The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice was updated in November 2016, placing even greater responsibility on study sponsors and CROs to develop and execute risk-based approaches to quality management. This new ICH GCP guideline — referred to as ICH E6 (R2) — includes an extensive addendum on trial monitoring that calls for sponsors to develop a systematic, prioritized, risk-based approach to monitoring clinical trials.
Risk-Based Monitoring Defined
Risk-based monitoring is an adaptive approach to clinical trial monitoring that directs monitoring focus and activities to the evolving areas of greatest need, with the most potential to impact patient safety and data quality. Thus, RBM shifts the emphasis from 100 percent source document verification to comprehensive, risk-driven SDV.
In practice, RBM involves routine review and statistical analysis of accumulating data, which can be used to identify missing or inconsistent data, protocol deviations, trends, and metric analysis. This review and analysis assists in the early and ongoing identification of significant errors during data collection, such as data manipulation and integrity problems and inconsistent data collection practices.
Key Components of a Risk-Based Monitoring Plan
According to ICH E6 (R2), the strategy, methods, responsibilities, and requirements for trial monitoring must be described and documented in a monitoring plan. The monitoring plan should focus on:
- Critical processes and data.
- Protection of human subjects and data integrity.
- Descriptions of the monitoring strategy, roles and responsibilities, and monitoring methods — and the rationale for their use.
- References for all applicable policies and procedures.
Reports of both on-site and centralized monitoring should be provided to the sponsor, and these should be reviewed and followed up on a timely basis to ensure that activities comply with the monitoring plan.
Factors Influencing the Frequency of Onsite Monitoring
ICH E6 (R2) states that reporting of centralized monitoring activities should be regular and may be independent of site visits. The following variables should be used to augment the frequency of on-site monitoring:
- Routine review of submitted data.
- Identification of missing data, inconsistent data, data outliers, or unexpected lack of variability and protocol deviations that may be indicative of systematic or significant errors in data collection and reporting at a site or across sites, or that may be indicative of potential manipulation or data integrity risks.
- Use of statistical analyses to identify data trends, such as the range and consistency of data.
- Analysis of site characteristics and performance metrics.
- Selection of sites and/or processes for targeted on-site monitoring.
The findings, decisions, and actions resulting from any centralized monitoring process should be captured, audited, and archived throughout a trial. In addition, assessment of centralized monitoring reports and associated actions taken should be based on objective, documented decision-making criteria, not left to the discretion of an individual.
Using Technology to Support Risk-Based Monitoring
RBM technology solutions are available to help sponsors implement a risk-based monitoring strategy. When evaluating an RBM system such as Remarque, sponsors should look for a solution that addresses all layers of risk, including risk identification and assessment, risk control and mitigation, risk communication and actioning, and risk review and updating. Sponsors should also consider how the RBM system integrates with other systems they are using, such as electronic data capture and clinical trial management. Ideally, these technologies would communicate with one another and be able to aggregate disparate datasets and deal with both unstructured and structured data to provide actionable information. They should also be able to apply sophisticated algorithms to the data to identify patterns and anomalies that help surface patient- or site-related risk based on preset thresholds.
 TransCelerate Biopharma Inc. (2013) Position paper: risk-based monitoring methodology. Available at: http://www.transceleratebiopharmainc.com/wp-content/uploads/2016/01/TransCelerate-RBM-Position-Paper-FINAL-30MAY2013.pdf.pdf.
 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Guideline for Good Clinical Practice E6 (R2), November 9, 2016. Available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_Presentation_06Feb2017.pdf.