Bob Bois

	With strong endorsements for more efficient and effective oversight of clinical investigations from regulators in both the United States and Europe, risk-based monitoring (RBM) has continued to remain in the spotlight, giving greater confidence to the clinical development industry that the approach is accepted and likely to become a standard trial planning and conduct paradigm. It’s no secret that RBM approaches offer a leaner, more strategic way to allocate resources across a study based on data criticality, patient safety, data integrity, protocol compliance, and impact to operational delivery. As a result, RBM continues to gain traction and companies are now actively beginning to implement monitoring strategies that are proportionate to identified protocol and program risks. But what are the implications of these changes for clinical study sites?

	With many RBM trials now underway, there is growing concern from clinical study sites about what impact RBM processes will have on their workload, budgets and monitoring support. Given there is no one-size-fits-all approach to follow, study sites have expressed several areas of concern when it comes to what RBM entails. And while there are certainly broad implications for sites when it comes to RBM, much of what study sites do will ultimately remain the same. 

	Protocol complexity, resource allocation and the availability of electronic data have all contributed to the industry’s focus on alternative monitoring approaches, supported by the FDA’s 

Reflection Paper on Risk Based Quality Management in Clinical Trials

.” Now the upcoming release of ICH E6 (R2) GCP regulations will explicitly require the application of a risk-based approach to quality management.

	TransCelerate BioPharma Inc. has developed a standard RBM approach to the planning and conduct of clinical trials with an aim to provide the greatest oversight and efficiency.

	More companies are now tailoring their monitoring plans to be proportionate to the identified risks of the trial. With this more tailored approach, sponsors and CROs are actually able to drive greater quality and efficiencies in clinical trial monitoring while improving oversight of patient safety and data quality. They can do this by focusing monitoring resources where they are most needed and identify general trends more quickly.

	This shift clearly has implications for study sites, but not as much as one might think as many issues are being resolved. However, there remain many concerns regarding RBM and its impact on study sites.

Concern #1 – RBM increases workload for sites

	Guidance from regulators has left the implementation of RBM somewhat open to interpretation, which occasionally has led to unsatisfactory approaches, (e.g. - sites being asked to fax in patient source documentation for ‘remote SDV’). A more strategic approach is to increase remote review of a site’s electronic data in aggregate form and to take appropriate actions to support the site, while at the same time allowing the CRA to engage in high value activities while on site, such as source document review and follow up of open action items. By focusing on critical data and processes on-site and visualizing aggregate clinical and operational data centrally, the CRO team can more readily partner with sites to realize better outcomes for patients, sites and sponsors.

Concern #2 – RBM imposes unrealistic data entry timelines on sites

	While it is true that data entry timeliness is a necessity, the benefits that come from entering data in a timely manner far outweigh any downsides. Keeping in mind that the principles of RBM are predicated on having visibility into trial data, sites are encouraged to enter data into an electronic data capture (EDC) system as quickly as possible so that the data can be aggregated, reviewed and responded to more quickly. This allows sponsors and CROs to maintain oversight of patient safety data as well as overall data quality in order to provide more real-time feedback to sites. Recognizing that factors exist outside of a clinical research site’s control that can impinge on data entry timeliness, particularly in vaccine trials where rapid recruitment is required, most CROs will work proactively with sites to help streamline the process and inform them about the downstream effects that can result from data entry delays.

Concern #3 – RBM reduces CRA quality control activities

	Sites have come to rely on Clinical Research Associates (CRAs) to support them in assessing the quality of their data and will continue to do so. However, even when using more traditional monitoring models, sites should not rely on CRAs alone to be an external quality control (QC) reviewer of data. The principles of RBM encourage sites to establish standard operating procedures (SOPs) and/or an internal process to engage in their own QC of data entered into the case report form (CRF). Instead of checking the accuracy of transcription of 100% of the CRF data, the CRA will focus on the review of source documentation, critical site processes and adherence to Good Clinical Practice (GCP). The CRA’s focus on these areas is of greater benefit to sites and accrues more directly to quality data and the safety of patients enrolled in the trial. 

	It is important to note that RBM does not decrease support to sites. Rather, on-site and off-site monitoring activities are planned for and assigned to the most appropriate resource. For example, CRAs engage in those activities that can only be undertaken on-site (e. g. review of source documentation, IP accountability). At the same time, sites receive additional support from central monitors who are immediately available to answer site questions. In addition, these central monitors have access to study-wide data that is aggregated and visualized to identify trends or potential risks earlier. This allows the central monitor to more readily provide feedback to the site and collaborate on any needed course correction.

	Study sites have always been responsible for quality control of their processes and data. RBM is an opportunity for sites to partner with CROs and sponsors, using the latest technologies for the shared goals of improving patient safety and data quality.

Concern #4 – RBM negatively impacts site budgets

	Site budgets are built around patient visits and procedures and verification by the CRA during monitoring visits. When introducing different monitoring approaches, such as central monitoring, sites are often left wondering how their budget will be impacted. The principles of RBM call for sponsors and CROs to communicate with sites as early in the process as possible to inform them of the monitoring strategy and allow sites the time to consider their resourcing needs and internal workflows in order to negotiate realistic trial budgets. Ideally, sites should have early visibility into the RBM strategy as it impacts the time needed to perform tasks such as communicating with a central monitor, maintaining rapid data entry and performing internal QC of CRF data.

The more things change, the more they stay the same

	The industry is still early in its adoption of RBM and the long-term value will depend on how widely it is embraced. But as more RBM studies get underway, sites may experience a difference when it comes to sponsor or CRO monitoring methods, but not in how they recruit and care for study participants.

	Regardless of which monitoring approach is applied, sites are still responsible for conducting studies in accordance with the protocol and GCP guidelines. Sites will continue to receive strong support from monitors, central monitors and medical monitors, only now that support will be enhanced by more frequent, real time aggregate data analysis and centralized data review, as well as a focus on critical data and processes on site so that issues, trends and potential risks can be quickly identified and course corrections made if needed.

	In the end, a strategic focus on the identification and management of risks to patient safety and study data integrity - are ultimately goals that everyone working in clinical research shares and can rally around.

, Senior Director of Clinical Monitoring Delivery/ Innovation at INC Research, is responsible for leading project teams in the development and implementation of Risk-Based Monitoring strategies. He has more than 20 years of experience in conducting clinical trials in varying capacities: CRA, Project Manager, Safety Program Manager, and Consultant and has worked for both sponsor organizations (pharma and device), as well as several CROs. He has a bachelor’s degree in mechanical engineering with a biomedical focus from Worcester Polytechnic Institute. Email: bob.bois@incresearch.com. Website: 

Articles

Risk-based monitoring continues to remain in the spotlight as an accepted and oft implemented approach that is likely to become an industry standard. However, concerns have mounted about the potential impact of these changes on clinical study sites.

Bob Bois

Articles

Risk-Based Monitoring: What Does it Mean for Clinical Study Sites?