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September 18, 2014

How To Avoid A Checklist-Based Approach To Risk Assessment

As Risk-Based Monitoring takes hold in the clinical space, it is becoming more important to ensure you are monitoring the proper data, processes, and indicators. The clinical space is growing at a rapid pace, and with the introduction of more trials and complex protocols regulating those trials, relying on a standard, cookie-cutter approach to risk assessment will only lead to trouble down the road.

Clinical Leader turned to inVentiv Health Clinical's Sherry Merrifield, Sr. Director, Clinical Monitoring, and Michael Macri, Director, Strategic Services, as well as Jeff Fetterman, President of inVentiv Health's ParagonRx, to better understand some of the strategies that can ensure a thorough, defensible risk-based monitoring approach.

Anna Rose Welch: As sponsors begin exploring RBM, what best practices have emerged to determine and document the risks in each trial?

inVentiv Health Clinical (IHC): The first step in any RBM process is risk assessment. The methodology of that risk assessment determines the defensibility of the findings and the RBM strategy that is driven by the risk assessment. To date, most risk assessments for RBM have been ad hoc in method. Our best practice has been the use of Quality Risk Management (QRM) methods, as specified in ICH Q-9, to create a body of evidence linking each individual risk – risks that could harm data integrity or human subject safety – to the specific risk minimization action and the specific key risk indicators.

In our practice of a Systematic Risk Assessment (SRA), we have selected several relevant QRM methods that fulfill the criteria regulators cited in guidance and reflection papers. The integrated method starts with a map of the clinical study process to ensure comprehensive review, followed by an itemization and prioritization of risks by a cross functional team. Finally, specific risk minimization actions and key risk indicators are linked to each of the high priority risks.

Our practice also includes a Clinical Risk Manager (CRM). The CRM understands the overall RBM process, and is responsible for the initiation and oversight of the risk management program for each trial. The CRM leads the risk assessment process and ensures integration of the risk minimization and monitoring actions into clinical study documentation (e.g., Monitoring Plan). This documentation captures the key risk indicators, mitigation plans, and functional group ownership of the critical data and critical processes, ensuring that realized mitigation actions are captured from identification through resolution.

This approach definitively answers the question that can be anticipated from regulators: How do you know you are monitoring the correct data, processes, and indicators? An approach that does not apply QRM methodologies cannot defensibly answer this question.

Welch: What areas have required the most resources to monitor throughout the process of a study?

IHC: In the past, considerable resources were directed toward generalized monitoring to see if quality standards were being achieved. By following the aforementioned approach however, a portion of those resources can be shifted to the front end of the study to conduct the SRA, to document those findings and the RBM strategy in the integrated Quality Risk Management Plan (iQRMP), and to diversify and focus monitoring methods around remote and centralized monitoring.

Overall, we have found that directing resources toward the SRA has been a key means of growth for our own RBM strategy. We've also found it necessary to include technology earlier in the RBM planning process, specifically in the form of a relational database to facilitate and archive the inputs and decisions of the SRA.

Welch: Have sponsors been directing you to focus on any particular "triggers," and/or have you determined any on your own that help you determine the areas that need the most attention?

IHC: In our process, the "triggers" are threshold values associated with each of the key risk indicators (KRIs) that signal the need for corrective action if there is a data excursion outside of the predetermined thresholds. The KRIs and thresholds are always defined by the SRA and link definitively to the high priority risks of the specific study. It is paramount that these KRIs and thresholds be tailored to each study, as a standard set of KRIs uniformly applied to all studies will not provide the sensitivity or specificity necessary to justify the decision process required for RBM. A standard, predetermined set of KRIs cannot create a defensible body of evidence proving that the critical processes and data for one specific study are being accurately or sufficiently monitored.

Welch: Have you found that RBM is best suited for a particular phase of trial?

IHC: There has been significant experience showing the benefit in using certain types of adaptive and risk-based approaches to monitoring in late stage Phase 3b and 4 studies.  We have found that systematic approaches to the risk assessment process provide the body of evidence necessary to support RBM methodologies as required by regulators.

By conducting an SRA early in any specific study, sponsors have the opportunity to avoid failures and issues in studies before they occur.  This same benefit can be applied across an entire clinical development program, which demonstrates the value of starting early in the clinical development process.

Welch: What are some of the potential financial and study-wide benefits of RBM?

IHC: All parties should keep in mind that the primary objective of RBM is to improve monitoring in a way that enhances data integrity and human subject safety. Financial effects, such as cost savings, are expected to be demonstrated in the long run (as they have been demonstrated in the application of QRM principles in other industries), but they are not the immediate objective of RBM.

We've found that RBM, in particular the SRA, identifies the critical data and critical processes for each specific study. In doing so, it targets data management and monitoring activities to focus only on the critical processes and high priority risks, increasing efficiency. The SRA has also identified non-obvious risks that led to KRIs that are unlikely to be identified by ad hoc or checklist-based approaches to risk assessment, ensuring collection of the highest quality data in support of the clinical trial submission.

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