According to the Code of Federal Regulations Title 21 and summarized in the guidance document "Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring", sponsors are required to provide oversight "to ensure adequate protection of the rights, welfare, and safety of human subjects and the quality of the clinical trial data submitted to FDA." This is an important requirement. A requirement we all take very seriously and implement countless processes to control. One of those processes is study monitoring, yet year after year one of the top findings from the FDA’s Bioresearch Monitoring Program (BIMO) is "inadequate monitoring." So, how does a sponsor company ensure adequate oversight of this aspect when the function is outsourced?

The typical answer involves these three steps:

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Sound familiar? If you have this plan, great. It may be more than adequate. However, resource constraints can make keeping up with IMVR review a challenge let alone sending valuable staff out travelling to investigator sites. Even if the staff are available for these visits, do they have the monitoring experience necessary to evaluate sites and/or monitors? The experience described below led to a realization that perhaps there is a better way.

The problem:

A small company was conducting a complex, rapidly enrolling, oncology study and was preparing for the New Drug Application (NDA)submission. Due to a number of challenges, a backlog of source data verification (SDV) emerged and the large CRO they were partnered with was having trouble securing adequate time-on-site for monitors.

The solution:

The sponsor company engaged a niche CRO with regionally-focused, highly experienced contract monitors to supplement the existing CRA workforce. Each of these monitors had over 20 years of experience and a history of helping companies in this very situation. Because of their therapeutic expertise, they were quickly trained and deployed as co-monitors to work with the CRO on reducing SDV backlog.

The outcome:

As expected, these monitors helped to chip-away at the backlog. Not surprising. What was surprising was that they quickly became a valuable tool for sponsor oversight. The contract monitors were able to interact, on-site, with nearly all of the sites and CRAs in the trial. This created a more robust feedback loop for what was occurring during site visits. The sponsor had a new level of transparency on site and CRO activity which allowed for greater consistency across the trial. Systemic issues related to protocol interpretation (by sites and CRAs) were identified quickly which led to a large reduction in data entry errors and query load. Unexpected safety concerns were discovered which improved the sponsor’s understanding of the safety profile. Fortunately these risks were identified in time to be corrected and created an overall improvement in study and data quality.
This strategy had little to no impact on the study budget because the co-monitoring was already necessary and the monitors were utilized as needed. Additionally, after the NDA was filed, these monitors were an easy extension of the Quality Assurance (QA) function. Their experience conducting site audits, familiarity with the sites, and knowledge of the trial made them perfectly suited to prepare investigators for potential FDA inspections. They conducted focused visits to train investigators and site staff on the FDA inspection process, common questions and common 483 findings.

Lessons learned:

The high site-staff and CRA turnover rate in clinical trials creates a challenge for any sponsor company to deliver consistent messaging, generate high-quality data and ultimately protect the rights and well-being of human subjects. Having highly experienced and well-trained individuals on board, even late in the trial, helped to overcome that challenge. Had they been on board from the beginning to evaluate CRA and site risks, a number of issues discovered late in the trial could have been avoided.
The standard sponsor-oversight plan consisting of training, IMVR review and occasional visit attendance is inherently reactive. Systemic issues can go undetected and quality can suffer. Ensuring each CRA and each site is well-trained from the beginning of and throughout the trial with visits by a sponsor representative can help to ensure quality. If you work for a large, well-resourced company perhaps this is an internal function and already part of your processes. If not, there are options which are straight forward and professionals who have experience in this capacity.
Implementing this strategy only becomes more important as the industry slowly shifts to risk-based monitoring. In a standard 100% SDV model, a 50-center study will generate around 450 monitoring visits per year. That gives the sponsor company plenty of chances to identify site risks or for CRAs to learn as they go. With risk-based monitoring those chances are drastically reduced and every visit counts. Remote data review will help to identify issues as they arise but when they do, the person deployed to the site should be well qualified.

To find out please, please feel free to contact the author, Collin Williams at