The Trial Master File holds critical study-related documentation that sponsors are required to maintain for compliance. The documentation referred to in Article 15(5) of Directive 2001/20/EC as the trial master fileshall consist of essential documents,  which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated.¹ This essential study specific documentation is also known as the TMF.

When managing TMFs, it is important that the documentation be accessible to team members when they need them, that they be kept securely and that they be managed throughout the trial lifecycle. Historically, TMFs were managed and maintained in paper format by default. Unfortunately, paper files do not easily support any of these objectives. There are four key areas where paper and electronic files may be assessed to determine their fit in a Trial Master File Strategy:

• Compliance — How does this format help/hinder compliance objectives?
• Global Accessibility — How does this format help/hinder global collaboration?
• Security — How does this format ensure the safety of critical TMF content?
• Efficiency — How does this format impact local access and global management of TMF content?

Challenges of Paper
Compliance: Paper files are difficult to search and navigate and cumbersome to maintain using manual tracking mechanisms. Paper files do not support rapid responses to agency inquiries in regulatory inspection situations and may give the perception that the content is not properly managed, if responses take too long to present.

When looking at the bigger picture, it is important to recognize who will be accessing the TMF content and why it is being managed in the first place. A well-organized TMF will support a thorough inspection or audit. From the CRO perspective, it is important to have insight into the TMF on an ongoing basis, throughout the conduct of the trial in order to manage operations and ensure compliance at each site while the study is still active. This enables the CRO to uphold the compliance expectations of sponsors and regulatory health authorities. From the sponsor perspective, it is also important to be able to respond promptly to any audit request and have oversight of CRO activities, project statuses, etc.

Global Accessibility: Paper TMFs create an additional burden for managers when other team members need access to the files. Paper can only be viewed by one person, in one location at one time. Paper must be secure yet when it is locked away in a file room, other team members need to travel to access it or make special requests for copies to be made. This problem is particularly acute for geographically dispersed teams. If a project manager wants to review and discuss a particular document with multiple team members, she must request or retrieve the document from the paper file, and then distribute (scan, copy or fax) to the other reviewers. This means additional work for the project manager and the same process is required for each document that is identified for review. Uncontrolled and redundant file content becomes an additional management encumbrance, making the situation even more difficult. This adds costs to the management process without showing any benefits.

Security: Trial-related data and documents are critical assets for any sponsor. Paper can be easily damaged or inadvertently destroyed during review. Duplication processes are time- and resource-intensive and create opportunities to insert errors that can be carried through to a review process.

Efficiency: Collection, maintenance, management and review of paper files is cumbersome. Paper demands serial processes and reduces opportunities for collaboration on TMF content throughout the lifecycle.

We are all familiar with the traditional challenges of managing and accessing paper files. Yet many companies are just beginning to evaluate moving from paper to electronic trial master files (eTMFs). Though this move is seen as a major initiative, the benefits of using digital files across the TMF lifecycle are significant and can provide continued value to sponsors.

Benefits of Electronic TMF Content
Compliance: eTMFs support sponsor compliance objectives by enabling rapid responses to health authority inquiries. Inspectors or audit participants can quickly search across an entire TMF to access and view relevant content. This process typically takes a few seconds compared to the paper retrieval process, which involves combing through boxes or cabinets of paper, retrieving relevant content and then delivering it (or a duplicate) to the requestor. As an audit or inspection progresses, this can take hours and, if the content is not correct, can influence the auditor’s and inspector’s perception of the sponsor’s compliance efforts.

Global Accessibility: eTMFs support collaborative processes and enable simultaneous review of TMF content. This adds a great deal of value, given the dynamic nature of the trial master file as it evolves over time. Availability of content supports collaboration across sites, CRAs, project managers and global sponsor teams. Requesters and reviewers of information can have the content come to them instead of having to travel to review paper files.

Security: Profile-driven security ensures controlled access and protection of compliance assets. Security access controls can be modified to support changing roles and activities throughout the TMF lifecycle. In addition, redundant electronic systems where copies of images are stored in multiple locations safeguard against destruction or damage of the TMF content while also enabling rapid restoration of electronic files in the event of a catastrophe.

Efficiency: An eTMF enables global teams to see the emerging content and address issues as they arise instead of waiting until the final paper copies are available for internal auditing. Any missing content can be identified, tracked and managed as the trial is being conducted. As a result, the time to TMF “close” can be reduced because issues are addressed as part of the ongoing process.

eTMFs also provide enhancements to working practices because they support management reporting that would otherwise be very labor intensive and time consuming in the paper world. Managers can see the current status of TMF files and can work to optimize electronic processes around the management of these files.

Many companies are using partners to support their clinical trial programs. These partners often need access to TMF content in the course of their daily duties. eTMF content can be shared quickly and efficiently when sponsors give access to the eTMF to their CRO partners. This means that partners have the same real-time access to the study information and can act on it accordingly.

Drivers of Change
Outsourcing has become a cost effective resourcing strategy across the clinical trial lifecycle. Many life sciences companies and their development partners must consider the complexities of using multiple CROs across clinical trials. Though this approach enables companies to choose partners based on regional capabilities, therapeutic expertise, or other study specific criteria, it presents challenges when addressing the study documentation compliance requirements, particularly in the paper world. The implications of process, logistical and reporting issues make this a strategic as well as an operational discussion. The resulting complexity can increase the risk of non-compliance while also eating up time and money that was initially saved by implementing an outsourcing strategy. And these costs will recur with each new study that is initiated. This scenario begs for a TMF approach that supports global collaboration across organizations and teams. Paper TMFs cannot support this complex scenario efficiently and paper-based processes will only add drag to the larger trial management process.

Standardization has also become key to the implementation, acceptance and continued use of eTMF content. The TMF Reference Model provides an organizational structure that can be leveraged across paper and electronic processes. Its adoption and use has provided a bridge for companies moving from paper to electronic trial master files. Standardization breeds automation and has enabled software vendors to take advantage of standards to automate traditionally manual, tedious or labor intensive tasks.

The pharma and biotech industries have seen a significant number of mergers and acquisitions in recent years. The portability of standardized electronic master file content is attractive to organizations that want to be seen as ideal acquisition candidates or potential development partners; eTMF content can be quickly and easily reviewed in a due diligence effort, requiring minimal resources to support the review and follow-up activities.

Finally, most companies are no longer banking on discovering the next blockbuster drug to meet their financial goals. In fact, many companies are looking inward for ways to decrease operational costs. Many large organizations have internal initiatives to identify areas of waste or inefficiency and to recommend or implement solutions to address these problems. As companies operate across global markets, paper-based files have become a relic. Electronic processes and standards promise efficiencies that can’t even be imagined in the paper world.

The Cost of Non-Compliance
There are tangible costs for paper or eTMFs that fluctuate as more trials are conducted over time. Yet there are even greater costs that must be considered when looking across the TMF lifecycle. The cost of non-compliance should be the greatest real cost driver in developing an eTMF strategy. Paper processes require significant management effort even though the organization doesn’t gain much recurring value from them. The lack of visibility creates a huge risk of non-compliance that often cannot be addressed until late in the process when final reviews occur. The risk of non-compliance is also greater in a paper model because standards and controls are more difficult to implement and monitor over time. This risk increases as the quantity of paper increases with the number of trials an organization is conducting.

As TMF content moves through the lifecycle, it is important to remember that health authorities can continue to request information about the study at any time. Quick and accurate turnaround of information is critical. This means that sponsors must maintain some level of oversight of the TMF to minimize the risk of noncompliance. Compliance is a continuing process that requires diligent oversight. This will ensure that the CRO partner and sponsor expectations are aligned and the compliance objectives are clear. This is true while the TMF is active and continues to be true when the TMF content moves to archive.

Moving from a paper to an eTMF may seem like an onerous task. There will be bumps in the road as your team transitions to processes that support an electronic TMF. But the benefits far exceed the challenges and the opportunities for improvement are continually growing. Maturing industry efforts toward standardization will continue to support this transition. These initiatives prepare the way by creating new opportunities to automate and simplify the complex TMF process while simultaneously decreasing the risk of non-compliance. The end result will be an efficient, compliant TMF program that continues to provide value to stakeholders throughout the TMF lifecycle. 

Reference

1. [European Directive 2005/28/EC]

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Sheila Mahoney is vice president of Business Development at Phlexglobal Inc. She can be reached at smahoney@phlexglobal.com. Toni Lakin is business development manager at Phlexglobal Inc. She can be reached at tlakin@phlexglobal.com.