The Trial Master File (TMF) tells the story of a study through all phases of drug development. The documentation filed gives evidence that the trial was conducted in accordance with standards of Good Clinical Practice (GCP) and regulatory expectations. This story becomes the cornerstone of inspection readiness. The purpose of a regulatory inspection is to confirm that the study was conducted in compliance with regulatory authorities and ICH-GCP, to confirm the integrity of the data, and to ensure human subject protection. How does Just in Time GCP (JIT) use the power of the TMF to influence the story of the study?
TMF – The Story of Your Clinical Trial
The TMF tells the sequence of events for a clinical trial that includes chapters and verses with subplots and intermingled stories. The question is, how do sponsors ensure a compliant, complete, and accurate account of the story of the study? The simplest answer is routine TMF completeness reviews. These reviews occur at set timepoints or milestones throughout the life of the study and are built into CRO TMF management and sponsor oversight activities. They ensure that completeness gaps and trends are identified and then remediated in a timely manner.
- Each milestone or specific study activity triggers different documents to be required in the TMF.
- Performing consistent reviews provides accountability to the responsible parties and issues actionable deliverables to ensure inspection readiness at all milestones.
- Aside from providing missing documentation, completeness reviews can provide valuable information regarding process gaps in standard operating procedures, inspection readiness, and GCP compliance.
A Deeper Dive: Missing Training
An example of missing documents that can have differing outcomes are site trainings. If protocol trainings are missing from a set of sites, was it because…
- Training was not collected?
- Training was not performed?
- Training was not documented?
If we identify that training was performed but not collected, this could be a training issue for clinical operations.
If the training was not performed, this would be a training issue for both the study team and the sites.
If we identify that training was performed, but not documented, we can implement a process to ensure that all sites are documenting training in a consistent manner.
Fixing a high-risk problem such as missing trainings allows sponsors to impact and oversee the outcome of the story. If these risks and gaps are not identified until the end of the study, then the story could show lack of inspection readiness, inappropriate oversight, and poor GCP/GDP.
Demonstrating Oversight
Communications are a common way to show oversight and provide additional information. Communications related to study management, protocol instructions, safety information, or key decisions should be filed in the TMF. It is important that the sponsor understands the stories the communications are telling because these are often reviewed by an inspector during a regulatory authority inspection.
Study plans are a critical component to managing the clinical trial and providing clear expectations to all parties involved. The Clinical Monitoring Plan is a high driver in compliance and monitoring activities. If monitoring is not conducted in alignment with this plan, there can be compliance ramifications. When performing completeness reviews, it is important to understand monitoring expectations so assurance can be given that the TMF documentation is aligned with the plan.
- For example, if the monitoring plan states that IP accountability documentation will be collected at each visit, but the CRAs are waiting until the end of the study to collect this. we can suspect a couple of things: the monitors have not been trained on the Clinical Monitoring Plan or there was a change in practice, but the plan was never updated. A routine completeness review of the TMF would identify this and give a timely opportunity to address and remedy the issue.
The key to completeness reviews is having proper documentation of the issues and to take swift action on findings. It is critical that action items issued as part of completeness reviews are resolved in a timely manner. This ensures proper oversight and it is a great opportunity to influence the outcome of the story in a positive way.
JiT As a Partner
JIT’s team of consultants, operations leads, TMF managers, and TMF specialists can be a short-term solution to resourcing needs or a long-term solution for your study team. We develop TMF plans, conduct ongoing risk-based completeness reviews, working with all parties to ensure you have an inspection-ready TMF. Contact Just in Time GCP now to talk about your TMF management service needs.
