Contributed Commentary by Martina Tanner, PharmaLex 

May 9, 2025 | Regulators are tightening their scrutiny of the trial master file (TMF), placing the onus on companies to be ready for evaluation. Inspection-readiness should be embedded from the beginning, rather than a reaction to a notice of an inspection. 

In their metrics reports, inspectors are citing oversight of the TMF and sufficient documentation to demonstrate that oversight as priorities. To address any insufficiencies, companies are being urged to adopt a process-driven approach to how they manage the TMF and have buy-in from all stakeholders—both internal and external. 

Access is another concern raised by inspectors, specifically, who has access to the TMF, to what extent, and why. We have seen instances of inspection findings when multiple people involved in a migration had access to unblinded documents simply because that access had never been revoked. This has become a more prominent issue with the eTMF because it is now much easier to give people in other parts of the world access and then fail to remove it. Inspectors expect sponsors to review that access and remove it for people who no longer need to see those documents. Sponsors should also consider the level and type of access given, for example, to determine whether unblinded access is really required for certain roles or vendors. 

Proactive vs Reactive  

Before an inspection, it is not uncommon for sponsors to express concerns about the state of the TMF and the potential for critical findings. The extent of those concerns will depend on whether that sponsor is proactive or reactionary.  

Sponsors that adopt a more proactive approach will have processes in place to manage oversight of the TMF throughout the study. They are coordinating reviews of the TMF, often with vendor support, ensuring documents are in place, and carrying out cross-checks between associated documents to identify gaps. In this way, when it comes to an inspection, it is more a matter of some tweaks rather than a panicked approach to managing documentation.  

For reactionary sponsors, it is often a scramble to be ready for an inspection on time. While time might be pressing, carrying out an assessment can allow those sponsors to determine how much to invest in TMF inspection-readiness efforts and where to prioritize their resources. It can help them better understand what condition their TMF is in and categorize the risk level—high, medium, or low—based on document quality, poor indexing, or missing documents. In so doing, these sponsors can mitigate the most serious issues with their TMF and reduce the risk of critical findings.  

Defining Good TMF Practices 

First and foremost, sponsors must demonstrate that they are meeting good clinical practice (GCP) standards with regard to the structure, content, management and archiving of the TMF. 

There are several key elements to good TMF practices. The first is timeliness. If all of a sponsor’s documents are dumped into the TMF just before an inspection, that will be a red flag for inspectors. Most TMF systems allow users to pull metrics about when the document becomes available, for example, if it’s a monitoring visit, when did that visit take place and when was the document filed. By having metrics to measure against, sponsors can make sure they, or their vendors, are complying with processes.  

Another important metric to consider is the sponsor’s own processes and timelines. Are those documents being filed at the frequency the sponsor has committed to? Quality of the documents should also be prioritized. As a best practice, sponsors should review the documents to determine their accuracy and to ensure there are no confidentiality breaches, for example, patient identifiers.  

Documenting the process is another core element when performing a quality review. Document any findings and the process involved.  

A risk-based quality review of the TMF is good practice, but it’s important that sponsors establish how they are defining that risk. Determine how that is documented, what was looked at, what the findings were, and what was done to address those findings. Is there a specific methodology that is followed during the review? If a particular section of the TMF is chosen for review, make sure there is clear and adequate explanation for why that section or those documents were chosen. Inspectors want the rationale behind these decisions.  

A Holistic Approach to the TMF 

Inspections are always stressful, but much of that stress can be alleviated by taking a more proactive, holistic approach. Much like our own health, looking after the TMF, continuously giving it the care and oversight it needs, will prevent a last-minute panic. Looking after the TMF, building proper oversight into business processes, will help to reduce the risk of critical findings and will remove some of the pre-inspection pressure for sponsors.   

Martina Tanner is service line lead, TMF readiness, at PharmaLex. She leads the TMF inspection readiness group and helps customers to pinpoint the key issues within the TMF in order to be inspection-ready. Martina has been with PharmaLex for 19 years, gaining expertise in all aspects of the TMF. She can be reached at mtanner@phlexglobal.com.  

Disclaimer: 

The opinions expressed in this article are solely those of the author. This material may include certain marketing statements and does not constitute legal advice. PharmaLex, and its parent, Cencora, Inc., strongly encourage readers to review all relevant information on the topics addressed and to rely on their own experiences and expertise when making decisions related thereto.