Guest Blog | A Quality By Design Approach to Clinical Trial Monitoring and eTMF Integration

Guest blog by ShareVault. 

Per ICH GCP, Clinical Trial Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), GCP, and the applicable regulatory requirement(s).

The primary goal of clinical trial monitoring is to ensure that the rights and well-being of human subjects are protected, the reported trial data are accurate, complete, and verifiable from source documents and the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

Over the years, Clinical Trial Monitoring has evolved. When the original ICH E6(R1) text was prepared, clinical trials were mostly paper-based and monitoring visits were conducted on-site at a set frequency for every site, regardless of their enrollment, monitor workload at the site, or changes at the site. With advances in the use of electronic data recording and reporting, the amended ICH GCP E6 (R2) guideline encourages implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting, while continuing to ensure human subject protection and reliability of trial results. Since the release of ICH GCP E6(R2) Addendum in November 2016, sponsors have revisited their approach to monitoring and ways to implement a risk-based methodology that includes remote, centralized monitoring.

What is Risk-based Monitoring?

Risk-based monitoring (RBM) is an adaptive approach to clinical trial monitoring that uses data analysis to determine the need for performing on-site, remote and centralized activities, and leverages a Quality by Design approach that focuses resources on high-risk areas that have the most potential to impact patients’ safety and data integrity.

On-site monitoring has proven to be an expensive and inefficient process. Sponsors need to employ or contract a high number of CRAs to perform 100% source data verification on-site and getting resources out to sites all around the world results in high travel costs that must be factored into the study budget. With risk-based monitoring, the main goal is to use the CRA’s time more efficiently and effectively and many sponsors have had success in leveraging remote monitoring to achieve this.

By implementing a centralized monitoring strategy where remote SDV is done by a centralized team, efficiency is increased since it enables multiple sites’ documentation to be checked by a single team and highlights potential issues and trends across sites. Based on this information, sponsors can be more proactive in deciding which sites require onsite visits and what the CRAs should be focused on when visiting those sites. This dramatically reduces costs while proactively managing evolving risks to maintain patient safety, protocol compliance, regulatory compliance, and data integrity.

An Electronic Trial Master File (eTMF) is an important addition to fully implement risk-based monitoring. A key component of trial conduct and Good Clinical Practice (GCP) is the management and oversight of all documentation. Where source data are contained within the CRF or when electronic records are added to the eTMF can be accessed and monitored remotely. This allows for more efficient use of monitor time to focus on protocol-related activities while onsite (e.g., informed consent, endpoints that are interpretative or subjective, drug accountability/randomization integrity, source data verification) versus documentation.

Patients themselves are following local guidelines and mandates for suspending travel and potential exposure to the virus. For clinical studies, that presents a serious risk of missed pivotal visits and assessments. Centralized and remote monitoring enables the study team to identify missing pivotal data and take appropriate action, e.g. extending the study, amend patient visit schedules, enable virtual trial visits from the investigator.

In terms of the Trial Master File, because there has been limited to no travel and a hold in on-site monitoring, the focus on TMF work has increased. There have been ongoing discussions with sponsors around the considerations and adjustments that may be needed that are different from standard inspection preparation activities. Virtual inspections (including remote eTMF access) may be a new reality, and with that, it is imperative that the TMF is contemporaneous, and not just the documentation, but also looking at what the preparation and logistics around remote inspections will need to look like. For example, confirming availability of key inspection contacts both at the sponsor side and CRO team with the likelihood that the majority will be working remotely and determining who would be involved in the rapid response team and remote “war room” activities. There will likely be updates to protocol due to changes in monitoring visit schedules and the associated documentation that should be filed in the TMF.

There many advantages of maintaining an eTMF, including:

• The ability to create and upload documents directly into the eTMF increasing filing efficiency
• Reduced paper
• Real-time tracking and remote access and viewing of TMF documents
• Enablement of remote monitoring and increased visibility into the site—CRAs have a means to securely assess site documents remotely, allowing them to check if a site has its documentation in order and conduct source data verification. With this, the CRAs identify in advance (remotely) which documents might have a problem so they can make better use of their time while onsite with the site staff and concerns and issues are dealt with faster
• Shortened study start-up timelines. Having an eTMF system in place during study start-up allows investigative sites, monitors and sponsors to collaborate more effectively on finalizing documents (such as IRB approval, submission of all necessary regulatory documents and finalizing contracts and budgets), ultimately reducing the time it takes to activate the site

Today, although on-site monitoring is still accepted by regulatory authorities and widely used in clinical research, it is understood that traditional on-site monitoring may no longer be the most practical or safest form of monitoring. The COVID-19 pandemic has accelerated interest in the remote monitoring approach.

Patients themselves are following local guidelines and mandates for suspending travel and potential exposure to the virus. For clinical studies, that presents a serious risk of missed pivotal visits and assessments. Centralized and remote monitoring enables the study team to identify missing pivotal data and take appropriate action, e.g. extending the study, amend patient visit schedules, enable virtual trial visits from the investigator.

In terms of the TMF, because there has been limited to no travel and a hold in on-site monitoring, the focus on TMF work has increased. There have been ongoing discussions with sponsors around the considerations and adjustments that may be needed that are different from standard inspection preparation activities. Virtual inspections (including remote eTMF access) may be a new reality, and with that, it is imperative that the TMF is contemporaneous, and not just the documentation, but also looking at what the preparation and logistics around remote inspections will need to look like.

For example, confirming the availability of key inspection contacts both at the sponsor side and CRO team with the likelihood that the majority will be working remotely and determining who would be involved in the rapid response team and remote “war room” activities. There will likely be updates to protocol due to changes in monitoring visit schedules and the associated documentation that should be filed in the TMF.