Regulatory authorities expect sponsors to maintain proper oversight of the trial master file (TMF), yet often an inspection notice catches companies off balance. Anticipating the inspectors should, ideally, be engrained in good TMF management. First, though, it’s important to understand what the inspectors want and expect.
The article explores what it means to be inspection ready, drawing on my years of experience in guiding companies and their TMF through the process.
A whole system approach
At a high level, inspection readiness is about planning, preparation, and practice. What this comes down to is making sure the documentation is in place, that the TMF is complete, and that there is buy-in from all the stakeholders.
All too often, the TMF is thought of as putting documents into files or an eTMF system. But it’s much more involved than that and must be embedded into a company’s processes if they are to be inspection ready.
Inspection notices don’t give companies a lot of time to prepare, so having a reactionary approach is laden with risk.
Risk-based quality reviews
A good practice in preparation for an inspection is to carry out a risk-based quality review and to have proper management of that review. Since inspectors want to see proper oversight of the TMF, they expect sponsors to adopt a process-driven approach.
So, when conducting risk-based reviews, sponsors need to specify how they are defining that risk. Is it documented? Is it done consistently? Is there a methodology behind the review that is adhered to? What is the rationale behind selecting a particular segment of the TMF to review? Inspectors want to see the logic behind the approach. For example, what types of documents are included in the review and which areas of the TMF are in focus?
By determining the key pieces of the puzzle that will help to tell the story – such as evidence of safety, evidence of data collection, and so on — sponsors can demonstrate proper oversight.
TMF access control and oversight
While missing documents will get flagged during an inspection, one particularly noteworthy issue is TMF access. The number of people who have access to the TMF, particularly to unblinded documents, is becoming of greater interest to the inspectors.
A common issue is that people handling a migration are given access during the migration process, but all too often that is never revoked. Today, with the move to the eTMF, it’s much easier to give people in different geographies access to the TMF, which can be valuable but also risky if that access isn’t monitored and revoked as needed.
For example, a vendor might have been given access while they were supporting the TMF, but three years later that access has not been revoked. Inspectors want to see how many people have access to the TMF, their login frequency, and what was uploaded and assessed.
In past notifications from the inspectors, problems that were raised include wanting the sponsor to demonstrate proper oversight of their contract research organization (CRO), as required by the regulators[1].
For example, in an inspections metrics report published in 2023, the Medicines and Healthcare products Regulatory Agency (MHRA) noted in a review of a sponsors TMF that it “demonstrated insufficient oversight of the conduct of the overall trial and lack of freedom to act leading to an inability to perform the functions of a sponsor effectively and appropriately[2].”
In addition to thorough access control, sponsors should be ensuring all stakeholders are involved in preparing the TMF for inspection. That includes not only internal stakeholders, but also vendors contributing to the TMF.
Inspection readiness review cycle
There are several elements involved in conducting a review. One is completeness. It’s important to regularly cross-check between associated documents to identify any gaps and not leave these reviews until an impending inspection.
Timeliness is also key. Most TMF systems allow users to pull metrics about document availability; for example, if it’s a monitoring report, when did the visit take place and when was the document filed? Having metrics allows sponsors to measure against targets and make sure their teams are complying with the process. Inspectors will be looking at this and will notice if a large volume of documents is deposited into the TMF shortly before the inspection[3].
Compliance with processes is another important consideration. Is the TMF plan being followed accurately in terms of who is responsible for specified tasks, as well as document naming and filing within the specified timeframe?
Within the documents themselves, the priority is accuracy and that there are no patient confidentiality breaches.
Across all these steps, it’s important that companies document their review. What were the findings? And what was done to remedy any issues found?
Adopt a plan, prepare and practice strategy
Despite the best of intentions, teams often do get caught up with other priorities and must quickly pivot to inspection-readiness.
The first step is to create an inspection plan, including a team that will lead the inspection preparation. Then review the inspection notice and consider clarification questions for the agency. Establish an inspection project plan with milestones, roles and responsibilities, and clarity as to who should be kept informed.
The main focus of the rapid inspection-readiness plan will be spent on preparation. Sponsors can make use of their TMF systems to generate reports on quality, completeness, and timeliness and make use of vendors’ systems to fill any reporting gaps.
Then conduct a risk assessment and identify areas of greatest risk, paying attention to common inspection findings, such as missing documents, failure to upload documents regularly, lack of oversight of outsourced studies, no clear audit trails, and insufficient training on systems.
The final part of the preparation is to develop and implement a remediation plan. What can be remedied in the time available and what are the priority areas? Create and measure remediation key performance indicators against progress and set aside resources to manage that remediation plan.
The last part of the strategy is practice, since having a practice inspection can help the team prepare. The practice should include an inspection workflow with a draft schedule, an internal communications channel to handle requests, and a check of the systems. Delineate roles and responsibilities, including the internal contact person, subject matter experts, vendor representatives, and any support needed. Finally, do a full walkthrough of the inspection workflow, assess any issues with accessing files, and incorporate feedback into the workflow.
Following best practice for a TMF inspection
Many companies are caught short ahead of an inspection notice, which can jeopardize the study. A reactionary approach to a TMF inspection can leave sponsors scrambling to prepare, especially where there are finite resources and limited time.
Companies that build TMF inspection readiness into their processes, with full stakeholder engagement, inspection readiness review cycles, and proper oversight are far better placed to manage inspections. Not only will such an approach dramatically reduce the risk of negative findings, but it will also mean having a good quality TMF at the end of the study, which will benefit the company in the long term.
About the author:
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.
[1] Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic), EMA. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-content-management-and-archiving-clinical-trial-master-file-paper-andor-electronic_en.pdf
[2] GCP Inspectorate, GCP Inspections Metrics Report, 29 March 2023, MHRA. https://assets.publishing.service.gov.uk/media/64357bfe89f19f00133cfb40/GCP_inspection_metrics_2019-2020.pdf
[3] GCP Inspections Metrics Report, 12 February 2021, MHRA. https://assets.publishing.service.gov.uk/media/602a8e3cd3bf7f03190cbe43/GCP_INSPECTIONS_METRICS_2018-2019_final_12-02-21.pdf
