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COVID-19 FDA Response:  Site Management and Monitoring

Posted by Sharon Duffy and Marina Acosta-Enslen on Mon, Apr 20, 2020 @ 10:00 AM

This blog post is the next in a series related to maintenance of the reliability and validity of ongoing clinical trial data during the COVID-19 pandemic. Previous topics included changes to study visits and assessments during COVID-19: subject safety considerations and documenting changes made during COVID-19: protocol amendments and the clinical study report. A future post is planned on data integrity: handling COVID-19 related missing data.

In this post, the focus is on site management and monitoring changes during COVID-19.

In the FDA Guidance on conduct of clinical trials of medical products during the COVID-19 pandemic, released initially on March 18th and updated on March 27th and April 2nd (with questions and answers), FDA addresses questions related to delays in on-site monitoring during the COVID-19 pandemic and recognizes access to trial sites may be limited or not available. With a focus on participant safety and trial data quality and integrity, the FDA expectation is that sponsors will identify alternative approaches to on-site monitoring and document these in updates to the Clinical Monitoring Plan. Some alternative approaches include enhanced centralized monitoring and off-site (remote) monitoring: review of subject status, data entry and query resolution, training, regulatory document review and collection, investigational product (IP) compliance, and safety reviews. More frequent off-site (remote) monitoring may need to be considered.

FDA has indicated that delays in monitoring should be carefully documented. Additionally, documentation should track protocol deviations and other GCP non-compliance issues that are a result of delayed monitoring visits due to COVID-19.

Side view of three artists working on computer at the office-1Study teams will be expected to conduct targeted risk assessments specifically focused on risks related to COVID-19 impacts on study conduct: new safety risks to trial participants; ability/willingness of trial participants to travel or travel restrictions that limit travel; continued availability of investigators, site staff and facilities; availability of trials supplies, vendors, and IP; gaps resulting from shifts in monitoring strategy due to restricted on-site monitoring. The outcome of this risk assessment should drive the mitigation response, which may include, but is not limited to: protocol amendments, holds on screening and enrollment, and updates to monitoring strategy and Clinical Monitoring Plan.

Study teams will need to determine which altered monitoring strategy best fits the current status of their studies. The study team should collect information on restrictions and the duration of those restrictions both for study participants and for on-site monitoring and confirm whether or not the site allows remote review of their electronic medical records (if applicable) or has some other secure way of reviewing site data remotely.

Study teams should ensure succession planning for themselves in the event of team member absences, limitations, or sickness related to COVID-19.

Vendor limitations or changes in service and reporting should be tracked and communicated to sites if impact is expected.


Sharon Duffy, Associate Director, Clinical Monitoring at Rho, has over 25 years of clinical research experience at both large and small CROs and sponsor companies. Starting as a CRA, she later moved into monitor training, process and compliance support. She received her B.A. in Biology from the University of Virginia.



Marina Acosta-Enslen, Associate Director, Clinical Management is a diversely skilled clinical research professional with 20 years of experience across Phase 1 through 4 studies. Prior to joining Rho, Ms. Acosta-Enslen has held positions in the areas of clinical monitoring, site level study coordination, site start-up, and clinical study management. Ms. Acosta-Enslen has extensive experience working on regional and global HIV, Oncology, Acute Pain and Vaccine clinical trials. Nearly half of her career has been focused in HIV/AIDS research working on NIH and industry funded clinical trials.

Statisticians and Critical Variable Review Help Streamline Data Management and Clinical Operations Activities

Posted by Brook White on Mon, Oct 24, 2016 @ 10:11 AM

Heather Kopetskie, Senior BiostatisticianHeather Kopetskie, MS, is a Senior Biostatistician at Rho. She has over 10 years of experience in statistical planning, analysis, and reporting for Phase 1, 2 and 3 clinical trials and observational studies. Her research experience includes over 8 years focusing on solid organ and cell transplantation through work on the Immune Tolerance Network (ITN) and Clinical Trials in Organ Transplantation (CTOT) project.  In addition, Heather serves as Rho’s biostatistics operational service leader, an internal expert sharing biostatistical industry trends, best practices, processes and training.

risk.jpgAssessing risk and using it to determine the focus of clinical trial activities has been an important goal in clinical research for a number of years now. One way statisticians can contribute to this is through critical variable review. In critical variable review, statisticians map the case report form (CRF) to the primary and secondary endpoints.

This review is important for several reasons and impacts all team members managing the clinical data. First, it ensures upfront that all of the data needed for the planned analyses are being collected. While this seems obvious, in an unfortunate number of cases, it is not until the end of the study that teams discover that all of the information needed has not been collected. Second, data managers can incorporate critical variables into the data management plan to focus edit checks, cross checks, and data cleaning activities on forms containing critical variables. Third, clinical monitors can focus the clinical monitoring plan on critical variables and ensuring key variables are reviewed during on-site visits but also during remote data monitoring.

Statisticians, data managers, and clinical monitors should start reviewing data as early as possible after first patient first visit with a focus on critical variables. Initially focusing on a report showing for each critical variable how many subjects are expected to have the data, how many have completed data entry, and how many are missing the variable. These reports can be used to identify issues early in a trial and determine how to address issues such site retraining that’s required, process changes when an assessment isn’t standard of care at a site, protocol deviations resulting from missing data, etc. As the study progresses descriptive statistics can be performed on the critical variables for investigators to review and ensure the study is progressing as expected without unblinding the study.

data-review.jpgAs data management evolves from data primarily being collected in an EDC system to data being collected from multiple sources such as EDC, ePRO systems, health electronic records, and central laboratories, additional strategies need to be implemented to ensure a clean integrated database for analysis. Instead of data managers providing all the data cleaning data managers, programmers, statisticians, and clinical monitors will need to collaborate. All members of the team should meet regularly to discuss progress and develop tools that will facilitate cleaning across multiple data sources. New tools and strategies will need to be implemented. We outline a few strategies we’ve piloted for collaboratively reviewing data early after database launch. Early looks at the data can provide a sense of how sites are entering data. Dealing early on with issues that arise will prevent lots of dirty data at the end of the study.

One strategy is an evaluation of all free text fields completed in the database. Sites may be entering data in the wrong place or collecting data that is not needed which can be fixed through site re-training. Additionally, this review can highlight additional fields or updates that need to be added to the CRFs.

Another strategy is code book reviews. A code book is a file which provides descriptive statistics on all fields in the EDC system that can be reviewed by all members of the study team. This is an easy way to identify outliers by data field and site-to-site differences. (Codebook examples and macros are available in Github.)

Statisticians and programmers can also compile data across multiple sources to identify what data fields are missing (ePRO not entered), what information doesn’t reconcile (e.g. biopsy date in EDC versus specimen collection system), what deviations may be expected from data sources outside of EDC, etc. and provide one succinct report for the data managers to facilitate communication with the site to reconcile and update data.

Additionally, constant communication between team members can bring to light common themes the clinical monitors are seeing during their visits, data managers are seeing through queries, and statisticians are observing during data preparation. This allows for early action which can minimize time spent at the end of the study to clean the data and lock the database.

One thing that has become abundantly clear is that a risk-based approach to clinical trials requires close collaboration between disciplines. Data managers, clinical monitors, and statisticians must work together in ways they have not in the past. Traditional models that rely on functionally-aligned silos will not allow risk-based approaches to succeed.

Webinar: Clinical Research Statistics for Non-Statisticians

4 Benefits of a Non-Regional Clinical Monitoring Strategy

Posted by Brook White on Thu, Jul 17, 2014 @ 05:06 PM

don't assign clinical monitors by geography

If you ask most CROs and Sponsor companies how clinical monitors (CRAs) are assigned to clinical study sites, the answer will be consistent: geography. Traditionally, CROs have employed a regional monitoring strategy for clinical trials, meaning a set of regionally-based CRAs (who often work remotely) are assigned to clinical study sites in their region. The main benefit of this model is a potential reduction in travel time and associated costs, since CRAs live and work in the same region as the study sites.

While travel related cost savings can be compelling, it’s important to consider the entire picture. In a traditional regional model, CRAs are often assigned to multiple studies at any given time, are required to handle grueling travel schedules with multiple site visits a week, and are forced to cope with the challenges of working remotely. Job satisfaction, monitoring quality, and project team cohesiveness can suffer and leave us wondering if there are alternatives to the regional model.

One viable alternative to the traditional regional model is a non-regional monitoring strategy. In a non-regional model, CRAs work in a central location (e.g. in the CRO’s local area) and are assigned to studies based on therapeutic expertise and availability, instead of geography. As a rule of thumb, for a typical Phase II study, 1 CRA is assigned to 8 to 10 study sites. Site assignments are made with efficiency in mind—one CRA might be assigned to all sites in a particular area of the country to allow for visit looping. There are many potential benefits to this alternative model, and we list four of the most significant benefits below:

1.  Increased monitoring efficiency and quality

In a non-regional monitoring model, CRAs are assigned to protocols and sites based on experience, not location, which means that CRAs can be assigned to fewer protocols simultaneously (preferably just one protocol). This model allows CRAs to be true experts on their assigned protocol(s), instead of juggling several different protocols. Protocol-focused CRAs are able to provide higher quality monitoring and better attention to their study sites. This model also reduces the number of CRAs that are needed to monitor a study and leaves the project team with a smaller, more focused team, which reduces administrative costs and leads to a more cohesive team.

2.  Reduces CRA burnout

CRA burnoutOne of the most reported causes of work-associated stress for CRAs is the need to juggle multiple protocols, which is a necessity in the traditional regional model.  CRA burnout can have significant cost and time implications for clinical trials, negatively affect monitoring quality and efficiency and team dynamics can suffer.  Using the non-regional monitoring model allows CRAs to focus on fewer priorities, which leads to more engagement and less burnout.

3.  Better project team integration

team integrationIn a non-regional monitoring model, CRAs are more fully integrated into the project team, both logistically (e.g. either working in the same office or able to easily attend meetings in the office) and functionally (e.g. being a true expert on one or two projects). This structure provides a sense of belonging, better team cohesiveness, more efficient meetings and increased ownership. Overall, this model contributes to CRA job satisfaction and a greater loyalty to the company, which often results in better CRA retention rates.

4.  Better set-up for risk-based monitoring

As the industry moves toward risk-based and centralized monitoring, it will be more critical than ever that CRAs work closely with the rest of their project team. Specifically, they will need to have strong relationships and seamless handoffs with project team members in data management and biostatistics who can assist with some of the strategies necessary to successfully implement a risk-based strategy. This type of team integration is more feasible in a non-regional monitoring model.

The clinical trial monitoring landscape is changing right now. The FDA’s recent issuance of its “Guidance for Industry:  Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring” demonstrates that the industry’s traditional approach to clinical monitoring can be re-configured in favor of more agile, efficient, and creative strategies. A non-regional monitoring model has the potential to increase the quality and efficiency of monitoring while increasing overall CRA job satisfaction and project team cohesiveness. 


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