Risk Based Monitoring

The current clinical trial climate demands that sponsors of clinical trials find ways to reduce clinical trial complexity, drug development costs, and get more value from limited research and development budgets.  Regulatory agencies such as the U.S. FDA, MHRA and EMEA have determined that due to the high resource demand and cost of the traditional approach to clinical trial monitoring there is a need to find more efficient ways to accomplish this much needed, but costly endeavor.

Risk Based Monitoring can enable life sciences companies to target and prioritize resources around identifiable risks relating to the safety of subjects and quality and integrity of clinical trial data.

Risk Based Monitoring Defined

Risk Based Monitoring (RBM) can be described in several different ways.  It can include Reduced Source Document Verification (SDV), Targeted Monitoring and/or Triggered Monitoring.  Source Document Verification has traditionally been done on 100% of data points collected in a clinical trial.  Reduced SDV limits the amount of SDV at the study, site and/or subject level.  Targeted Monitoring is a way of reducing SDV to a targeted number of data points.  Triggered Monitoring sets a trigger which can be defined as the detection of an issue or amount of data outstanding that requires SDV.  Optimal RBM strategies incorporate Targeted, Reduced and Triggered Monitoring.

In the FDA’s draft Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring, they speak of Risk-Based Monitoring as an alternative approach to “frequent on-site monitoring and 100% data verification for all trials.”  [1]  One of these alternative approaches includes using remote, monitor-like resources, in a centralized or in-house monitoring role.  Other approaches involve leveraging technology both as a communication tool with investigative sites and as a tool to manage risks throughout the clinical trial.  The best RBM approaches involve completing a study risk assessment to develop a monitoring plan that best suits the study.

Risk Assessment Done Right

Utilizing an RBM strategy can only work well if the risks applicable to the study are well defined and the appropriate risk management strategy is implemented.  At the onset of the trial, enough time must be spent to assess the protocol for scientific or medical risks, regulatory risks and operational risks.

When assessing scientific or medical risks you should ask: Is the study a device or drug study?  What is the targeted patient population?  What are the study objectives?  What are the expected adverse events?  What specific labs or procedures must be monitored?

The types of questions to ask when assessing regulatory risks include:  What are the expected regulatory authority submission timelines?  What countries will the study be conducted in?  Are there any specifics to the investigator contract?  Does the protocol need to be reviewed by any regulatory agencies?

Operational risks can be assessed by asking:  What is the expected enrollment rate for the study?  How complex is the protocol?  How many vendors will be needed during the study?  What are the study timelines?  How will site staff be trained on study procedures?  How will data management edit checks be created?  What are the critical data variables for this study?

Answering all of the above questions will allow you to create a monitoring plan and RBM strategy for the study.  This will help to determine the metrics that should be collected and monitored throughout the study to manage the risks assessed at the beginning of the trial.  Thresholds should be defined as to when a metric becomes an issue and requires action.

Importance of Technology

The use of technology is important in implementing your RBM strategy.  There are several commercially available remote data capture (RDC) and clinical trial management systems (CTMS) that can support a risk based monitoring approach.  Off the shelf systems allow clinical trial data to be entered and reported on manually.  More advanced systems can be set up to automatically flag data to review and alerts can be set up to notify those who need to take action when an issue exists.

As the industry adopts RBM strategies, technology vendors that cater to the clinical trial industry have started to incorporate RBM capabilities into their tools.  One such RDC tool can be programmed specifically to limit the monitor to only a specific set of data for SDV such as the data tied to efficacy endpoints or safety related data.  This can then reduce the time needed for SDV and thus reduce the amount of monitoring visits required to be completed on site thereby significantly reducing the cost of monitoring the trial.

The CTMS must ensure that the information entered onto monitoring visit reports (MVRs) can be collected into a database for further reporting and analysis.  Managing clinical trial risk is one of the most difficult tasks surrounding risk based monitoring.  Several of the metrics related to risk are evaluated by monitors during their monitoring visits and collected onto their MVRs.  Being able to analyze the data entered onto the MVR can flag when an issue exists at a particular site.

For example, determining the level of involvement of the Principal Investigator (PI) is an important metric for determining site quality.  In Dana-Farber Harvard Cancer Center’s Guidance on Investigator Interactions with Monitors, it states “Principal Investigators must take an active role in the monitoring process by … meeting with the monitor…”  [2]  If there is a question on the MVR that asks if the PI was available during the monitoring visit, the CTMS can then gather that data and depending on the level of risk that is determined at the beginning of the trial, can flag as an issue when the PI is not available at one, two, or three (etc.) monitoring visits.

Maintaining Quality

It is important to utilize a quality monitoring plan to ensure that employing a risk based monitoring strategy will not result in compromising data quality and integrity.  This includes the creation of robust edit checks within the RDC system as well as consistently viewing data trends.  Using a central or in-house monitor role to review important data visualizations can reduce clinical trial costs.  An in house monitor is a less expensive resource than a remote based CRA traveling to investigative sites to complete on-site monitoring visits.

There is no data to support that completing 100% SDV of all subjects leads to better quality data at the site.  In fact, according to Ken Getz in a Mar 2011 Applied Clinical Trials article, he references a Society for Clinical Data Management report that notes that “SDV is an intensely detailed task that is prone to human error and inaccuracies”[3].  Focusing too much time on the one task of SDV also diverts the monitor’s attention from other possibly more important tasks such as improving site relationships, focusing on subject safety, and resolving systemic site related issues.

Conclusion

To run successful clinical trials in today’s environment of increased clinical trial monitoring resources and costs, the clinical trial industry must look to incorporate new ways of thinking into monitoring processes.  Regulatory Agencies have already embraced new ideas such as risk based monitoring while still ensuring that patient safety is well managed and data quality and integrity is not compromised.  Approaching risk based monitoring in a strategic way can support your business by reducing the costs of traditional on site monitoring while leveraging new technologies to manage risk.  The result is a faster time to market, reduced monitoring costs and focus on value-added tasks.  When done right, risk based monitoring becomes the best way to oversee clinical trials.

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[1] U.S. FDA, Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring Guidance, Draft, (August 2011)

[2] Dana-Farber/Harvard Cancer Center: Guidance on Investigator Interactions with Monitors, 29 June 2012

[3] Ken Getz, “Low Hanging Fruit in the Fight Against Inefficiency,” Applied Clinical Trials Online, 1Mar 2011

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