We recently wrote about how implementing a risk-based monitoring (RBM) plan can improve clinical trial performance with clearer data, fewer site visits, lower costs and improved patient safety.
Here, we go into more detail about how best to create an RBM plan to enjoy these benefits.
What to Do Before Writing the Risk-Based Monitoring Plan
In an article for Applied Clinical Trials, Moe Alsumidaie, head of research at CliniBiz, lists what he regards as four of the most important tips to follow when writing an RBM plan:
Tip 1: Use a risk assessment categorization tool (RACT) to identify and rank risks. This will “improve the quality of risk assessment results,” he says.
RACT delivers the best results when used in the protocol development phase, Alsumidaie explains, “and can greatly mitigate study risks by enabling study teams to re-design the protocol, and study operations.”
Tip 2: Identify critical study risks. These can be anything from data collection and transfer to enrollment, and should be categorized according to data related to the study’s endpoints and patient safety.
Tip 3: Use critical risks to perform better analytical measurements. This is when key risk indicators (KRIs) become useful, which the RBM Consortium defines as “an objective measurement of a study-related parameter against a pre-set threshold providing a signal about the risk of a study process or any of its deliverables.”
Tip 4: Write the RBM plan in a structured and coherent way to make it accessible to auditors who may not be familiar with the study.
The monitoring plan should:
- Introduce critical study risks.
- Elaborate on each risk explaining why it is critical, how it will impact deviations and how it is connected to KRIs.
- Monitor non-critical study risks and non-critical study data.
- Be adaptable to accommodate changing methodology.
Creating an Risk-Based Monitoring Plan Requires a Holistic Approach
Jim Streeter, global VP of Life Sciences Product Strategy at Oracle, says it’s important to take a “holistic approach to RBM.” This includes setting up the clinical trial management system (CTMS) solution to include a RACT to help identify risks at the outset of the study.
KRIs will help trial researchers set up their RBM plans by understanding how to monitor and resolve risks as they arise. That data is added to a CTMS, while source data verification (SDV) support continues.
“As we look at risk, we need to ask, ‘How do we handle those risks? How do we address them? How do we record them back into the CTMS?’ It's important to record these,” Streeter explains.
This is not only essential to the integrity and success of a study, but it helps with NDA submissions as “regulatory agencies want to see at the beginning of the study that its risk was defined, how that risk would be addressed, and then at the trials end, that those risk mitigating steps were taken,” Streeter concludes.
The Parts That Make a Risk-Based Monitoring Plan Whole
In a Clinical Leader article, Ashok Ghone, Ph.D., VP of global services at MakroCare USA, also notes the need for a holistic approach to RBM and that includes risk assessment and risk management, as well as using systematic monitoring and controlling/mitigating risks throughout the study.
Ghone’s key aspects of an RBM plan include:
- Define KRIs, how to measure them and when to correct them.
- Outline monitoring strategies such as centralized, on-site and off-site monitoring, and how resources will be shared across these methods.
- Describe the roles and responsibilities of team members with “expertise from cross-functional areas.”
- Communicate and document centralized monitoring activities, including documentation process, issue escalation, and coordinating risk control and resolution.
- Decide on the technology to use.
- Ensure overall quality management by using efficiencies metrics and planning audits.
The Risk-Based Monitoring Plan Should Include All Stakeholders
Part of taking a holistic approach to RMB planning requires consideration and inclusion of all parties involved.
RBM plans need to be customized to individual studies and set up in a way that allows for easy analysis of data sets, Sollers College writes. But they also need to outline how CRAs and contract research organizations (CROs) will communicate the monitoring results.
Thinking about how the RBM plan includes IT system “evaluate the clinical protocol’s study sites and staff skill sets” is also important.
Action Plan for Risk Management
Planning how to monitor risks requires decisions on how they should be managed. Nancy Kathlen, senior manager global regulatory affairs at MakroCare, says that once study risks have been identified, a successful RBM plan requires seeking out the root causes of those risks. This is followed by how likely they are to occur and the significance of the impact they might have on the study.
What works well, Kathlen advises, is for trial researchers to use a 1-3 or 1-5 risk matrix and then to allocate risk levels accordingly. Rank scoring as low, medium or high-level risks, with the last requiring greatest emphasis when creating the RBM plan and allocating resources to deal with them.
The more pertinent risks, especially those that surpass any predefined risk threshold, will also require action plans to deal with them as they arise.
Four Actions To Take
There are four types of action plans for risk management, which Kathlen describes as follows:
- Avoid. To be implemented when there is no doubt the levels of risk will render the study impossible or incomplete.
- Transfer. Appoint another team outside “the sphere of influence” that can assume the risk.
- Accept. Refers to weighing up the balance of risk versus reward and then accepting that level of risk.
- Mitigate. This can involve minimization, elimination or reduction of risk or simply increasing the chance of detecting risks.
The Benefits of Centralized Monitoring
An RBM plan needs to involve plans of action to deal with risk. That requires mechanisms to track and control study risks, and identify any new risks that rise, Kathlen explains. This is best served by a combination of onsite and centralized monitoring.
The latter, which is remotely carried out by research team or contracted third parties away from trial site, offers advantages over onsite monitoring, including:
- Better monitoring of critical data and processes to improve trial quality and patients safety through analytical and visualization tools.
- Earlier risk identification.
- Fewer onsite visits.
- Better “oversight of study vendor/CRO or CRAs performances.”
Finding the Right Metrics
Linda Sullivan, Metrics Champion Consortium cofounder and president, reminds us of the wisdom of industry consultant Margaret Fay when it comes to RBM: “Plan, Do, Check, Act.” The idea is that improvement is possible only through measurement.
RBM, therefore, is improved by agreeing to standardized metrics “to plan and predict performance by identifying known risks, followed by a proactive stance on risk management, including upfront assessment and mitigation and ongoing risk monitoring,” Sullivan explains.
Considering this “feedback loop” when creating an RBM plan can help researchers “limit risk upfront in clinical trials, instead of reacting after the fact.” This is also reliant on past performance, Sullivan explains, and needs researchers to be asking and answering the correct performance questions and using metrics for better data analyses.
In 2016, Greg Ambra and Jean Battikha from DZS Clinical Services introduced the idea of targeted central statistical monitoring to help smaller research organizations identify the right metrics for them.
“tCSM utilises a unified eClinical platform that gives sponsors of small- to mid-sized organisations the opportunity to take a more proactive approach to statistically monitor administrative and clinical data, and to effectively identify risks without having to analyse each data variable,” Ambra and Battikha wrote in the journal International Clinical Trials.
“By defining many – but not necessarily all – of the KRIs early in the process, sponsors can implement a statistically driven and effective RBM system, including off-site monitoring and a more targeted approach to on-site visits, thereby lowering costs and improving efficiencies.”
Before and After Risk-Based Monitoring Plan Implementation
John Rodermund and Marcin Makowski from AstraZeneca refer to the different components of an RBM plan as being pre-implementation and post-implementation.
Pre-implementation refers to:
- Quality planning based on specific study risks.
- Devise a monitoring plan with centralized, remote and on-site monitoring included.
- Central review of data to determine amount of monitoring and intervention and at site level.
- Incorporate technology that allows for integration of data from different systems.
- Data that is entered in real-time.
- Ensure that the capability of risk monitors “to handle centralized monitoring signals of new nature.”
Slow Adoption of Risk-Based Monitoring
Despite the advantages of an RBM approach, the uptake has not been ubiquitous.
Researchers find that despite the ICH’s 2016 requirement for “sponsors to develop a systematic, prioritised, risk-based approach to monitoring clinical trials,” this has not happened. In fact, far from being a “gold standard,” RBM has not been widely adopted by sponsor organizations.
Of the study respondents, 13 percent were unfamiliar with RBM and 21 percent had used RBM in a clinical trial.
Barriers to the use of RBM include:
- Insufficient knowledge and training in RBM.
- Greater cost due to IT demands.
- Higher workload for trial staff.
The study concluded that training and greater awareness of regulatory requirements are needed to improve implementation of RBM in clinical trials.
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