The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) defines a trial master file (TMF) as “the story of how a clinical trial was conducted and managed”. This means it must contain all the essential documents for a regulator and inspectors to review and evaluate the conduct of a clinical trial.
Although traditionally undertaken in a manual, paper-based process, increasingly pharma companies and charities carrying out clinical trials are embracing electronic TMF (eTMF) approaches in an attempt to drive cost -savings and efficiencies in the back-end of the drug development process.
Reflecting on the two years since it began implementing Veeva Vault eTMF, Cancer Research UK (CRUK) head of clinical operations and data management Stephen Nabarro discusses the benefits it brings to the cancer charity, as well as the challenges that have been faced to date and how he hopes technology will continue to drive clinical trial efficiencies for CRUK.
Flaws of the traditional paper TMF approach
“As a model [paper TMF] doesn’t work well…it’s not good practice,” Nabarro notes. It is a manual process, whereby filing and indexing is done by a person by hand – not only is this time-consuming, but “in reality, stuff falls through the cracks” and there is “inevitable human error”.
“Because the workforce is [moving towards] more and more people being home- based and dispersed, to say our official master and key documents for delivering a trial reside in an office in London is ineffective.”
And of course, physical storage space has a cost in itself, as there is a regulatory requirement to archive all documents for 25 years, meaning “there [is] a financial element of…getting everything up into the cloud and getting rid of paper.”
Time efficiencies from implementing eTMF
These flaws of paper TMF mean there can be significant advantages from moving to active use of an eTMF platform, if the process is properly managed.
Focusing on time efficiencies, Nabarro notes the benefit of getting away from manual processes for CRUK. He explains, as an example, that previously there was a person whose job it was to “take all the documents out of the filing tray, finding the right lever arch file and putting them in that folder”, which takes 15 hours a week across all of CRUK’s trials.
Using an eTMF makes document owners responsible for their documents and uploading them into the system, where it is automatically filed – removing the manual filing step entirely. This also makes document owners accountable if there are any issues with the document.
Another benefit is that in an electronic system, “you can instantly get a report or log from the system” and because the eTMF is web-based “you can access it from any computer anywhere in the world,” Nabarro explains.
Veeva vice-president of research and development strategy Rik Van Mol adds: “Our eTMF is managed in real time…document and content management capabilities are baked into the TMF tool, allowing documents to be curated and handled cradle to grave in the system.”
Van Mol also notes Veeva’s eTFM does more than just capturing and archiving the documents, which is the main way it differentiates itself from competitors.
Improving quality control and inspection readiness
As well driving time and resource efficiencies, Nabarro notes that implementing eTMF “can really drive quality on a permanent basis. We are permanently inspection- ready as a result.”
Nabarro explains using Veeva’s eTMF means everyone knows where the “single source of truth” regarding guidance about the drug and its clinical development is. He states the documents in the TMF are crucial “as they ensure patient safety and data integrity” related to that trial. As already noted, it is very easy to update documents in the eTMF so anyone can access the latest version from anywhere.
This compares to a paper world where regulators couldn’t be sure that everyone involved in the clinical trial was using the same version of the TMF; according to Nabarro, usually clinical research associates download a copy on to their desktop, and not necessarily be sure they had the most up-to-date version saved.
Van Mol continues: “Regulators really want to see a steady stream of documents being added [to the TMF]. [Not] a spike in documents being added in preparation for an inspection.”
“You can show your inspector that your eTMF is completed at any moment in time and that it is to the right quality.”
Challenges in implementing eTMF
“It’s easy to implement the technology and to write the processes of what people should be doing, but [it’s] very hard to get people [on board],” Nabarro states. “And the [two] need to be intertwined to have a successful implementation and embedding of technology.”
One notable example he gives is linked to the “single source of truth” and how although in theory this should improve inspection readiness and drive higher quality work, it can only do so if there is a culture change in the organisation.
On seeing that a scientist had only logged on to the eTMF once, Nabarro’s team contacted him to ask if he was having issues and whether they could help. To which the scientist replied, and Nabarro paraphrases, “I just need the protocols, so I just stuck a copy on my desktop and access it that way.”
Nabarro explained his team at CRUK tried to focus on answering the ‘what’s in it for me’ questions from researchers – he notes “the end users [of eTMF] don’t think about how this is better in the eyes of the auditor or how it is saving the charity money because we don’t need paper storage.”
It was important to CRUK to “make sure that first impressions were positive” and therefore, it more quickly became “embedded in the culture to actively use eTMF” along with its efficiency driving capabilities.
Nabarro concludes: “We’ve implemented [eTMF], we’ve successfully embedded it, and that final piece of making it became part of our culture is ongoing.”
Looking to the future, he is hopeful that CRUK, and the industry as a whole, will leverage technology to drive further efficiencies in delivering clinical trials – perhaps by removing the manual, paper-based work of trial sites and creating at least semi-virtual trials where patients are empowered to use technological solutions during their participation in trials.