When faced with an FDA inspection, sponsors, CROs and sites must be ready to present trial master files (TMF) that are up to date and give a comprehensive account of the study. And the most efficient way to ensure they are is to maintain a constant state of inspection readiness with a regular TMF review schedule.

What does it truly mean to be inspection-ready? According to Laura Wiggins, TMF services project manager at Just in Time GCP, it’s being able to detail the full course of a trial through the TMF — to tell its tale and paint a clear picture of all that occurred during the study.

“We know that no study is ever perfect, but we want to be able to tell the story of your study,” Wiggins said during a WCG webinar, where she provided tips on TMF inspections. “Inspection readiness is ensuring that the people, processes and evidence of trial conduct are present for regulatory review.”

This concept of “inspection readiness” is critical and revolves around focusing on TMF quality, timeliness and completeness. Reviewing the TMF periodically to ensure it’s being properly maintained — with documents organized, complete and readily accessible — is essential. It’s a good idea to start these reviews by going down through the TMF map, or index, checking documents and ensuring all filing locations are accurate, Wiggins says. This is especially important because things can and do change throughout a trial, and certain documents may end up needing to be filed that weren’t anticipated at trial start.

“Take your TMF map and walk through each zone. Go right down the line,” she said. “Walking through that TMF map, you can take every artifact and really drill down, what did we have vs. what did we expect?”

For study team staff, for instance, you’ll want to check and make sure that curricula vitae (CV) and training documents are filed for all employees, including any handover documentation (documents that explain the tasks and responsibilities of outgoing staff members to their replacements) as applicable. For the investigational product(s), all relevant documents and records should be filed and approved as required, while documentation for each lab involved in the trial, such as head of facility CVs, accreditations and so forth, should similarly be reviewed to ensure they’re up to date, approved as required and present. And patient documents like logs and serious adverse event reports should be checked carefully to ensure they don’t contain protected health information. These documents should also be cross-checked to verify that information, such as the number of randomized participants vs. number of participants visited at a site, all matches, Wiggins advised.

And every piece of information must be in the right place in the file. Challenges finding documentation are serious red flags in the eyes of the FDA and draw out inspections that could have otherwise gone much easier, notes Eric Pittman, program division director for the FDA’s Office of Bioresearch Monitoring Operations. Thus, it would behoove sites and sponsors to have a well-organized methodology in place for maintaining their TMFs.

“A sign of the lack of preparedness for an inspection is the [organization’s] difficulty in locating records needed,” he said. “The lack of an organized system for records leads to additional questions and ultimately increases the time an investigator is on-site.” (CenterWatch Weekly, May 6, 2019).

As part of a deep TMF review, also evaluate study plans, agreements, transfer of regulatory obligations, monitoring plans and oversight plans to ensure that they were truly followed.

Beyond reviewing the TMF intermittently, having a solid TMF plan is critical to achieving quality, completeness and timeliness, but problems will obviously arise if the plan isn’t followed. A strong TMF strategy establishes the frequency of completeness reviews, filing timelines and responsibilities for filing documents, but it also establishes evidence. Some key things to consider include:

• Which SOPs were followed and if there is evidence they were followed;
• Whether the vendors/CRO train all study team members and if there is documentation filed in the TMF for this;
• Whether oversight was conducted and evidence that the internal study team knows its responsibilities;
• Documentation of changes and deviations that can be traced, linked to data and supported by reasonable proof of resolution; and
• Compliance with regulatory requirements for reporting.

Electronic trial master file (eTMF) systems can help with the task. They can flag documents that aren’t finalized — documents that may still be in progress, rejected by quality control or awaiting quality control review. This assessment is helpful for rounding up documents still in need of approval.

Clues can also be drawn from previous completeness and inspection readiness reviews, Wiggins said. Go through past assessments (which should be documented in the TMF to show proof of oversight) with an eye for queries and whether they were answered. While this can help identify queries that may be blowing in the wind, it may also identify a lot of work to be done, she cautions. But doing this can bring different functional groups into the mix that may have competing priorities and different perceptions of the TMF’s importance.

“You might need to assess what queries are of highest importance to review and close based on your timelines and available resources. We all know it’s hard: there’s time constraints and resource constraints, so sometimes you’re going to have to triage those queries,” she said. “In doing so, you can help engage functional groups with a clear and common goal.”

Getting different functional groups involved and identifying the people within them who can help contribute toward TMF inspection readiness is also critical. Overall, departments should fully understand how their content is linked to inspection readiness. Missing CVs or training files from one group, for example, means that the TMF is incomplete. Help all groups understand their obligations and risks and offer support on managing them, Wiggins says.

“You want to bring functional groups together for a common goal of understanding the story of the study and find champions within each department who can help drive change,” she said.