Although risk-based monitoring (RBM) has been a hot topic in the clinical research community for some time now, implementation and execution of the strategy in clinical trials is still in the early stages. The traditional standard of on-site visits, combined with 100% source data verification (SDV), has given way to a new mode of thinking at the U.S. Food and Drug Administration (FDA). The FDA now accepts an approach to clinical studies focused on critical study parameters and relies on a combination of monitoring activities, including centralized data collection and monitoring.

The FDA’s guidance, “Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring,” acknowledges that clinical trials have become much more complex and geographically dispersed over the last 20 years, even as progress in electronic systems and records and improvements in statistical assessments have created opportunities for alternative monitoring approaches. The FDA emphasizes the underlying intent is, as always, patient safety.

A risk-based approach to monitoring does not suggest any less vigilance in oversight of clinical investigations. Rather, it focuses sponsor oversight activities on preventing or mitigating important and likely risks to data quality and to processes critical to human subject protection and trial integrity. Moreover, a risk-based approach is dynamic, more readily facilitating continual improvement in trial conduct and oversight. For example, monitoring findings should be evaluated to determine whether additional actions (e.g., training of clinical investigator and site staff, clarification of protocol requirements) are necessary to ensure human subject protection and data quality across sites.

TKL Research recently conducted a Phase II randomized, double-blind study concerning mild to moderate atopic dermatitis. The study utilized 20 U.S. sites as well as 10 outside the U.S. A total of 195 subjects were screened and 121 subjects randomized. Insofar as was possible, TKL tried to mirror the FDA guidance on RBM in the conduct of this trial. This is our experience.

What the FDA Wants
The FDA is basically looking at three areas in regard to your centralized RBM strategy: routine review of data, statistical trend analyses and site performance statistics.

Routine review of data means you have a plan to flag missing or inconsistent data as well as data outliers and protocol deviations.
Although with traditional monitoring strategies, we view statistical trends and anomalies at the end, in RBM approaches, statistical trends are reviewed in real time for range, consistency and completeness as well as for unusual distribution of data at one site and/or across all sites.

Site performance statistics, such as unexpected screen failure rates, high withdrawal rates, eligibility violations or data reporting delays are also reviewed during the course of the trial, so that corrective action, such as additional training or protocol amendments, can take place.
Implementing an RBM program affects the development process in a number of ways. By focusing on critical study parameters and relying on a combination of monitoring activities to oversee a study, the roles and responsibilities of everyone involved in the trial must be discussed and clearly defined.

We found it useful to hold in-depth discussions with all of the members of the trial team, including the project leader, safety associates, regulatory associates, clinical trial managers, statisticians and data managers to encourage cooperation and make sure everyone was clear on their roles and responsibilities.

Creating the Clinical Monitoring Plan
Following the FDA guidance, our goal was to create a straightforward, concise clinical monitoring plan (CMP) that eliminated as much redundancy as possible and was capable of being altered as the trial progressed.

One of the key aspects in creating a CMP is assessing risk for all aspects of data collection and trial conduct, including establishing the chances of an error occurring, the impact of errors on subject protection and data integrity, and the organization’s underlying ability to detect these errors. Risk assessment is a complex subject all on its own, but fortunately there are tools to help you work through the process and, for this study, we used the Risk Assessment and Categorization Tool (RACT) developed specifically for the pharmaceutical industry by TransCelerate BioPharma Inc.

Using RACT, we assessed risks of the program and protocol; identified and documented critical data and processes; assessed potential risk indicators; and developed a plan for monitoring execution of the study.

Creating the Monitoring Strategy
In consultation with the trial team, we developed a list of the critical variables to monitor during the trial, which included:

• Signed informed consent form
• PK research sub-study ICF
• Childbearing potential
• Target lesion identification
• Percent of body surface area covered
• Inclusion/exclusion criteria
• Adverse events/severe adverse events
• Overall investigator global assessment score
• Overall eczema areas and severity index score
• Visual analog scale (VAS) pain score
• Quality of life assessments

We also developed a monitoring strategy that was divided into three tiers. Tier 1a included 100 percent SDV of all data variables (critical and non-critical) of the first subject randomized at each site; Tier 1b consisted of 100 percent SDV of all data variables (critical and non-critical) of 25 percent of the randomized cohorts; and Tier 2 included collection of only the critical data on the remaining 75 percent of randomized subjects. Remote monitoring tasks (date trend analysis, query response review, listings review) were also defined and documented in the CMP and in a separate trip report for remote activities.

Although our use of centralized monitoring techniques was limited, we did employ a combination of targeted and reduced monitoring techniques to create an efficient, smooth running trial in alignment with the FDA’s guidance for risk-based monitoring.

Keys to a Successful RBM Trial
There are a number of valuable lessons research organizations can learn from our experience that will simplify implementing RBM in future trials.

Be certain the communication pathways between team members are strong and well-established, and that everyone has a clear understanding of roles and expectations from the outset. A successful RBM-based trial is cross-functional and requires active participation from everyone involved.

The clinical monitoring plan must be clear and concise, but thoroughly complete, with critical study-specific information identified and processes developed to gather, analyze and act on data during the trial. During training, remember that it’s important to provide specific examples of the kinds of triggers that will result in additional monitoring of investigator sites.

Finally, if electronic data collection will be a part of your CMP, it’s important to ensure you have the technical capabilities in place for a secure capture, monitoring and transfer of data.

Conclusion
Sponsors of clinical trials are seeking ways to reduce clinical trial complexity and drug development costs while getting more value from limited research and development budgets. Regulatory agencies, such as the FDA, have determined there is a need to find more efficient ways to approach clinical trials. RBM enables researchers to target and prioritize resources around the identifiable risks that relate to the safety of subjects and quality and integrity of clinical trial data, and to create monitoring strategies that are aligned with the risks and purposes of each specific trial. 

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Lynn King is a veteran research professional with more than 20 years of experience in the drug-development industry. A proven leader of projects, teams and individuals, including 18 years of management experience, King’s experience includes hands-on monitoring and project management experience as well as coaching, mentoring and training roles in both the CRO and pharmaceutical environments. She holds a bachelor’s degree in biomedical ethics and public policy and a master’s degree in healthcare administration.