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Risk-Based Monitoring Improves Study Outcomes

Risk-based monitoring is a comprehensive and holistic process that incorporates the knowledge and expertise of subject matter experts with the validation of data analytics.

For an effective clinical trial, data must be accurate, verifiable and represent minimal risk to the participating subjects. Risk can be catastrophic to the drug development process, causing inefficiencies and delays in a drug getting to market, adding cost to an already-expensive process.

For this reason, risk-based monitoring (RBM) is an effective way to manage clinical trials. RBM is more than just monitoring clinical study data at the site — it is a comprehensive and holistic process that incorporates the knowledge and expertise of subject matter experts with the validation of data analytics to ensure a continuous reevaluation of risks.

The Food & Drug Administration (FDA) fully supports RBM approaches and expects the industry to engage in flexible solutions to protect patient safety and ensure data integrity. For more details, see E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) and the TransCelerate Model for RBM.

Evaluate study risks

Each clinical trial will have its own unique risk profile that warrants a flexible approach to identifying and mitigating risks in clinical trials. Risks should be managed at stages and should begin with assessing risks at the clinical trial site. In addition, the protocol should include the design, planning and execution stages of a clinical trial.

Prior to study start, a detailed study risk assessment should be conducted to identify study-level risks that would need to be mitigated either prior to study start, or if they could not be mitigated prior to study start, would need to have increased oversight during the study. Any risks related to monitoring should be incorporated into the remote and on-site portions of this RBM plan. Other risk-mitigating activities associated with training and pre-study visit (PSV) requirements should also be specified within this plan.

Site selection and risk profiles

Prior to the start of the study, sites should be selected utilizing a structured risk-based approach. Risks that were outlined during the detailed study risk assessment process should be incorporated into the PSV requirements and clinical research associates (CRAs) will conduct the PSV with a focus on identifying and documenting the sites capabilities related to that risk.

Once site PSVs are conducted, the person responsible for the RBM program will recieve information regarding current/potential study risks, the sites should be assigned a total risk score which is based on site capaibilites related to a standard set of site risk factors.

Taking into account where individual sites fall within these risk levels, the RBM designee will share recommendations for site selection with the project manager.

The RBM designee will provide the project manager any site risk mitigation plans that can be resolved before study start for follow up. The CRA(s), as well as other project team members, will manage these issues via SharePoint, CTMS or similar electronic system. Once final sites are selected, the individual site risk profiles (e.g. low, medium, high) will set the baseline level of monitoring intervention at the site. The risk profile should be evaluated at consistent time intervals.

Protocol risk assessment

During trial design and planning, identify a set of structured risk review guidelines, and incorporate subject matter experts in the review cycle such as (i.e., physicians, biostatisticians, data management). The FDA considers the scientific protocol the most important document in clinical trials and, a comprehensive review of the protocol will assist in providing the right foundation to identifying and mitigating risks

Upfront implementation of this RBM approach may create additional efforts than historically seen; however, the benefits will significantly outpace the upfront expenditures in the realization of reduced risk and greater operational efficiency.

RBM is also quite holistic in its approach, assessing risk at multiple levels and utilizing multiple tools and technology to facilitate the process. The various RBM process steps identified below are the essential components of this holistic and integrated RBM approach:

  • Protocol risk assessment
  • Critical data and processes
  • Site risk assessment
  • Study risk profile
  • RBM plan
  • Analysis of current trial data
  • Adaptive monitoring strategy
  • Vendor management
  • Training and oversight
  • Issue resolution and future risk mitigation

Evaluation and modification

As part of the RBM process, activities are continually evaluated and modified as needed due to changes in study design or newly identified risks. In general, there are two phases to RBM; study planning and study execution. The RBM Plan acts as the link between the planning and execution phases.

A successful RBM strategy will be consistent and structured, with every aspect of operational processes defined and outlined. Observe interventions such as current site issues, data management metrics (such as query aging and resolution time), identified risks that trigger a holistic action and specific activities related to on-site, remote and centralized monitoring. It is essential to document the risk/resolution process in a way that allows others to successfully carry out the activities that are required to reduce or eliminate the risk.

Study planning

  • Protocol design
  • Risk identification/mitigation
  • Identify critical data
  • Site selection
  • Risk profile

Study execution

  • Risk analytics
  • Centralized data review
  • Interventional tactics
  • Provides a state of operational control

Consider using data analytics to bring the RBM model together. Data from multiple sources can be reviewed to generate a comprehensive and supportive process to understand the level of risk. The technology can provide transparent access to information and will allow thoughtful data driven decisions; information from biostatistics, data management, pharmacovigilance, sponsor, CRO, CTMS and other sources can be used to support the structure, functionality and successful execution of a clinical trial.

Risk mitigation via site training requirements

Comprehensive training prior to the conduct of a study is critical to ensuring that investigators and study staff perform the activities correctly. Risk-based monitoring plans must ensure that:

  • Monitoring activities include sufficient time for discussion of investigator’s and site staff’s responsibilities, feedback and additional training, if needed, during the conduct of the study.
  • Training (e.g., teleconferences, webcasts, online training modules) and communication methods are in place for providing and documenting ongoing, timely training and feedback, as well as to provide notification of significant changes to study conduct or other important information, without reliance on onsite visits.

Risk mitigation via CRA training requirements

  • The RBM directives should be integrated into the overall clinical monitoring plan
  • Continuous study level assessment and training to include triggers and actions
  • CRAs must conduct source document review (SDR) and source document verification (SDV) as outlined in the plan.
  • CRA should respond to established triggers and implementation of agreed actions
  • Minimize knowledge transfer gaps by ensuring CRA and project team continuity
  • CRAs should be trained to identify risk indicators and the importance of documentation and follow up of these issues

Some risk factors to consider

  • Site level of commitment (PI oversight)
  • Protocol deviations
  • High enrollment rate
  • SDV backlog
  • CRA turnover/site turnover
  • Informed consent process issues
  • Early termination rate
  • Monitoring frequency
  • SAEs and AEs
  • Study file notebook issues
  • Audit issues
  • Query rate/turnaround time
  • Incomplete or missing data
  • Query aging


There is no one solution to fix all risks. Each study design will have its inherent risks, so make sure you document all risks and resolutions. Involving your quality assurance team can provide crucial guidance and insight into the RBM landscape and help ensure compliance and good outcomes.