A complex oncology study in multiple myeloma cancer, myeloproliferative and myelodysplastic syndrome was enrolling 30% above the anticipated recruitment rate, with even higher enrolment in the United States, as shown in Figure 1.

The higher actual enrolment rate was attributed to significant scientific interest in the study and IP, due to limited treatment options and orphan drug designation of the investigational agent.

The electronic case report form (eCRF) was heavily front loaded, with a high volume of data to be collected in the first three treatment cycles. Hence, data accrued quickly in the US sites based on their accelerated start-up timelines and higher recruitment. The volume was quantified as approximately 45,000 eCRF pages generated per quarter.

The immediate challenge was to clear this data backlog in a time when on-site visits by CRAs were limited due to COVID-19 restrictions. Going forward, we needed to manage the high volume of incoming data, and retain a stable team of clinical research associates (CRAs), to ensure that patient safety was adequately monitored.

Site activation and recruitment in the US occurred approximately one year before other regions. The study originally started in two countries and then expanded to 23 countries, while enrolment continued in the initial two. Because of the rapid enrolment shown in Figure 2, as well as site and data access due to the COVID-19 pandemic, data volumes for review built up exponentially.

• The monitoring plan called for onsite monitoring every 8-12 weeks with targeted source data verification (SDV).
• Because of the rapid patient recruitment, the CRAs assigned in accordance with the original recruitment plan needed new tools and a new approach to manage the high volume of source review and source data verification.
• There was a need for additional monitoring visits at higher frequency to address and maintain data review.
• The need for additional monitoring visits was compounded by limited access to sites during the COVID-19 pandemic. COVID-related restrictions resulted in closure of sites to onsite monitoring. A number of sites were not adequately set-up for remote monitoring, which added to the backlog of data for review.
• Obtaining access to site electronic medical record (EMR) at US sites involved additional complexities; and institutional requirements for CRA vetting prior to granting access could take up to 12 weeks. Additionally, some US sites would only allow remote EMR access to a vetted CRA within the US time zone of that institution’s business hours.
• Lastly, sites themselves had a high backlog of data to be entered, and bolus data entry accounted for further substantial backlog of data to be reviewed.
• In Q4 2021, the SDV rate for the project was at 36%.

Because onsite monitoring in the US was restricted due to COVID-19, remote monitoring of EMR was implemented. However, the high data volume required a significant higher resource allocation than planned or available at short notice. Because there is a shortage of experienced CRAs in the US, ICON established its global remote monitoring CRA hub.

The remote hub CRAs are highly experienced CRAs including in complex indications such as oncology, and are all located outside of the US. Their remit is to obtain access to the site/institution EMR and perform source data review and source data verification, as well as other monitoring activities if required.

The hub CRAs are located in different time zones selected based on where clinical expertise is available, where there is a willingness to work in the US time zone, and where monitoring activities would be cost-efficient.

As a result, this allows monitoring to occur at many of the sites for extended periods instead of only during a standard 8-hour workday in the US.

The seniority of the assigned hub CRAs accounts for the high level of experience and understanding of the monitoring requirements of this complex oncology study. This aided in fast deployment of the team, so that following an intense customer and protocol training period, the hub CRAs began monitoring remotely with the aim significantly reduce backlog in a short amount of time, whilst data continued to be accrued through data entry and enrolment continued. Furthermore, additional hub CRAs were deployed to meet ongoing data cleaning and source review demands.

Factors contributing to the success of ICON CRA hub model on this project include:

• Accelerated and targeted sponsor training (e.g. investigational product accountability was not applicable and hence removed from the required list of training)
• Greater access to experienced CRAs with knowledge in complex indications
• Rapid deployment of hub CRAs to sites/institutions for which they had been previously vetted

Assigning hub CRAs to collaborate with in-country travelling CRAs resulted in a cost-efficient way to reduce data backlog and resolve queries more expediently, resulting in cleaner data faster.

At its maximum, the hub CRAs comprised half of the CRAs monitoring US data and the hub CRA team had lower turnover compared to the travelling local team. This provided stability and consistency of knowledge in the CRA team, continuity of project-specific processes, and improved relationships with site staff.

Over a period of four months, the SDV completion rate improved as shown in Figure 3.

• The project team now has a structured and long-term approach for monitoring of each site due improved stability and continued knowledge in the assigned CRA team.
• The monitoring team continues to reduce the backlog and manage current data as enrolment continues to advance and volume of data generated is increasing.