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Research Development & Clinical Trials oversight of patient safety and data quality. The building blocks of a strategic data-monitoring plan are targeted and triggered monitoring strategies. Targeted monitoring may involve various techniques, such as continuous, fixed, and random sampling methodology. This strategy includes a reduced SDV approach that is aligned to critical data, patient visits or selected patients, depending on the risk-benefit profile of the trial. Triggered monitoring supports an added level of risk management by predefining triggers for planned or additional on-site and off-site attention. These triggers are event-based around data volume and data quality and determined by thresholds of accumulative work and/ or quality. To maximize the potential of targeted and triggered monitoring, the role of centralized monitoring should be leveraged. Centralized monitoring is ideally positioned to coordinate targeted and triggered strategies. Many organizations limit the functionality of centralized monitoring to an administrative role that coordinates on-site activities. However, the potential contribution for this group goes far beyond this administrative role. There is evidence that centralized monitoring can be more effective than on-site monitoring in detecting data anomalies, such as fraud and other nonrandom data distributions. In addition, electronic data capture (EDC) systems are making it possible to implement centralized monitoring methods that enable decreased reliance on on-site monitoring. The availability of data in aggregate form provides central monitors visibility to potential risks or trends, which may warrant additional scrutiny off-site or on-site. To realize these potential benefits, it is important that centralized monitoring teams are multidisciplinary. The ideal team will have clinical monitoring experience coupled with data analysis skills. These teams should also possess strong medical and safety surveillance perspectives. Coming on the horizon is the promise of using statistical methods to augment existing monitoring strategies. The concept here is to use the reported data to guide the review and verification process. By applying statistical methods to identify inconsistent data points or patterns of data at a site, these signals can then be used to focus additional data review and investigations. These methods can also look for many other signals, including analyzing the data for trending, whether in the values themselves or attributes of that data such as the time of data collection. Data can be analyzed to determine if there is a directional bias or inconsistent variability (too much or too little) at a site, within a patient, or across an entire trial. The benefit of this approach is to further reduce the amount of data clinical researchers need to look at. They can plan to review less data initially, knowing that the statistical methods will provide a safety net to trigger additional guided data investigations as needed. EARLY PLANNING IS PIVOTAL Before deciding on the optimal monitoring approach for a trial, establishing a strong operational strategy is essential. Beginning the process early in development will allow for a more holistic approach 52 LifeScienceLeader.com October 2013 to streamlining the protocol and risk identification. Building the operational strategy starts with the biopharm and CRO aligning their therapeutic expertise and leveraging that knowledge with historical data to clearly define potential risks and identify critical core data. Clinical teams should appropriately identify risks that are related to patient safety, potential barriers to regulatory approval, and risks to the delivery of quality data on time or within budget. These risks must be identified and fully vetted by a cross-functional team, with particular attention paid to three main categories: scientific and medical risks, regulatory risks, and operational risks. Once trial risks have been identified, the goal is to eliminate, reduce, or mitigate them as much as possible. If a risk cannot be completely eliminated, biopharms and CROs must ensure that they clearly document the risk mitigation strategy, including which data, tools, or systems will be used to signal when that risk is about to occur and what type of remediation will be necessary. It also is important to isolate those trial procedures or activities that are considered essential to supporting the evidence needed for product approval. This will enable more informed discussions about potential areas where there may be excessive procedures in place that could expose patients to risk. CLINICAL TRIAL EXECUTION AND CONTROL After a trial's operational strategy has been established, the focus shifts to the delivery of the strategic data monitoring plan. Monitoring activities should focus on the critical measurements identified in the protocol and on preventing important and likely sources of error in their collection and reporting. Biopharms and CROs must put systems in place that provide the data transparency needed to support a strategic data monitoring plan — one that may combine a centralized approach with targeted or triggered strategies. The ability to use tools that aggregate large datasets is critical and enables a more risk-adaptive monitoring approach to be adopted across a trial. Potential metrics could include differential data between sites around patient recruitment, serious adverse events reported, and reports of noncompliance. Simply collecting large amounts of data, however, does not mean statisticians will be able to identify unfavorable trends, potential risks, or safety issues. With the many data repositories that already exist, the challenge is integrating data streams into reliable intelligence that allows biopharms and CROs to make better and more timely decisions. It comes down to how well disparate data can be leveraged to make the right data available at the right time to support planning and operational delivery of clinical trials. About the Authors John Whitaker, Ph.D., is senior VP of clinical innovation at INC Research, a global CRO providing the full range of Phase 1 to 4 clinical development services. Amy Kissam is executive director of integrated clinical processes at INC Research.