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The Medidata Platform

Protocol Representation Model (PRM) in the Real WorldRichard Young | Director, EMEAMonday, 17th December, 2012Optimizing Clinical Trials:Concept to Conclusion 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMPer Patient Costs USD ($)Pharmalot, reporting data from Cutting Edge Informatics, 26 Jul 2011 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMChallenges of Clinical DevelopmentStruggle to adapt to emerging world of genomic-based drugs# 2011 Medidata Solutions, Inc. 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMAdd examples of systems utilised......100-160 in DM, Clinical and Stats3From Data to IntelligenceConfidence in DECISIONTime / ResourceRAW DataCLEAN DataStandard ReportsAd hoc ReportsWhat Happened ?Why ?What Will Happen ?Best Outcome ?EXPLOREPREDICTOPTIMISE 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMAdaptive Trials- might increase the information value per $$ investment (in a resource constrained environment)- are an enabler fora) team-building (discovery, clinical, biostatistics, IT, regulatory, project management, clinical operations, marketing) andb) earlier and better planning, decision-makingc) simulation guided clinical drug development4Protocol Representation ModelCDISC has a standard model for the protocolProtocol Representation Model (PRM)The PRM was developed to Support the generation of a protocol document, Support research study (clinical trial) registration and tracking, Support regulatory needs, Facilitate single-sourced, downstream electronic consumption of the protocol contentIn SIMPLE terms, PRM enables us toDefine the core clinical componentsDefine the relationship between the components# 2011 Medidata Solutions, Inc. 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TM

# 2011 Medidata Solutions, Inc. 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMSummary of Study Design (EXAMPLE)This is a prospective, randomized, double-blind, double-dummy, placebo controlled, forced-titration, multicenter, parallel group trial. Stage I or II hypertensive patients, age 18 years of age or older, who meet all other inclusion and exclusion criteria and successfully complete the placebo run-in period will be randomized at the site level.Protocol Representation Model# 2011 Medidata Solutions, Inc. 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMAs researchers know, the protocol, in terms of a clinical research study, is the plan, or blueprint, that describes the studys objectives, methodology, statistical considerations, and the organization of the study. Much in the way that an effective business plan lays out the foundation for what is expected in beginning a successful enterprise, a well-designed protocol is the map that is vital to the overall success of a clinical trial or study. Everyone involved in the research study needs the protocol; this includes but is not limited to the investigator, the site personnel, the clinical project managers and monitors, the data managers, and the statisticians. Additionally, the protocol is a requirement by regulatory authorities for regulated clinical research studies. A fully developed clinical protocol is essential for regulatory purposes including Investigational New Drug (IND) applications, Institutional Review Boards (IRB) and Ethics Committees.7Summary of Study Design (EXAMPLE)This is a prospective, randomized, double-blind, double-dummy, placebo controlled, forced-titration, multicenter, parallel group trial. Stage I or II hypertensive patients, age 18 years of age or older, who meet all other inclusion and exclusion criteria and successfully complete the placebo run-in period will be randomized at the site level.Protocol Representation ModelSubject age descriptionConfigurationDegree of blindPopulation disease description# 2011 Medidata Solutions, Inc. 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMSTANDARD CONCEPTS8Meta Information about ContentContentSubject age descriptionAge 18 years of age or olderConfiguration

Parallel group trial

Population disease descriptionStage I or II hypertensive patientsDegree of blind

Double-blind

Protocol Representation Model# 2011 Medidata Solutions, Inc. 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMSTRUCTURED CONCEPTS9

Protocol Representation Model# 2011 Medidata Solutions, Inc. 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMProtocol Representation Model# 2011 Medidata Solutions, Inc. 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TM11A New World..........Results:Simplify protocolsReduce number of procedures and cost per patientReduce effort setting up downstream systemsEliminate effort associated with cleaning and analyzing excess dataAvoid amendments/reworkReduce cycle time (creation and review of clincial deliverables)Reduce duplicate data entry, reformatting and rewriting of informationPeople/Behaviours:Process:Technology:More disciplined approachWillingness to seek peer feedbackBusiness acumen - ability to assess trade-offs bertween time cost value & riskFocus on outcomes & audience (start with the end in mind, consider consumers)Shift from study level to project level planningPlan -> Design -> DocumentLeverage project level informationApply study specific informationGenerate clinical deliverablesStreamline review & approvalElectronic study design tool (inc. content management capabilities and publishing templates)Integration with upstream planning and study registration solutionsdownstream data collection solutionsbenchmarking data and clinical standards

Shift from clinical document management to information managementIncrease the quality and consistency of clinical informationAlign objectives, endpoints and proceduresStrategy/Goal:Demonstrate traceability from strategy to plan to study designSupport parallel development of Protocol, RAP, eCRF and CSR Leverage industry benchmarks

2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TM69% of all protocols have at least one amendment

46% of all amendments occur BEFORE first patient first dose

37% are considered somewhat or completely avoidable

Adds 61-days and cost $450,000+ to implement each amendment12A New World Realised

PRM 2011 Medidata Solutions, Inc. Proprietary and Confidential 2012 Medidata Solutions, Inc. Proprietary and Confidential#Optimizing Clinical Trials: Concept to Conclusion TMThe Typical Protocol in 2012Average of 13 endpoints 1 primary and 5 key secondary

Median of 170 total procedures85 procedures support primary and key secondary endpoints

Median 50 inclusion and exclusion criteria and 180+ case report form pages

Requires study volunteers to make 11 visits over an average of 175 days14Source: Tufts CSDD, 2012 Mean Number of Data Points Collected per Study15Source: Medidata Solutions Worldwide, 2012 Rising Protocol Complexity and Burden (All TAs, All Phases)00 0304-07 08-11Unique procedures per protocol (median)20.528.230.4Total procedures per protocol (median)105.9158.1166.6Total investigative site work burden (median units)28.944.647.5Total eligibility criteria3149N/AMedian study duration in days140154175Median number of CRF pages per protocol55180N/A16Getz, Campo, Kaitin. Variability in Protocol Design Complexity by Phase and Therapeutic Area. DIJ 2011 45(4); 413-420.Source: Tufts CSDD Ongoing shift from acute to chronic diseasesPipeline composition shift from traditional NCEs to biologicsFocus on doing more in earlier development phasesPhase IV becoming more robust and sophisticatedGrowing requirements from purchasers and payersHabit and legacy protocol templates and authoring practicesRisk mitigation/risk avoidancePrimary Drivers of Protocol Complexity1717IMPACT: Trial Performance (All TAs, Phases II-III)Less ComplexMore ComplexDifferenceStudy volunteer screen to completion rate52%23%Half as EffectiveTime from Protocol Ready to FPFV(median)115 days129 days+12%Time from Protocol Ready to LPLV (median)413 days714 days+73%Number of Amendments1.93.2+68%Source: Tufts CSDDGetz, Wenger, Campo et al. Assessing the Impact of Protocol Design Change on Clinical Trial Performance. AJT 2008 15(5); 450 - 457

18IMPACT: Amendment Prevalence

19Note: All values are means

*Analysis excludes protocols without any amendments

Protocol PhaseNumber ofAmendments*Number of Changesper AmendmentPhase I2.05.6Phase II2.66.8Phase III3.68.5Phase IIIb/IV2.38.3ALL PROTOCOLS2.46.946% of all amendments

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