The Risk-Based Monitoring in Clinical Trials

Clinical trial monitoring is a critical component of drug development that ensures subject safety, data quality, and protocol adherence. The optimal way to apply risk-based monitoring (RBM) remains uncertain, with tools and techniques varying widely. The regulatory standards’ non-prescriptive character, limits in software technology, operationalization problems, and a lack of adequate Proof of improved results have all hampered its widespread implementation.

Introduction

The conventional strategy for clinical site monitoring entailed routine on-site visits at a predetermined frequency, implemented equally across sites regardless of risk level, and mainly depending on source data verification (SDV) to assure data quality and patient safety. However, there is increasing evidence that SDV is considerably less beneficial than previously assumed, and it may be decreased by more than 90% (and completely abolished in extensive studies) with no discernible influence on data quality. Most Proofs read SDV-identified data mistakes are random in origin and uniformly distributed across sites and treatment groups and may be detected using basic edit checks and statistical techniques. Indeed, according to a recent examination of site monitoring data, centralized monitoring operations might have recognized 95 % of the results of on-site monitoring visits.

These findings have prompted regulatory agencies and industry consortiums, such as to adopt risk-based monitoring (RBM) methodology that combines centralized and off-site review of important study parameters with an adaptive on-site monitoring approach that places a greater emphasis on risk-mitigation activities, such as Good Clinical Practice, source data review (SDR), and training. RBM, in essence, separates critical data from critical processes and provides a framework for site monitors to prioritize the high-value compliance checks over the low-value task of fixing transcription errors, which can be detected much more reliably and efficiently using computer-based techniques.

Process

The methodology is based on the main dimensions of a risk-based approach to clinical trial monitoring: quality by design, central monitoring, and triggered, adaptive on-site and remote monitoring.

· Quality by Design

Protocol evaluation, study risk assessment (including subject involvement and data flow mapping), initial site risk assessment and selection, essential data and process characterization, and RBM plan preparation are all phases of the quality-by-design approach.

· Central Monitoring

Review aggregate data from an ongoing trial using analytics and visualizations to identify poorly performing investigational sites, detect unusual patterns in inpatient- and site-level data, predict potential issues, mitigate risk areas, and correct clinical trial execution problems. Central monitoring also involves comprehensively handling results and concerns discovered throughout the process.

· Adaptive, Triggered On-site and Remote Monitoring

During the trial’s subject enrollment and study maintenance stages, we employ adaptive, triggered monitoring procedures that include lowered levels of SDV, SDR, on-site monitoring, higher levels of remote monitoring, and started monitoring activities. Our central monitoring system employs a top-down approach to detect and manage risks at the data point, visit, subject, location, nation, and study levels. To allow thorough examination via multiple reviewer lenses, the following significant kinds of central monitoring were recognized and addressed: risk review, medical review, statistical review, and data review (vide infra). These activities are assisted by a risk and issue management system, which enables central monitors, site monitors, and project managers to manage all issues that emerge as a result of a clinical trial, including those resulting from quality by design, central monitoring, and on-site and remote monitoring activities. Problems are assessed for duplication, urgency, and suitable assignment before being resolved.

Technology

The risk assessment and categorization tool is based on a template designed to facilitate a guided review of programme and project risk by cross-functional teams, identify and document mitigations, and integrate with our risk and issue management system to ensure identified risks and mitigations are followed up on until resolution. The risk review tool enables central monitors to conduct regular, comprehensive risk reviews (at the study, country, and site levels), make recommendations to adjust monitoring intervention based on individual risk indicators and overall site risk, and review site details to identify specific issues and assign mitigation actions, and assess whether mitigation actions are practical.

Conclusion

The objective of RBM is to enable more effective and efficient monitoring by moving resources from high-performing sites (light/dark green) to low-performing areas (orange/red). The default (standard) intervention level is indicated in yellow, representing the amount of supervision that would be increased if all of the sites were traditionally monitored. As a result, a rise in the number of green places indicates a reduction in risk (safety, quality, and compliance) and monitoring work (cost).

These findings show that our RBM technique may considerably enhance clinical oversight while also lowering costs by more intelligently allocating monitoring resources to the areas requiring the most attention. A more thorough review is being conducted and will be given elsewhere.

References

1. US Food and Drug Administration. Guidance for industry. Oversight of clinical investigations a risk-based approach to monitoring. Available at: https://www.fda. gov/downloads/Drugs/guidanceComplianceRegulator yInformation/Guidances/UCM269919.pdf. Published August 2013. Accessed April 7, 2018.

2. TransCelerate. Position paper: risk-based monitoring methodology. Available at: http://www.transceleratebiophar mainc.com/wp-content/uploads/2013/10/TransCelera teRBM-Position-Paper-FINAL-30MAY2013.pdf. Published May 30, 2013. Accessed April 7, 2018

International Committee for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonized guidelines. Integrated Addendum to ICH E6(R1): Guideline for good clinical practice. E6(R2). Available at: https://www.ich.org/filead min/Public_Web_Site/ICH_Products/Guidelines/Effi cacy/E6/E6_R2__Addendum_Step2.pdf. Published June 11, 2015. Accessed April 7, 2018.