Risk-based Monitoring Strategies For Improved Clinical .

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Risk-based MonitoringStrategies for ImprovedClinical Trial PerformanceTo address draft regulatory guidance for risk-basedclinical trial monitoring, sponsors should considerstrategies that utilize social, mobile, analytics and cloudtechnologies to create responsive methodologies thatsatisfy both the spirit and letter of these new guidelines. FUTURE OF WORK

Executive SummaryGlobal regulatory agencies require sponsors to overseetheir clinical trials and ensure proper monitoring of theinvestigation. Sponsors need both infrastructure and processesto protect the safety of their research subjects and ensure trialdata integrity. In 2011, both the Food and Drug Administration(FDA) and the European Medicines Agency (EMA) releaseddraft guidance for the conduct of risk-based monitoring toassist sponsors in better meeting their regulatory obligations.While these guidelines provided the regulatory perspectiveand rationale for risk-based monitoring strategies, they did notmandate specific methodologies for implementation.1-5 The lackof an industry-based precedent regarding trial effectiveness— and the unknown impact of risk-based monitoringmethodologies — pose stiff challenges for sponsors, whomust implement well-articulated and documented risk-basedmonitoring solutions.Traditional systems for managing clinical trials typically includea combination of software and paper-based processes intendedfor a variety of purposes, including project managementand milestone tracking; safety/pharmacovigilance reportingand tracking; document management; trial master filemaintenance; and electronic data capture and querymanagement. In these systems, data from disparaterepositories are not integrated into alerts that prompt usersto take risk-mitigating action in the manner prescribed by theguidance. Information is tracked within these separate systemsand made available to users through disconnected, preprogrammed status reports. The lack of technology enablersand heavy reliance on manual tracking to analyze disparatedata are among the major obstacles that sponsors face asthey determine how to create risk-based monitoring strategies,using only their existing infrastructure and technology assets.A new platform is needed to accelerate the gathering andunderstanding of clinical trial data. Risk mitigation strategies2FUTURE OF WORKJune 2013

have little value unless they are executed, monitored andanalyzed continuously throughout the trial’s lifecycle.Sponsors and their global project teams need a comprehensiveand compliant solution, one that allows trial oversight throughreal-time proactive risk assessment. Rather than mirroringdata from static repositories on a standard tracking interfaceor report, project teams need automated, smart logic-basedworkflows, alerts, escalations and audit trails to identify issuesand provide consistent and traceable “actionable outcomes” toreduce risk and improve overall quality and compliance.The availability of real-time, continuously analyzed data andconfigured workflows greatly reduces, or even eliminates,the potential for individual bias in issue management anddecision-making. Team members are not relegated to their own– and possibly flawed — interpretations of the issues, therebynegatively impacting the compliance and quality of the study.The key to efficiently enabling risk-based monitoring isensuring a continuous flow of study and site data, combinedwith analytics, which are then monitored for trends to informRISK-BASED MONITORING STRATEGIES FOR IMPROVED CLINICAL TRIAL PERFORMANCE3

real-time decision-making. With cloud-based and real-timeaccess to actionable risk and performance indicators through aprivate infrastructure available via the Internet, global projectteams would have complete visibility to critical information,analytics and associated workflows, providing clinical trialsponsors with a consistent method to evaluate, manage andmitigate risk.This is a key differentiator from traditional clinicalmanagement and reporting systems currently in use. Havingthis capability allows clinical trial sponsors to focus mitigationefforts on the issues representing the greatest risk to researchsubjects and the study. Real-time data consolidation also helpsalleviate the burden for staff members that currently rely oninadequate and inefficient manual processes to create andmaintain a meaningful compliance posture.The key to efficiently enabling risk-based monitoringis ensuring a continuous flow of study and site data,combined with analytics, which are then monitored fortrends to inform real-time decision-making.The current regulatory climate presents unique opportunitiesfor leveraging technology to meet both the letter of theregulations and the intent of the recent draft guidance. Thiswhite paper explores how new technologies, proprietarysoftware and well-articulated and documented algorithms canbe integrated with existing software systems used in clinicaltrials to create an operational environment that enablessponsors to increase regulatory compliance and the overallefficiency of their trials.4FUTURE OF WORKJune 2013


A Brief Historical PerspectiveLet’s take a moment to examine how and why we arrived here. Although someacademic centers and government organizations, such as the National Institutesof Health (NIH), have conducted successful outcome studies without the use ofextensive on-site monitoring, the pharmaceuticals industry has not followed thispath.6 The industry’s long-standing practice and perception is that the gold standardfor meeting regulatory monitoring obligations is frequent onsite monitoring visits,i.e., 100% source data verification (SDV) with regularly scheduled monitoring visits.7The perception of “more is better” persists even amid growing concerns thaton-site monitoring practices are inadequate to ensure patient safety and dataquality. Besides being labor and resource intensive, such monitoring practices areinherently reactive and retrospective in regards to error detection. Because of this,risks to subjects can be missed or responded to in an untimely manner. The lag timein responding to deviations or significant risks that occur in the trial depends, inpart, on the timing of the issue in the monitoring cycle.Note that the converse is also true; that is, a disproportionately high level of oversightcan be expended for relatively low-risk situations. Interestingly, the 2009 ClinicalTrials Transformation Initiative (CTTI) survey showed that while most respondentsutilized centrally available data (meaning data gathered off-site) to evaluate siteperformance, only a small percentage typically used centralized monitoring toreplace on-site visits.8 The FDA believes that targeted risk-based approaches thatfocus on the most critical data elements will result in more effective monitoring andhelp to overcome many of the limitations of on-site monitoring.9Draft Guidance on Risk-based MonitoringEuropean Medicines Agency ReflectionsThe EMA suggests that sponsors take a quantitative approach to the issue andascribe numeric values to specific risks identified in the protocol (both high and lowrisks). When acceptable tolerance limits are surpassed, the appropriate monitoringescalation is triggered, (e.g., additional on-site visits). However, if a deviation fallswithin the set tolerance range, then it may be considered an “expected deviation”per the monitoring plan for the protocol.The EMA states that tolerances/range limits should be defined early and documentedin a monitoring plan. For those variables that are important to the trial objectives,the plan could include more emphasis on central monitoring, quality assurance andtargeted SDV.10 The EMA guidance exists within the framework of the Clinical TrialsDirective and accommodates a range of risk-adapted approaches that will simplifyclinical trial processes.11Food and Drug Administration PerspectiveThe FDA draft guidance shares many of the central tenets of the EMA’s reflectionpaper, including the requirement for sponsors to do the following:6FUTURE OF WORKJune 2013 Use a variety of approaches to fulfill their responsibilities related to monitoringinvestigator conduct and the progress of investigational drug and deviceexemption studies. Conduct a risk assessment to identify and evaluate risks critical to studying dataand processes.

Design a monitoring plan tailored to address the important and likely risksidentified during the risk assessment (including remote, targeted and reducedSDV).12, 13The guidance highlights the importance of documenting the monitoring plan afterassessing the project risks and needs. It also recommends that sponsors analyzeongoing data to continuously assess and adjust the monitoring strategy.14 This isa vastly different approach from the traditional method of prospectively planningmonitoring visits at regulator intervals, regardless of therapeutic area, trial phaseor trial complexity.Both the FDA and EMA encourage sponsors to adopt strategies that reflect arisk-based monitoring approach using a combination of monitoring strategies andactivities. The approach should include a greater reliance on centralized monitoring,a sharp focus on critical study parameters (such as those specific to the safety andprotection of human subjects) and a plan to address data integrity risks.15-18The Way ForwardSo, how do we get there from here? Industry sponsors must proactively and prospectively embrace risk-based monitoring, relying on the regulatory thinking andresearch presented in the guidance documents, as well as their previous experiencewith traditional monitoring methods. Sponsors are left to determine the appropriate strategies based on their own assessment of their operational and patientsafety risks.Sponsors entered the millennium armed with various IT systems that produce andstore data in segregated silos, providing users with little useful real-time intelligence or holistic understanding relative to data that resides in other silos andrepositories (see Figure 1). The result: Despite collecting tremendous amounts ofdata, stakeholders cannot necessarily identify unfavorable trends, potential risksor safety issues. Thus, they need a component or capability that consolidates datacontinuously and automatically, to fully integrate data from disparate systems andmaximize their investment in existing infrastructure and technology assets.Systems of Record Information FlowInformationfrom Client Systems ofin a TypicalClinicalFlowTrialRecord in a Typical Clinical TrialBUSINESS INTELLIGENCE LAYER NEEDEDSAFETY/PVGTMFEDCCTMSFigure 1RISK-BASED MONITORING STRATEGIES FOR IMPROVED CLINICAL TRIAL PERFORMANCE7

Given the myriad of hardware- and software-based systems, data repositories andprocesses that already exist, the challenge will be to integrate data streams intocohesive intelligence that enables stakeholders to make better and more timelydecisions. It is critical that the chosen methodologies are transparent and that thedecision process is fully documented and defined. Sponsors should be able to demonstrate that these processes are consistently followed by key stakeholders whoare experienced and authorized to make these decisions.Social, Mobile, Analytics and CloudThe release of these draft regulatory guidance documents in 2011 coincided with animportant juncture in the evolution of corporate IT. The next master architecturefor enterprise IT is based on social, mobile, analytics and cloud technologies, or theSMAC Stack (see Figure 2). The constancy of these technologies in a wide array ofconsumer-facing markets, including the historically conservative banking industry,has laid the foundation for a new master corporate IT architecture to enter theenterprise world.19Key to successful utilization of SMAC technologies is holistic deployment. In combination, the four components exert a multiplier effect (e.g., mobile inputs drivingreal-time analytics) that can serve as the foundation for breakthrough businessresults. In our view, the SMAC Stack will drive exponential growth in both computingdevices and data. According to estimates, by 2020, up to 100 billion devices will beconnected to the Web, and corporations will be managing 50 times the data thatthey deal with today.20 The pharma companies that will be best positioned to meetrisk-based monitoring guidance, as well as conduct efficient and compliant trials,are those that can reduce reliance on on-site monitoring and maximize use of collaboration, communication and predictive analytic capabilities.Catching the Fifth Wave of Corporate ITBusinessProductivitySMAC stackstacSMAC2012-?IInternetnternet bute 76-1991976-1992TimeFigure 28FUTURE OF WORKJune 2012

A critical success factor is tying SMAC technologies to key core knowledgeprocesses; that is, putting processes rather than technology first, and then maintaining focus on the most important constituents.21 Technology for the sake oftechnology will not win the day. Pharma companies need to understand whichprocesses are necessary and ensure that the required knowledge base is infusedinto those defined processes. This is very much in keeping with the philosophy ofrisk quantification espoused in the draft guidance documents.A critical success factor is tying SMAC technologiesto key core knowledge processes; that is, puttingprocesses rather than technology first, and thenmaintaining focus on the most important constituents.The Solution: Cloud-Enabled Collaboration,Predictive AnalyticsWe have developed a private cloud-based, hosted performance managementplatform that provides efficient and active oversight of sponsor companies’ clinicaltrial portfolios (see Figure 3). It does this by monitoring study and site performanceusing collaboration and predictive analytic capabilities