From regulatory developments and standardization initiatives to technology trends, 2025 might not be a “big announcement” year for the Trial Master File (TMF), but companies that aren’t paying attention may get left behind.
Rob Jones, Product Manager for the TMF Practice Area at PharmaLex, speaks with us about the main TMF priorities for companies in the year ahead.
Q: A hot topic of conversation is the next version of the TMF Reference Model, version 4. Before we get into that, let’s talk a bit about the Reference Model in general and why it’s important.
Rob: Well, the Reference Model goes back to work initiated by Karen Roy, Lisa Mulcahy and others back in 2009, which now lives under the standards body CDISC[1]. In the simplest terms, the Reference Model is a single, unified interpretation of the regulations and best practices regarding the content of the TMF and is managed by experts from across our industry. Its main aim is to support every single trial and every single person trying to manage the TMF. It includes all essential records needed to show the conduct of a trial and the quality of the data produced is in line with core regulatory requirements.
It’s been a while since we saw our last major review with Version 3 being released back in 2015, with some further refinements in 2018 (version 3.1)[2]. In October this year at their US interchange conference in Arizona, CDISC announced its roadmap for Version 4[3] which guarantees to be a big shift for us.
Q: I’m sure that a new version will be welcome after so many years. What do you anticipate will happen with updates in 2025?
Rob: First, it’s important to note that Version 4 won’t be released until 2027, but that doesn’t mean we will all be standing still and waiting. In 2025, the TMF standards sub-group will start exploring what Version 4 will look like and bring together the teams who will help put together the next version. It’s also going to be the start of the new shift with a new person taking over from Karen Roy as Chair of the TMF Reference Model steering committee.
The team in Arizona at the CDISC Interchange shared that the new charter for the Reference Model is now finished and teams are looking at reviewing the zones, that others will be looking at standardized sub-artifacts (which, spoiler alert, will be requirements in v4), as well as reviews of standardized indexing, operational metadata and controlled terminology.
The zone committees, the Investigator Site File (ISF) committee, and the metadata committee have all been working in the background for some time and they will be collaborating more closely in 2025.
Q: Do you see more of a shift to digitalization in 2025 with the TMF?
Rob: There will no doubt be a few things moving forward and people will probably start to experiment a bit more with the large data model, but the thing that’s always going to hold us back as an industry is the fact that to really take advantage of these large language models — which are all the rage right now — we will need to be more collaborative. The challenge is both the phenomenal amount of data required and the fact that we are a very siloed industry. Throw in the fact that we are also a very risk-averse industry and taking advantages of some of these things becomes harder and harder.
Businesses are worried about crossing regulatory barriers, reputational damage, loss of data, and information getting to competitors. There are definitely forward thinkers in the industry, but often those are companies that don’t have access to the level of data to take the industry to that next step in digitalization of the TMF.
What I expect we’ll see happening is smaller groups, particularly from other industries, coming in and being the disruptors. They’re the ones that will challenge the status quo. Once that happens, every company will jump on board. Just look at cloud-based systems. We all know people felt a level of comfort being able to look at those blinking lights in a server rack.
Q: What’s your top advice for companies with regards to preparing the upcoming changes in 2025?
I think 2025 will be the year that we all look back at and realize this was the start of the big shift. So, my advice, keep your ears to the ground, because what happens in 2025 is going to be very telling as to where we finally end up. It will be the year that the work of the reference model committees really starts. Regulators are going to have a look at changes to their documentation once ICH 6(R3) goes live with the final guidelines[4], so companies need to be aware of that. ICH E6 (R3) is a full re-write and carries on from ICH E8 bringing in new standards and new ways of approaching trials[5].
There’s a danger of becoming complacent and assuming that, because there are no big announcements coming in 2025, you can sit back and relax. Companies don’t want to be caught flat-footed, so prepare your own TMF processes and review what has happened in recent years.
Make sure you are aligned with current regulations, that you are aware of any draft regulations, and that you understand your responsibilities. For example, ICH 6(R3) talks about the need to have full oversight of your TMF. Companies often outsource to contract research organizations (CROs) and never see the TMF until it’s transferred back to them. You aren’t going to get away with that anymore. Make sure you’re engaging with your CRO and you have real access to the data.
A few other considerations are that 2025 marks the full transition to the Clinical Trials Information System (CTIS)[6], so make sure documents that need to be filed in the TMF are in suitable locations, because right now the reference model doesn’t have a specifically defined area for CTIS records. There is also the retention period requirement where both sponsors and investigators will have to archive the content of the clinical TMF for at least 25 years after the end of a trial[7]. That raises questions about how you are going to store that data, especially data coming from your CRO. You can’t keep that on a DVD or USB stick for 25 years, so have you considered a foolproof way of protecting and storing that data for such a long time?
The other thing to think about is, given we’re using technology more and more, including for how we connect, what is the impact of the data we are recording? Consider Teams meetings, for example. Do you need to keep chat logs from your Teams meetings? I think we need to make common sense decisions about that type of data. Treat it a bit like those water cooler conversations we used to have when we were all office-based. We didn’t record them and upload them, did we? No, we went back to our desk and sent those ideas in an email after the discussion and those were then placed in the TMF.
Q: Being a bit provocative, can you offer one forward-looking step that companies should be looking to take in 2025?
Rob: To be honest, and bear in mind that I am the product manager for an eTMF solution, I do not see how it will be possible to be compliant with a paper TMF any longer. If we look at requirements as part of ICH 6(R3) and all the requirements within the Clinical Trial Regulation (CTR), mandatory use of CTIS, oversight, reporting, etc. –everything is electronic now. When you add to that Version 4 of the TMF Reference Model around standardized structures, metadata, digital data and so on, I cannot see how a paper TMF will be compliant. There’s going to be pushback on that.
Companies are concerned about costs and every new system is a new thing to pay for and maintain. But the question companies need to ask is, can they stand in front of an inspector in a few years, look them in the eye and say “we’re compliant with all the requirements” if you still have a paper TMF? I just don’t see how you can.
[1] Trial Master File Reference Model, CDISC. https://www.cdisc.org/standards/trial-master-file-reference-model
[2] Trial Master File Reference Model Discussion Forum, Resource Archive, CDISC. https://tmfrefmodel.com/resources-archive
[3] 2024 CDISC + TMF US Interchange Program, 23-24 Oct 2024. https://www.cdisc.org/events/interchange/2024-cdisc-tmf-us-interchange/program
[4] ICH Harmonised Guideline, Good Clinical Practice (GCP) E6(R3). https://database.ich.org/sites/default/files/ICH_E6%28R3%29_DraftGuideline_2023_0519.pdf
[5] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH. https://database.ich.org/sites/default/files/E8-R1_Guideline_Step4_2021_1006.pdf
[6] EMA Clinical Trial Information System (CTIS) Information Day, DIA, Oct 2024. https://www.diaglobal.org/en/ema/conference-listing/2024/10/ema-clinical-trial-information-system-ctis-information-day
[7] Guideline on the content, management and archiving of the clinical trial master file, EMA, Dec 2018. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-content-management-and-archiving-clinical-trial-master-file-paper-andor-electronic_en.pdf
