The clinical trial master file (TMF) is “the collection of essential documents which allows the conduct of a clinical trial to be reconstructed and evaluated”. It is the story of how a trial was conducted and key decisions made during its conduct. It is also a regulatory requirement. Even under normal circumstances, managing a compliant TMF is a complex undertaking that most clinical sponsors struggle with.
Given that trials may involve hundreds or thousands of patients in multiple geographies with a range of external stakeholders' involvement, the TMF can easily run to hundreds of thousands of records. Many companies treat the TMF as a necessary evil and, as a result, fail to exercise enough real control over its management. From our experience working with clinical sponsors, we see five common problems associated with the TMF, including:
- Missing records of essential documents.
- Poorly defined TMF structure.
- Records filed in the wrong locations.
- Untimely filing of essential documents.
- Poor-quality oversight of the TMF.
The COVID-19 crisis has multiplied these challenges for TMF management severalfold. As different countries and regions have become impacted by the virus, trial managers have had to take numerous steps to prevent disruption, such as virtualization, modified site-monitoring practices, home-based infusion, changing country footprints and sites, and program extensions.
In crisis mode, it is easy to relegate quality assurance documentation to second place. However, health authorities (HAs) are clear that good clinical practice (GCP) is not being suspended during the crisis.
Challenging as it may be, the right steps need to be taken now to manage the TMF in order to minimize the risk to patient safety, data integrity, critical inspection findings, and major remedial costs later.
The best way to respond
First of all, clinical sponsors need to accept that significant additional activity will be needed to ensure that the TMF is kept under control during and after COVID-19. It will not be enough to continue with business as usual.
Based on our recent work with clinical sponsors, we recommend four key steps:
- Assess the risks
- Document the impact
- Develop a plan for ensuring
- Maintain the storyboards
1. Assess the risks
The first step is to understand the risks of COVID-19 for the trials you are running. One complication is that HAs in different countries and regions issue new guidelines regularly. It is important to work closely with your regulatory intelligence and quality teams to understand the guidelines, as well as identify differences and commonalities in requirements. Categorizing these differences is helpful to ensure that you have a clear overall picture.
2. Document the impact
Because events move quickly, you need to ensure that you have a complete and documented account of what is currently happening in the trial – by country, by study, by site – and if and how any changes are being made in response to the crisis. Documenting the reasons and rationale for any changes to your normal business practices and procedures is key.
3. Develop a plan for ensuring GCP
This core step involves defining how GCP will be maintained given the changes necessitated by COVID-19. Deviations are bound to occur across key elements of the study including:
- Patient treatment.
- Site communication and engagement.
- Data integrity/study interpretability.
- Vendor oversight.
- Site monitoring.
- Specific decision-making by study.
A robust plan should be developed to ensure the TMF records reflect the deviations.
4. Maintain the storyboards
Given that HA inspections may not occur for several years for current studies, maintaining a clear and complete story of events as they happen is important. This is especially true when situations change weekly or even daily, because it leads to increased volume of notable decisions being made and risk of knowledge loss if storyboards are not developed and maintained through the pandemic period.
Recent advances in data analytics, artificial intelligence, and machine learning (ML) have the potential to transform clinical operations. For example, we have pioneered an ML-powered predictive analytics tool for managing clinical trials. Such tools can be further leveraged to improve TMF management by providing early indication of deviations and supporting rapid decision-making to ensure GCP.
If you would like to know more about ADL’s expertise in clinical trial strategy and operations, please contact us.