Over the last 10 years, clinical trials have changed substantially in response to increasing globalization and study complexity, along with new technological capabilities and industry guidelines,7. With these noticeable transformations, sponsors are increasingly revisiting their monitoring methods to uncover new efficiencies and develop more robust risk management processes that can enhance ongoing patient safety and data quality.
At the forefront of this movement is risk-based monitoring (RBM) – a broad term for a variety of clinical monitoring methods that combine people, process and technology, enabling project teams and Clinical Research Associates (CRAs) to focus on the most important risks in clinical trials.
CRAs and the use of informatics technology
When RBM first emerged from industry and regulatory guidance, the need for a cost-effective, technology-based RBM solution was apparent. To address this gap, Covance developed Xcellerate® Monitoring, an award-winning analytics suite that delivers state-of-the-art data integration, supporting all aspects of central monitoring, including risk monitoring, medical review, statistical monitoring and data review.
This advanced working model is fully aligned with the FDA2 and EMA4 guidelines and TransCelerate principles, which encouraged pharma, biotech, CRO and ARO groups to adopt risk-based approaches in clinical trial execution – essentially directing the industry to “monitor smarter.”
With an addendum to ICH GCP (E6)7 planned for release in late 2016, the further adoption of RBM methods should be expected as the industry embraces advances in technology and risk management processes which offer new opportunities to enhance patient safety, increase efficiency and improve data quality.
The important role of CRAs is similarly evolving to embrace:
Increased Application of Specialist Skills
Risk-based monitoring technology platforms, like Xcellerate Monitoring, provide CRAs enhanced visibility to site performance, which permits greater focus on the patient safety and data quality aspects of clinical monitoring. Prioritizing on-site monitoring activities allows CRAs to refine and utilize specialist skills when reviewing critical data points and process compliance at the site level.
Greater focus on high-value compliance checks
TransCelerate recommends de-prioritizing Source Data Verification (SDV) for transcription errors, as they offer limited value by using approximately 10 to 15% of the trial costs for only 1.1% of the total data corrections. Instead, the practice of Source Data Review (SDR) is encouraged, an activity that involves the review of source documentation to verify quality and ensure compliance with the protocol and critical processes1. By looking beyond simple transcription checks and delineating critical and non-critical monitoring targets, CRAs can conduct the vital process review activities while their project teams gain greater flexibility in customizing baseline monitoring intervention levels.
Adaptive and Triggered Monitoring
Building on the Quality by Design (QbD) features implemented during study planning phase, risk-based monitoring plans prioritize high-value monitoring activities and outline adaptive monitoring interventions for CRAs based on quantifiable site risk. Through a continual process of data-driven risk profiling that adapts as risk profiles evolve, CRA efforts can be focused on high-risk study sites—maximizing the value of CRA activities when on-site. Triggered monitoring activities through Xcellerate Monitoring also provide the CRA with an essential level of flexibility to support efficient and effective on-site monitoring during patient enrollment and study maintenance phases.
Shifting from an “Auditor” to a “Coach” with Increased Remote Monitoring
CRAs will increasingly conduct remote or “off-site” monitoring to manage administrative tasks and to conduct quantitative compliance checks that can be handled without travelling to individual sites in person. Supported by developing technologies and strengthened site relationships, remote monitoring adds valuable flexibility and efficiency to clinical monitoring methods. As a result, the CRA role is shifting from that of an “auditor” to a “coach”—actively supporting site staff to take greater ownership of process compliance and accurate data reporting.
Holistic Central Monitoring
The visibility of a trial’s performance at the site and subject level is now enhanced by advanced data analytics technologies, supporting more informed decision making for clinical monitoring teams and their site-focused CRAs. At Covance, our RBM Central Monitors use Xcellerate Monitoring to identify, quantify and visualize study risks based on a continuous process of structured risk assessment. With this process, CRAs are empowered to efficiently review high-value data at individual study sites and effectively manage issues and risks remotely between on-site visits. CRAs also serve as the single point of site contact for Central Monitoring staff such as physicians, statisticians, data reviewers and RBM Leads—a practice that further strengthens relationships with investigative sites.
Looking Ahead to Maximize Value and Opportunities for CRAs
The demand for robust analytics, technology and data integration capabilities continues to grow with the increasing digitalization of clinical trial data. Yet even with the expansion of remote and centralized monitoring activities, a CRA’s responsibility for proper evaluation of site performance and issue management does not change. Competent and highly skilled monitors are still required to make accurate and consistent judgments.
Beyond the role of the CRA, new roles may be required within risk management teams as this holistic approach to site management evolves to include a wider range of centralized and specialized positions including specialist Central Monitors for medical, statistical or data review and RBM Data Integrators working to collectively identify and mitigate risks at all levels of the trial with a holistic approach to risk management.
Through Xcellerate Monitoring, Covance has transformed clinical trial risks into measurable returns for clinical research stakeholders with initial improvements in data quality, patient safety and cost efficiency, noting an average 20% less critical/major findings per Clinical Quality Control (CQC) visit, up to 36% lower site management spending, 18% lower travel spending and up to 66% fewer missing eCRF pages at sites—statistics that support the premise of smarter monitoring6.
As RBM adoption grows and becomes the industry standard for maintaining patient safety and improving data quality, CRAs face unique opportunities to thrive as clinical monitors in this shifting landscape. From leveraging analytics for data-driven decisions to adding new efficiencies with increased off-site monitoring, it will be exciting the witness the evolving role of the CRA to advance risk management and improve the conduct of clinical trials.
- TransCelerate BioPharma Inc. Position Paper: Risk-Based Monitoring Methodology. 30May2013. Available at http://www.transceleratebiopharmainc.com/assets/risk-based-monitoring/. Accessed 02Sep2014.
- Guidance for industry: Oversight of clinical investigations – A risk-based approach to monitoring [August 2013 Procedural]. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf. Accessed 09Sep2014.
- ICH E6(R2) Expert Working Group (EWG) Business Plan – Endorsed: 5 June 2014 Accessed: 30May2016 http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_Business_Plan_July_2014.pdf
- Reflection paper on risk based quality management in clinical trials (EMA/269011/2013). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/11/WC500155491.pdf. Accessed 30 November 2015.
- Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products version: 10th October 2011. Accessed 30 November 2015. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/343677/Risk-adapted_approaches_to_the_management_of_clinical_trials_of_investigational_medicinal_products.pdf
- Reference: Covance RBM White Paper: January2013. Available at http://www.covance.com/content/dam/covance/assetLibrary/whitepapers/Transforming%20Risks-Xcellerate%20Monitoring-WPCDS007.pdf.
- Reference: ICH Harmonised Guideline: Integrated Addendum to ICH E6(R2): Guideline for Good Clinical Practice http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Addendum_Step2.pdf
- Evaluating Source Data Verification as a Quality Control Measure in Clinical Trials, Therapeutic Innovation and Regulatory Science 2014, Vol. 48(6) 671-680