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The pharma industry has had a year to address MHRA’s April 2014 update to the definition of a critical GCP inspection finding to include trial master files(TMFs) that are “not readily available or accessible”. How has it fared? Rik van Mol reports.
The life sciences industry has had a year to address the Medicines and Healthcare Products Regulatory Agency’s (MHRA’s) April 2014 update to the definition of a critical GCP inspection finding to include TMFs that are “not readily available or accessible”. In that time, a growing majority of companies have adopted operational and technology strategies to meet or even exceed the MHRA’s expectations.
Although a motivation to move towards eTMFs was indisputable, the technology landscape at the time this transition began was not structured to support increased regulatory and changing business models. Since then, some technology providers have addressed these challenges by evolving the eTMF from a static, end-of-lifecycle archive repository into an active, in-process, accessible solution.
A year after the MHRA update, the industry is starting to make progress. More and more sponsor organizations and CROs are leveraging purpose-built eTMF applications to increase the scope and functionality of their TMFs, providing unfettered accessibility and inspection readiness while improving the overall efficiency of clinical operations. “We had an audit last year, and it was much easier to prepare and to ensure completeness,” said Linda Danielson of the International Drug Development Institute (IDDI), a Belgium-based clinical data service provider.
The start of the transition: paper and inefficiency
Variances in the design and sophistication of early systems help explain the MHRA’s assertion that many TMFs failed to meet inspectors’ expectations for accessibility and completeness. When Veeva Systems surveyed more than 180 TMF owners earlier this year, one-third of the organizations reported working with either local file-share systems (18%) or cloud file-share options such as FTP sites (15%). More than one-quarter (28%) of respondents reported using generic content management systems to store and share clinical trial documents, whereas only 18% had implemented life sciences-specific eTMFs.
According to Franciska Darmer, a former auditor with a global drug maker who recently joined Veeva, early versions of eTMF systems were little more than electronic filing cabinets. “Local file shares and FTP sites were the go-to choice for many early adopters. Unfortunately, these systems lacked robust functionality, failed to process the vast volumes of documentation associated with a clinical trial, and did not meet the accessibility requirements of the inspection process.”
“To be inspection ready, sponsors must be able to quickly organize all documents related to the trial, and make them easily accessible to inspectors,” Darmer continued. “In cases where sponsors didn’t consider the external usability of their eTMFs, inspectors were forced to navigate cumbersome filing systems and thousands of unrelated documents, plus could not access trial documents in real time.”
“Government inspections are a critical part of protecting people, but they are complex and time-consuming, both for pharmaceutical manufacturers and the FDA, due to the sheer volume of data and documents that have to be scrutinized,” said a spokesperson for the FDA. “There was a transition period when more manufacturers started moving their paper documents into basic electronic systems, but many were still difficult to access.
“However, for those organizations that have made the switch to modern, accessible technologies such as cloud eTMFs, we’ve seen a significant improvement. The same inspection that involved paper documents five years ago, today takes less time and is more complete, streamlining the inspection process. As technology matures and the industry becomes more accustomed to this new model, we anticipate continued improvements in inspection efficiency.”
Key attributes of successful next-generation eTMFs
To improve the inspection process, sponsors and CROs have begun moving to purpose-built cloud eTMF solutions. In fact, with an increase of 15% on 2014, one in four (24%) sponsors and CROs now rely on next-generation systems to meet four key requirements:
Integrating the latest eTMF technology into modern working practices
“The vast majority of proposals CROs submit today include some form of modern eTMF support,” said Nigel Jones, Vice President of Global Clinical Development at TFS, a global full-service CRO headquartered in the UK. “We invested in a robust, accessible eTMF solution to support our expansion across continents, and have since realised the cost and time savings that come from a streamlined, automated system for sharing and storing all trial documents. In the past, our project managers could spend weeks working with a client to prepare the TMF for inspection. Now our researchers use the time they used to spend chasing documents to act on trial data, rather than just collecting it.”
In particular, cloud-based solutions are well-suited to supporting this type of paperless environment, as they offer the highest level of collaboration across a diverse set of participants. Sponsors ensure consistency and adherence to process controls by creating documents directly in the eTMF system. With multiple parties submitting information to the TMF remotely throughout the lifecycle of the trial, automated standards are in place to ensure quality up front. Missing documents are brought to sponsors’ attention throughout the trial, and incomplete documentation is identified early in the process and sent back to the study team for immediate correction. A sponsor’s ability to quickly identify and rectify errors means that quality control is built into the process. The result is a TMF that is always inspection ready.
Renee Fate is a senior manager responsible for document management at Kythera Biopharmaceuticals, a clinical-stage biopharmaceutical company that develops therapies for the aesthetic medicine market. Fate said that Kythera’s new eTMF system provided the rapidly growing company with a single platform on which to collaborate with partners efficiently and ensure inspection readiness at all times. “Since adopting a cloud eTMF, we’ve been able to shave at least 40% off the time needed to reconcile TMF documents at the conclusion of a trial. Now we have full visibility and can track the status of the TMF in real time for the duration of the study.”
Even before the MHRA issued its guidance to simplify eTMF navigation, one of the biggest challenges that sponsors and CROs faced when implementing eTMFs was getting people to use them. Typically, eTMF and content management systems proved overly complex and cumbersome to navigate. Over the last year, more sponsors have started implementing improved eTMF systems with simplified operations to satisfy inspectors’ ease-of-use requirements. Technology providers are adopting best practices from consumer e-commerce, developing familiar, Amazon-style user interfaces that allow all parties – including regulators – to share, review, and access trial documents without extensive training or understanding of the system architecture.
Now, using an eTMF is becoming a natural part of the clinical trial process workflow, which ensures that study findings are reported as they happen and status reporting is more accurate and effortless. Real-time insight into trial progress allows the entire team to finally collect data throughout studies, and use that data to make better decisions about commercial strategy and therapy effectiveness. Over time, data-driven trial optimisation will result in more efficient trials and faster time to market.
Some forward-thinking organizations are already unlocking the benefits of TMF metrics. In the Veeva 2015 Paperless TMF Survey, the companies that reported extensive use of performance data saw markedly more benefits from their eTMF systems than those that did not collect metrics. For example, these organisations noted greater audit and inspection readiness (82% versus 25%), easier collaboration with sites (41% versus 25%), and faster study startup (41% versus 8%).
Kythera’s eTMF solution allows the internal auditor to regularly run a full range of standard and ad hoc reports, giving a more accurate view of trial progress. According to Fate, “When everyone has visibility into the reports, it removes a lot of questions at team meetings and on the phone with our CRO. We are all spending less time meeting and more time working.”
Automated filing and accessible data-sharing systems mean that internal auditors have the opportunity to redefine their roles and do more with less. Cloud eTMF solutions allow auditors to manage the quality of TMFs remotely and in real-time, ensuring compliance without the need to visit multiple sites and spend weeks at a time on the road.
“In the past, our auditors were used to enduring a 48-hour or longer wait for a box to arrive from off-site storage, only to find that it didn’t contain the desired document,” Fate described. “Today, the correct documents are retrieved in seconds. With our cloud eTMF, my audit teams are travelling less, and spending more time ensuring quality and analysing trial effectiveness. Having immediate, remote access to the appropriate documents is transforming our audit team’s role from compliance manager to insight gatherer.”
Sponsors, CROs, and health authority inspectors all have similar goals: to be able to access the TMF easily, whenever and from wherever they are. Cloud technology provides this type of ubiquitous access, but when also linked innately to clinical processes, the TMF becomes more than just an electronic record. Fully unlocked, next-generation eTMF solutions can be strategic assets that not only dramatically improve the inspection process, but also offer sponsors the type of insight within and across trials that drives long-term improvement for clinical programs.
The switch to solutions that support global compliance, as well as improve overall study efficiency and effectiveness, is likely to continue not just to meet health authority requirements, but also to bring potentially life-saving products to market faster. The success these pioneering organisations are achieving could have a significant impact on the shape of study management and the clinical technology landscape for years to come.
About the Author
Rik van Mol is Vice President of R&D Strategy at Veeva Systems.