Analytics Argus Safety Or 3 rd Party Safety Argus Safety Or 3 rd Party Safety Siebel Clinical Or 3 rd Party CTMS Siebel Clinical Or 3 rd Party CTMS Mobile CRA Emperica Inspections Emperica Inspections

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | TransCelerate Risk Based Monitoring White Paper Solutions supporting Risk-Based Monitoring Today – InForm, CTMS, Mobile CRA, Clinical Development Analytics, Argus Safety, Empirica, Argus Analytics Solutions with Risk-Based Monitoring Features Planned – OC/RDC, CTMS, Clinical Development Analytics, Trial Analyzer Coverage of TransCelerate’s Risk-Based Monitoring Methodology by Oracle Solutions – Over 90% coverage of risk indicators identified in position paper with functionality and metrics found out-of-the-box in Oracle’s Analytics solutions Clinical Development Analytics Argus Analytics – Additional or custom indicators can be easily added to the CDA Warehouse and/or Dashboard Overview of Oracle Coverage

Copyright © 2014, Oracle and/or its affiliates. All rights reserved. | RBM Summary Risk based monitoring is in its infancy Regulatory agency are key supporter Investments in RBM will continue, standardization is key Key Stages- Planning, Design, Execution, Analysis, and Disclosure Process and change management investments New and changing role Real time and historical data access is key Platform approach is required There will be challenges

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