Introduction:
Trial Master File (TMF) experts are acutely aware of the growing complexity involved in meeting compliance obligations and improving overall quality and completeness.
As those working in the field know from experience, building and maintaining a robust TMF means staying on top of everything from changes in regulations to advances in AI and automation, as well as navigating partnerships.
The recent Fierce TMF Summit in Savannah, Georgia, gave participants the opportunity to hear from their peers and share their own valuable experiences in the fieldi.
We asked PharmaLex Trial Master File experts to provide a quick overview of their insights and key takeaways from the event. In upcoming blogs and webinars, our experts will take deeper dives into how companies are addressing these topics, including AI usage in TMF management, the impact of ICH E6 (R3), and overcoming resource constraints.
Room for improvement
Rob Jones, Director of Professional Services at Cencora PharmaLex, said it was clear from the summit that many companies, especially smaller ones, were still struggling to justify investment in the TMF.
“It’s not as simple as ‘we do this, we’re going to be two times more efficient and that’s going to save us money’,” he said. “You need to prove its worth early on and show benefits along the way.”
TMF Program Lead Erin Markle, who presented a session on TMF closeout with Rob, concurred.
“A lot of people are incredibly intimidated by the Trial Master File and how to navigate it,” she said. "Certain key members of the study teams weren’t necessarily seeing how important the TMF closeout can be and how it can contribute to budget implications, delays, and archival matters.”
Another theme to emerge was the difficulty of training infrequent users. Aaron Grant, Vice President Solutions Consulting, said there was a lot of brainstorming about how to get people to do the right thing the first time.
“How can you leverage things to get people who aren’t in the system much up to speed to do what they need to do quickly?” he asked. “It’s a human problem with technology capabilities – training needs to be documented and system help needs to be very controlled.”
Jake McDonald, Manager of Business Analysis and Solutions, noted a common hesitancy among teams to buy in to all functions of TMF management.
“They think it looks like an extra 10% of what they have to do and sometimes they feel it shouldn’t have to be done,” he said. “There were a couple of presentations on how to promote buy-in from those users and it was great to see the different methods of trying to alleviate the issue.”
Regulation and inspection concerns
There was a lot of discussion about ICH E6 (R3) on Good Clinical Practice, which aims to provide a “unified standard on the mutual acceptance of clinical trial data” across member countries and regions.ii
With the guideline still out for consultation, there was concern during the Summit about how it could affect the management of essential records, including the TMF.
"The big thing is that it’s a full rewrite of that regulation, rather than an addendum, and people are wondering what that is going to mean,” Rob said. “The original came out in 1995 and the addendum in 2016, so that’s 20 years of something (and) suddenly having a brand-new regulation. It’s still very much “let’s wait and see.”
Rob also noted continued concern and confusion among attendees about audit trail reviews, which he believes is driven more from inspection results than regulation.
“My feeling is that comes from the issue that we’re still straddling this line between paper and electronic, and we don’t want to make the decision of saying ‘no, paper isn’t suitable anymore’,” he said.
“It’s very complicated and if people were to do what the inspectors are talking about, it’s a big job. It’s not realistic. I think everyone’s looking at it and saying ‘what is it that they actually expect from us’?”
With ICH E6 (R3) also addressing remote inspections, Aaron said the Food and Drug Administration’s (FDA) push to give inspectors more remote access to systemsiii was a hot topic.
“People were talking about how they want more access before they show up (for formal inspection),” he said.
The role of AI
Jake noted a positive shift in discussions about AI, from concerns about potential risks to ways to address those risks, with people growing more comfortable with the technology.
“They’re open to new methods of its use, which starts to advance the outlook of what AI can do within the realm of clinical trials,” he said.
“There was a panel of users who were talking about how they’ve worked with AI, the benefits they’ve seen, and how they’re dealing with shortcomings. It lays the groundwork for potentially being able to draw information from documents to help plan further studies.”
Aaron said there was an interesting conversation around digital workers (i.e., bots) and validation. “It’s so much easier to treat them more like people than computer systems when you talk about validation, or how you integrate AI into your workflows,” he said.
Erin also sees merit in this approach to AI and that means allowing for fallibility. “People want AI to be 100 percent accurate, but there’s still going to be things that it may not be perfect on,” she said. “You need a second pair of eyes – the human – to detect and determine where certain things should go in the TMF, especially when it comes to auto-classification of documents.”
The way forward
While it was clear that the challenges for organizations navigating the TMF remain significant, the key to managing change lies in collaboration.
And for Rob, that advocacy must come from the top. “The companies working best are those that have people at the top who care about the TMF and champion it. If the people in your TMF don’t champion it, they are only going to get so far.”
Consumer Success Leader Janice Cassamajor said the spirit of cooperation was evident throughout the summit.
"There is an undertone of true partnership in most conversations, especially with contract research organizations (CROs),” she said. “There is a desire for community among TMF stakeholders to share best practices.”
Rob said the networking around the formal presentations was just as important.
“Pharmaceuticals is very guarded and people get up on stage and say what they are allowed to,” he said. “What’s nice to see is that once people are off stage, they are happy to sit down and talk with anyone and share, warts and all, what’s happening, their experiences, feelings and frustrations.”
This article/blog is intended to communicate PharmaLex's capabilities which are backed by the authors’ expertise. However, PharmaLex US and its parent, Cencora, Inc., strongly encourage readers to review the references provided with this article/blog and all available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto as the article may contain certain marketing statements and does not constitute legal advice.
[i] Advancing TMF Processes, Culture and Excellence. https://www.tmfsummit.com/
[ii] https://database.ich.org/sites/default/files/ICH_E6%28R3%29_DraftGuideline_2023_0519.pdf
[iii] https://www.fda.gov/media/160173/download