Floods, fires, accidental disposal, and misplacement of paperwork are all very real risks when it comes to storing and maintaining trial master files (TMFs). Even a cat sneaking into the office and soiling clinical trial documents is a risk, adds Flex Databases business development and marketing director Evgenia Mikhalchuk.
Data on paper is also harder to analyse, read, and understand, compared with a digital version. Enter electronic TMFs (eTMFs), which can address these issues. eTMF allows the software user to track trial progress and ensures that key forms are completed.
Since the pharma sector is already well within the digital world, major eTMF hurdles regarding the process of transitioning from paper to digital have been mostly overcome. The current challenge lies in correctly using eTMFs to prevent delay, which can become costly. There are ways to manage eTMFs without adding additional burden to clinical trial sites, as well as ensuring the trial is inspection- and audit-ready.
eTMF allows transition from paper to digital
Most of pharma has moved on from paper. For example, young biotechs like Cullinan Oncology never dealt with paper based TMF. “In our offices we have a lot of desks with file cabinets, but it is mostly for spare pens and the occasional snack,” CMO Dr Jeff Jones says.
But there are still cases where clinical trials use hard copies, such as investigator-led studies. It is hard to quantify how many sponsors or CROs still have cabinets filled with paper documents. Companies are not “raving” about how much of their data is still on paper, Mikhalchuk adds.
When transitioning into an eTMF system, every pharma company needs to decide whether it should maintain the eTMF or outsource this to a CRO, says Jones, adding Cullinan Oncology is currently at this crossroads. “It is like any other database, and it is ultimately dependent on the people that maintain it, but it really requires appropriate upkeep,” he adds.
Historically, companies would entirely rely on the CRO to host and manage eTMF systems and trial sponsors would have limited access, says Egnyte vice president of products Greg Neustaetter. But now, there has been a trend of sponsors licensing the eTMF systems themselves and providing CROs the software, allowing the sponsor to have increased real-time data visibility, he explained. “Many [sponsors] wanted to have much greater visibility and control over the data, because they are the ones spending money and it’s the future of their company that is at stake.”
Who should license eTMF?
Sponsors owning the eTMF license means it would have full ownership of the data, despite the CRO still being responsible in uploading information into the software. This is nuance is crucial, as relationships between sponsors and CROs may be on a trial-by-trial basis, Neustaetter says. Sponsors doesn’t want to be beholden to the CRO for the next couple of decades as trial data needs to be held by the license owner for ethical, legal, and regulatory reasons, he adds.
But there are still cases where a sponsor, especially a smaller biotech, would work with a CRO with the outsourced company’s own eTMF, says Egnyte life science director Abhay Kini. If the CRO has its own eTMF, it allows the CRO to have a helicopter view of all statistics, quality metrics, and milestones across all projects.
If the eTMF is owned by a CRO, the sponsor should create its own team to be intricately engaged in understanding what is happening in the trial at any given time, Kini says. Such a team would make sure data and documents are collected appropriately, he adds. “[The sponsor] has to keep a pulse on how things are progressing.”
For sponsors or CROs looking to implement or transition into a different eTMF, a team working closely with the software vendor is also ideal. “There will always be resistance when trying to learn how to use new things, so it is important to ensure change management within the corporate culture and teams,” Mikhalchuk adds.
Need to lift burden off sites
Whether the eTMF is licensed by the sponsor or CRO, its use should not be forced on the trial sites themselves, says Hugo Cervantes, vice president, Vault Clinical Strategy at Veeva Systems. Sites often run multiple studies at the same time, which can mean different eTMF systems, thereby risking errors.
With multiple eTMFs, trial sites might have to log in and out of different systems multiple times during the day, and there is the risk of accidentally uploading a document on to the incorrect system, Mikhalchuk says. “[We need to] avoid sites having sticky notes with passwords around the table,” she says.
One solution is that sponsors or CROs provide the trial sites a preconfigured website where they can upload documents, Neustaetter says. This website can alert delegated people who can address notifications, he adds. This way, the trial site is isolated from the intricate details how eTMF systems work, reducing day-to-day burden.
Alternatively, the sponsor or CRO can provide sites with an email address that is connected to the eTMF, Mikhalchuk says. After the documents are emailed, the system allocates them to correct folders and the sponsor or CRO can check the quality of the submitted documents.
Trial sites can have their own electronic regulatory binder technologies, such as investigator site files (ISFs). Some of these binder technologies can be automatically connected to the sponsor or CRO’s eTMF, improving the flow of documents, Cervantes says. Such binder technologies allow sites to manage their own clinical trial documents.
eTMFs should be inspection-ready
When TMFs were still paper-based, companies would rush to update TMF documents before an inspection or audit, Cervantes says. “Luckily, the industry has moved away from this,” he adds. Yet, remnants of this work culture remain.
If a sponsor or CRO has hundreds of sites at different stages within the same trial, it is hard to stay on top of which documents are needed at each site. Therefore, it is important to collect the data and documents contemporaneously while the study is going, Neustaetter says. “You shouldn’t wait until a trial milestone is completed to go back and find all the documents from the last three months. You don’t know when an inspector or an auditor may come to look at your data,” he adds.
“You shouldn’t wait until a trial milestone is completed to go back and find all the documents from the last three months.”Greg Neustaetter
Data integrity is key, and organisations need to adhere to the industry-adopted “ALCOA principle,” meaning that data needs to be attributable, legible, contemporaneous, original, and accurate, Kini says. Any deviation from ALCOA needs to be captured and history of changes recorded.
Sticking to the TMF reference model is also important. Some companies might be inclined to treat a document or store data in a different way, which can get them in trouble down the line, Neustaetter says. “The model has been created by hundreds of different organisations who’ve seen thousands of different trials, so there is a reason why the model is set up the way it is,” he adds.
eTMF should be viewed as vital tool in the clinical trial toolbox, not as a separate entity. Yet, while every aspect of our lives is moving to become digital, some pockets in the industry are still somewhat hesitant about trusting the technology. Mikhalchuk says, either they still don’t really know how to use a computer or they think that systems like eTMFs are there to spy on them; but digitalisation is here to make life easier. This way, there is backup to protect key documents from environmental disasters or accidents. And sometimes, from cats.
- eTMFs allow users to have real-time visibility of clinical trial progress and ensure completion of all necessary documents. Sponsors and CROs share the responsibility in ensuring the data is high quality.
- Including clinical trial sites in managing eTMFs can burden their operations. Instead, preconfigured websites, direct-to-system email addresses, or separate technologies like ISFs can be used to streamline trial monitoring.
- eTMFs should be updated contemporaneously to avoid last minute rush to complete necessary forms ahead of inspections or audits.