As experts in biostatistics, Quanticate have been actively involved in advising and implementing Risk Based Monitoring solutions utilizing central statistical monitoring technologies developed by our in-house team of expert statisticians.
Whilst there has been a lot of interest in recent years around risk based monitoring and adaptive methodologies to optimize clinical development, the recent addendum to the ICH E6 (R2) has now moved the use of risk based approaches from something that innovators were using to an essential requirement of all clinical trials.
As explained in the new ICH guidelines; “The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials..… The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).”
A risk based approach therefore requires consideration at an early stage and will need to be considered for inclusion in the protocol, Statistical Analysis Plan (SAP) and monitoring plan. Having an experienced statistician involved will be a requirement to optimize the study, incorporate a risk based targeted approach and ensure approval. In order to determine the degree on centralization, statistical methodologies are needed. The guidelines recognize this by confirming, “Centralized monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians).”
One of the keys to successfully implementing a centralized monitoring solution is ensuring that an appropriate method of data review is included in the study design. As such, it is important to work with clinical data management to collect data, use a tool to visualize the data and utilize statisticians in the review of the data to direct the Clinical Research Associate (CRA) to target specific sites for additional Source Data Verification (SDV).
Having expert input into the protocol and SAP to help reduce on-site source data verification and allow centralized review will ensure that the approved study is efficient whilst assuring data quality and patient safety.
ICH E6 (r2) provides insight into the expectations by stating:
Review, that may include statistical analyses, of accumulating data from centralized monitoring can be used to:
(a) identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations.
(b) examine data trends such as the range, consistency, and variability of data within and across sites.
(c) evaluate for systematic or significant errors in data collection and reporting at a site or across sites; or potential data manipulation or data integrity problems.
(d) analyze site characteristics and performance metrics.
(e) select sites and/or processes for targeted on-site monitoring.
In practice, monitoring can be performed centrally and is accomplished by targeting patients or sites based on outlying, inlying, erroneous, operationally deficient or potentially fraudulent data. Use of a tool that incorporate statistical algorithms to identify risk factors is needed and access to statisticians can help interpret results.
FDA guidance outlines three steps in a risk based approach to monitoring:
Detection of critical data and processes
For critical data to be detected as causing a potential risk, a sponsor must know and identify the values and parameters that they expect data to fall within. Therefore when a data flag is raised, it can be identified as a potential risk. Intelligence from previous studies can be drawn upon to help quantify these metrics as high, medium or low risk.
The mitigation for a given identified risk can change throughout the trial and the categorization of the risk does not need to be entered when initially working with the RACT (Risk assessment categorization tool). Examples of high risk data points include any of those which impact patient safety, the use of trial sites with little or naive experience of clinical trials or endpoint data categories.
Perform a Risk Assessment
When risks have been identified they can be visualized using a 'traffic light system' for clinical operations to assist in conveying these findings to site, a risk assessment must be conducted which involves investigation of the risk and its origin (Source data review), and the implementation of risk mitigation methodologies, enacting corrective action to prevent further risks and resolve current risks. These may include re-education of the site, motivational visits, amending a recruitment plan, escalation to a global level or in extreme cases the issuing of warning letters.
Develop a Monitoring Plan to incorporate a risk based approach
A monitoring plan should be in place and at Quanticate we can provide the consultancy required for the change management aspect of Risk Based Monitoring. As a protocol is always the starting point of a clinical trial, when considering RBM strategies for your trial you need to include the monitoring plan at this stage and include the necessary amendments to the clinical monitoring plan (CMP) template.
FDA guidance states that a clinical/trial monitoring plan (CMP/TMP) must ‘’describe the monitoring methods, responsibilities and requirements of the trial”. This critical document will stipulate which data points need to be monitored, the frequency of monitoring coupled with communication and escalation plans for all stakeholders involved in the trial.
The Risk-based Monitoring (RBM) strategy above is becoming an integral concept in pharmaceutical clinical research, which has the potential to reduce clinical costs and improve data quality, while simultaneously reducing time to submission of an Investigational Medicinal Product (IMP). The FDA are now, as an integral part of their approval process performing statistical analyses on all data sets submitted for approval, hence, it is strongly advised that all studies both ongoing and about to commence, integrate some degree of RBM and statistical monitoring to meet these recently implemented standards.
At Quanticate we can offer Risk Based Monitoring via our portal and our custom built, in house, centralized monitoring platform and risk dashboard. This technology enables RBM to occur as all selected clinical trial data flows within the dashboard and based on the pre-set parameters and agreed risk factors parameters, displays data within a heat map that enables the identification of outliers and risks. This can facilitate monitoring at problematic sites only. Potential erroneous data is seen in advance to improve the quality of the trial data and patient safety. SDV can be reduced and sites that are performing well, will not require rigorous monitoring and one is also able to reduce budget allocation for CRA travel time.
In this webinar, you will learn how implementation, evolution and change management are critical for a successful remote monitoring program. But how does a remote monitoring program harmonize with current Source Data Verification practices?
This ebook will explain rSDV's definition, present explored and piloted practices of conducting rSDV, the shortcomings of traditional monitoring and 100% SDV, and showcase the cost savings that can be incurred, as well as process efficiencies compared to traditional trial monitoring when using an rSDV approach.
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