The TMF clampdown has prompted a shift to sophisticated electronic systems

MHRA guidelines on trial master files — where are we one year later? Asks Jennifer Goldsmith, Veeva Systems.

In April 2014, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) updated its definition of a critical GCP inspection finding to include trial master files (TMFs) that were “not readily available or accessible.” The Agency asserted that this change was partly driven by the fact that more than one-third of TMF inspections are delayed due to incomplete or inaccessible files. In response, the global life sciences industry heightened its focus on managing TMF content compliantly as part of a larger movement away from paper to fully electronic trial master files (eTMFs). This drive is bolstered by the increased use of service providers such as contract research organisations (CROs) to support the clinical development process.

Although the motivation driving the move towards eTMFs was undisputable, 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 organisations 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.

Twelve months of transition

While companies start to make the move to next-generation eTMF solutions, 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 250 TMF owners in 2014 in the largest eTMF survey to date, over half of the organisations reported working with either local file-share systems (26%) or cloud file share such as an FTP site or Dropbox.com (18%). More than one-third of respondents reported using generic content management systems such as EMC Documentum or Microsoft SharePoint to store and share clinical trial documents, whereas only 13% had implemented life sciences-specific eTMFs.

Sponsors that replaced paper TMF files with such local network file shares did not foresee the resulting reporting and quality-control challenges. For example, one of the biggest challenges is that these systems often served as a company’s central repository for all clinical trial documents and data globally. Lacking any significant form of configurable security, these systems made all trial documentation visible without restriction, forcing sponsors to create mirror files containing just the relevant documents for inspectors. Even with this mirroring, inspectors often still had to wade through unrelated trial data.

The next evolution

To improve the inspection process, sponsors and CROs have begun moving to purpose-built, cloud eTMF solutions. In fact, five of the world’s largest drug makers and half of the leading CROs now rely on next-generation systems to meet four key requirements:

1. Continual inspection readiness and unlimited accessibility.
2. Comprehensive trial documentation, with no incomplete or missing documents.
3. Easy navigation with intuitive user interfaces.
4. Rich insight to improve operational efficiency.

Specifically for the global life sciences industry, the updated MHRA definition meant next-generation eTMF systems became a business must-have practically overnight. Nigel Jones, vice president of Global Clinical Development at TFS, a global full-service CRO headquartered in the UK, believes the simplicity and accessibility of cloud-based eTMF systems have become a prerequisite for doing business with global drug makers. “The vast majority of proposals CROs submit today include some form of modern eTMF support,” he said.

Unexpected advantages

Many first-generation eTMFs were built around functionally simplistic “electronic filing cabinets” that retained paper-based processes, such as printing and scanning documents. But sponsors, CROs, and inspectors found these early systems did not deliver the benefits of truly paperless TMFs. “The entire trial process is rapidly moving away from paper,” Jones observed. “Today the majority of clinical trials are done with electronic data capture to save the data-entry step and enable the collection of important trial performance data.”

To support the paperless model, next-generation eTMF systems offer electronic processes for information sharing and storage. Individuals no longer send paper to central records management teams. Rather, the responsibility for filing documents into the eTMF is distributed across the clinical ecosystem, making it critical to assign and communicate ownership of TMF documents. When all parties have defined roles in the study SOPs, sending files electronically and ensuring task completion are quick and efficient.

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.

Some forward-thinking organisations are already unlocking the benefits of TMF metrics. In the Veeva 2014 eTMF 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 improved document quality (63% versus 29%), greater audit and inspection readiness (56% versus 25%), easier collaboration with sites (54% versus 32%), and increased SOP compliance (49% versus 16%).

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.

Driving life sciences

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 programmes.