How Risk-Based Monitoring Can Improve Clinical Trial Operations

With a move away from source data verification toward risk-based monitoring (RBM), trial sponsors and research teams can reap the rewards of centralized monitoring.

In this post, we explore the advantages of an RBM study, what to consider when employing this strategy and how the ICH GCP E6 (R2) Addendum mandates it. Let’s start with what centralization and risk-based monitoring actually mean.

The Meaning of Centralization

Camie Britton of Parexel tells Clinical Leader that centralized monitoring for the pharmaceutical industry is an evolving term and much has changed over the years. These days, centralized monitoring approaches “typically focus on the collection and interrogation of operational status and clinical data to adapt site monitoring and other clinical research interventions in accordance with various risk thresholds,” she explains.

Defining Risk-Based Monitoring

Julia Gorelova and Kirill Soldatov at PSI refer to RBM is an “adaptive approach to clinical trial monitoring” that moves the mindset from collecting lots of data and monitoring it indiscriminately to determining data that is “critical to patient safety and study endpoints.”

The purpose of risk-based monitoring is to focus resources and analysis on the data that matters and to guide trials with a clearer and more patient-centric approach.

The Benefits of an RBM Approach

With a clearer idea of how centralization works, Lynn King at Clinical Leader highlights the advantages of risk-based monitoring. These include fewer onsite visits and a shift from “100 percent source data verification (SDV) toward a combination of activities, including centralized data collection and monitoring.”

Part of this is because, rather than routine monitoring, RBM focuses specifically on risks that are pertinent to each trial site. “Handling every single risk the same way has proven to be inefficient, and, therefore, risks should be prioritized to be managed correctly,” King says.

Another benefit of employing RBM is that resources are proportionately allocated to levels of risk, rather than every risk receiving equal resources. The result, King argues, is safer patients, better quality data and more efficient trials as each approach is customized and nuanced.

Martin Giblin, vice president at Quintiles, explains how his company conducted a survey into the key considerations regarding RBM studies. He advised trial researchers to write up key risk indicators (KRIs) and establish protocols for responding to them.

Additionally, Giblin suggests that RBM will help researchers:

  • Use data more efficiently to track risk better and fix problems faster, while improving feedback and diagnosis
  • Improve data quality through real-time data monitoring by focusing and ranking key data points and how to clean them
  • Carry out fewer planned site visits based on triggers from data analysis, which brings down monitoring costs.

Cost Savings from Risk-Based Monitoring

Thomas Underwood at Quanticate says RBM, with the correct evaluation of risks, can help trial researchers go from using 100 percent source verification data to around 65 percent. Suitable risk evaluation also means sites need to be visited, in most cases, only when circumstances occur as outlined in the monitoring plan. These might include unusually high or low numbers of  adverse events, or other key metrics differing with similar sites.

Greg Ambra and Jean Battikha at DZS Clinical Services introduced an idea in the November 2016 issues of International Clinical Trials that could help smaller companies or companies with tight budgets gain even better access to RBM’s benefits.

Their method, known as targeted central statistical monitoring (tCSM), pre-defines certain key risk indicators — plus any other useful indicators — so researchers can more nimbly turn trial data into usable insights.

This method “creates cost efficiencies that can significantly benefit [the companies] without compromising data value or patient safety,” Ambra and Battikha wrote.

Combining Risk-Based Monitoring With Onsite Visits

A centralized statistical analysis team performing RBM does not negate the need for onsite visits. Moe Alsumidaie at Applied Clinical Trials describes pharma company Novartis’ monitoring  process as multifaceted with both onsite and risk-based monitoring.

The initial phase requires onsite monitoring to “evaluate study site quality specifications” for questions of staff training, potential protocol deviations, and issues of misconduct and noncompliance.

Assuming conditions are met, the onsite field monitor (FM) then passes on key recommendations to the central monitoring team to take over with continuous centralized monitoring. Sometimes the site will be judged as better suited to traditional onsite monitoring.

When the RBM team takes over, it “monitors the data in nearly real time to uncover inconsistencies, deviations, and data errors.” It also “conducts performance assessments to unveil poor performance, potential noncompliance, and misconduct.”

If any red flags are raised based on key risk indicators (KRIs), the RBM team deploys an FM to the site for a visit. Adopting this dual approach ensures the time savings and efficiency of RBM with the localized and first-hand analysis of onsite visits.

There Could Be More Work Involved

RBM is becoming increasingly more common and Nick May at Parexel argues that the cost savings are positive. He does warn that there may be more work involved for CROs if RBM is not carried out properly.

There can often be an increased complexity to data entry with higher numbers of online forms and automatic validations required.

To overcome the data requirements and increase the value of data, May advises trial investigators to enter data into the CRF “within a few days of the patient visit – regardless of when the next onsite monitoring visit is scheduled – reducing the volume to be entered at one time and, thus, resources required to complete the data entry.”

The effect is that the sooner medical reviewers can access the data, the sooner they can identify any potential risks, which results in more accurate data and safer patients.

What To Be Aware Of When Moving Toward An Risk-Based Monitoring Approach

While RBM is growing more popular, Sarah Ray at Cutting Edge Info, says “many clinical teams have shied away from embracing RBM in fear of damaging study results.” But this fear is misplaced, she argues.

Citing FDA guidance, Ray notes that RBM is a “dynamic, more readily facilitating continual improvement in trial conduct and oversight.”

Ray says when shifting from traditional source data verification to RBM, trial researchers should be aware of the following:

  • While RBM does not mean researchers will be required to do any less monitoring, there will be fewer on-site trials.
  • RMB focuses on “the most critical elements of a study design.”
  • RBM focuses on vulnerable data that can be easily corrupted and must be held to regulatory standards.

All of the above depends on “proper risk identification,” Ray says. This means trial research teams must pinpoint areas where data quality may be threatened. “RBM creates the opportunity for individual trial teams to tailor a monitoring plan to fit the unique needs of their studies, sites and subjects,” she explains.


The ICH E6 (R2) Addendum And What It Means For Risk-Based Monitoring

RBM is important not only because it can make trial data more accurate and studies more cost-efficient, but because regulations demand it.

The International Conference on Harmonization (ICH) Good Clinical Practice E6 (R2) addendum, created in 2016 and in effect from June 2017, mandates RBM for all clinical trials.

The United Language Group, an organization that helps companies achieve operational and business compliance, explains that ICH E6 (R2) helps regulatory authorities in different countries. This is so because data from ICH-compliant trials is more trustworthy and because it is “collected, recorded, and stored in an ethical way.”

The addendum was added to “standardize existing guidelines” from the FDA, European Medicines Agency (EMA) and other regulatory agencies to make internationally run clinical trials, more consistent with more accurate data and higher quality pharmaceuticals.

The E6 (R2) requires the “adoption of a centralized, Quality Risk Management (QRM) system to be used throughout the clinical trial process.”

With the revision, the ICH defines a QRM system as “a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle.”

“Complying with E6 (R2) requires working with internal stakeholders and external partners to make any necessary changes to the organization,” the group says.

Why ICH E6 (R2) Addendum Is a Positive Change

Steve Young, chief operating officer at CluePoints, says the finalized version of the ICH’s Guidance For Good Practice addendum E6 (R2) in 2017 means trial sponsors are being compelled to pursue an RBM trial design.

This is a positive outcome, Young argues, as it presents “tremendous benefits” and “significant opportunities” to organizations through intelligent analytics and centralized statistical monitoring.

ICH E6 (R2) states “the sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The sponsor may choose onsite monitoring, a combination of onsite and centralized monitoring, or, where justified, centralized monitoring.”

The aim is for improved operational procedures and simplification of data collection.

The addendum recommends RBM through a centralized monitoring team to provide “additional monitoring capabilities that can complement and reduce the extent and/or frequency of onsite monitoring and help distinguish between reliable data and potentially unreliable data.”

Whether or not trial sponsors can see the cost benefits of Risk-Based Monitoring, proper implementation will help them gather more accurate and relevant data, improve patient safety and ensure regulatory compliance.

Images by: auremar/©123RF Stock Photo, andreypopov/©123RF Stock Photo, wrightstudio/©123RF Stock Photo

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