In the world of clinical trials, if it isn’t documented, it didn’t happen. It’s a philosophy that has informed and embedded, standardized reporting approaches into on-site and remote monitoring.
But how do sponsors and CROs apply the maxim to the increasingly popular centralized monitoring model?
Frédéric Blais, PhD, Director Central Monitoring, CluePoints, explains how to record risk signals and corrective actions in a way that allows inspectors and regulatory authorities to “rebuild the story”, and enables study teams to harness the power of Risk-Based Quality Management (RBQM).
Since the ICH E6 (R2) addendum guideline was launched in 2016 to reinforce the insistence on the use risk-based approaches to clinical trials, an increasing number of companies, especially mid-sized pharma and small biotech companies have embraced the emerging method.
And in doing so, they have realized that the benefits extend far further than the essential compliance element. By enabling sponsors and contract research organizations (CROs) to focus on the data that matters most to each study, RBQM provides a way to monitor patient safety throughout, whilst planning and running more efficient trials that have a higher chance of operational success.
COVID-19 has accelerated progress in this area, as study teams moved to continue their work despite infection control measures such as social distancing and stay-at-home orders. This has resulted in sponsors having no other choice but to implement or increase their central monitoring capacity throughout in-flight and planned trials.
The people who have embraced centralized monitoring already understand that documentation is essential to ensuring a clinical trial is planned, registered, completed, analyzed, and reported in accordance with good clinical practice (GCP). They have been working within clear, robust frameworks that record and track on-site and remote visits via the clinical triage management system (CTMS) for years.
But centralized monitoring is a new way of looking at the data, and it requires new approaches to record keeping.
Document the Risk Signal Journey
Centralized monitoring, which compares patients, sites, regions and countries to spot patterns and identify outliers, provides study teams with statistical observations which could potentially point to participant safety or data quality issues.
To meet regulatory requirements, it is not enough to simply use this information to carry out an analysis – the process from signal identification to signal resolution must also be documented. Teams need to be able to demonstrate that they have considered each signal, and that any necessary action has been taken, as well as provide the rationale for their decisions. The impact of the actions taken need to be followed closely until signal closure.
Risk Signal Management
In CluePoints terminology, a risk signal is a statistically meaningful observation within assessed data. The signal management process starts when all risk signals generated by Data Analysts (either our own experts or those of the sponsor/CRO depending on who is using the software) are assembled in a risk signal report and is then provided to the Clinical Operations team and other stakeholder groups.
The sponsor or CRO then usually holds a cross-functional meeting, bringing together expertise from across these internal departments to ensure as much diversity in perspectives as possible. This internal meeting takes place soon after the release of the risk signal report, typically within 7 to 10 days. It is key to determine whether each risk signal points to an issue or not and lists all the potential causes which could explain the statistical observation. Finally, the team will select the most appropriate mitigation status and the next steps of investigation.
To create a robust audit trail which will document the full process, clients are provided with a ´Signal & Action Tracker´. This tool allows the study teams to document the mitigation status, (i.e., Alert, Watch, Standby or Closed) along with the rationale behind each choice and the action if applicable.
When a risk signal is mitigated in “Alert” and an immediate action is needed, it is important for teams to clearly specify what they expect the downstream personnel, usually the CRA, to do next. In some cases, the action will be further investigated, and the CRA will work with the identified site to understand the root cause of the issue.
It’s important to note that a signal points to a potential, not a definite, data quality issue. As such, the CRA should never accuse the site of misconduct, but rather use open questions to gather as much information as possible about their working practices.
They should also never dismiss the signal by assuming the reason is the most obvious one. If the approach is not root cause oriented, corrective action cannot be targeted.
Risk Signal Management in Action
If, for example, the risk signal was delayed entry of data into the Electronic Data Capture (EDC) solution, the study team or CRA may assume that the site staff are unaware of protocol requirements and suggest retraining as a solution.
However, other possible root causes could be a technical issue with the EDC, or the person responsible for data entry being off work, with no back-up identified. In either case, protocol requirement training would be no use. As a consequence, an open and fit-for-purpose discussion is the only way to ensure that the risk signal will be assessed from different perspectives and that the most appropriate corrective and preventive action will be put in place.
Ultimately, solutions only work when they are targeted at the risk signal’s root cause – but that’s only half the story. Because in regulatory terms, if a risk signal review isn’t documented, it didn’t happen.
CluePoints' Audit Trail Tools
As centralized monitoring continues to grow in popularity, it is important to ensure we apply the same level of rigor to documentation as we do in traditional monitoring methods.
One of the biggest strengths of the CluePoints platform is its ability to document all the steps involved in signal management in one place (i.e., the signal & action tracker). Our clients can record risk signals and the appropriate mitigation status, as well as the rationale behind these decisions. They can document the actions required of the study team, as well as the CRA’s feedback.
It means that inspectors and regulatory bodies can track the whole signal management process and rebuild the story, from the identification of the risk signal to any investigation and corrective action. And it allows sponsors and CROs to harness the power of centralized monitoring to protect data quality and patient safety, while ensuring regulatory compliance.