A European perspective on the challenges of paper files and the value of its replacement.
In Europe today, each study's Trial Master File (TMF) is commonly still paper and is often scattered across many locations in many countries. With this disparate model comes many disadvantages and risks. An Electronic TMF (eTMF), where documents are brought together in one place, backed up electronically, and visible over the Internet from anywhere any time of day, provides a solution.
In the world of a project team, the TMF does not get the attention it deserves. Document managers may use all their efforts to create a perfect and up-to-date TMF, but the project team is always more focused on the key project milestones, such as first patient first visit, end of recruitment, database lock, and final report production.
The TMF, however, relates the story of the trial. According to ICH Section 8, it "individually and collectively permits the evaluation of the conduct of the trial and the quality of the data produced" and it serves to "demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and the regulatory requirements."
PHOTOGRAPHY: GETTY IMAGES ILLUSTRATION: PAUL A. BELCI
By law, we have to have TMFs—The European Directives of 2001 and 2005 and National Laws demand it, but also ICH GCP, the Declaration of Helsinki, and Company SOPs require a TMF to be maintained. ICH GCP 8.3.11 requires the retention of "relevant communications that document any agreement or significant discussions regarding trial administration, protocol violations, trial conduct, or adverse event reporting."
What is the reality of the TMF today? The majority of European companies still operate on paper TMFs, especially when studies are contracted out to CROs. While some pharmaceutical companies do have active eTMFs in place, other companies have eTMF initiatives, but often these do not capture the entire TMF, rather just the more essential documents.
The power of being able to review, audit, and inspect TMFs electronically is then lost, along with the business continuity advantages of having the entire TMF electronic. Interestingly, a couple of the larger, more electronically oriented CROs are initiating eTMFs, reinforcing the significant business advantages they bring to the table. Nevertheless, paper is still king in Europe.
In the paper world, TMF documentation is spread across numerous countries, and even more locations. Storage facilities vary, from environmentally protected rooms to the home offices of clinical research associates (CRAs). Inevitably, this multiple location TMF ends up containing a huge amount of duplication (everyone wants a copy of all important documents) and consists of multiple and variable filing systems that are isolated.
What is potentially more worrying is whether everyone is working from the same documents. There is nothing worse than reaching an investigator site and realizing that they haven't received the most recent protocol amendment. Or doing some last minute audit preparation and finding a key document is missing.
Being so spread out and entirely paper-based means that the TMF fails to be the management tool it could potentially be. Instead, it is viewed as a huge paper burden at study close-out, when the various clumps of documentation need to be consolidated into one clean, concise, and legible TMF. Also, by relying on a paper TMF you unnecessarily make yourself vulnerable to emergencies, such as a flooded or burned warehouse. If there's no backup, when it's gone, it's gone.
To really understand the challenge of the TMF, clarity is needed on the origin of the documents. Unlike the majority of regulatory documents that are created internally and version-controlled, anywhere between 10% and 50% of a TMF is created outside of client control, and there is huge variance as to paper (often because of wet-signatures) or electronic collection (see Figure 1).
Paper vs. Electronic TMFs
Eclinical is firmly embedded in the clinical research industry. Electronic data capture (EDC) has finally taken hold, and the majority of major pharma companies have an eClinical program, with EDC an integral part of their workflows. The final destination of all successful trial results is a regulatory submission. The electronic Common Technical Document (eCTD) has been the mandatory method of electronic submissions since 2008 in the United States and will be for Europe by the end of 2009. And the starting point for much of eCTD documentation is the TMF. So why is it still paper?
The concept of an eTMF is very simple: It is a secure, centralized, visible to all, electronic version of the paper TMF. But the stumbling block is the diversity of documentation sources, so an eTMF has to become a bundled mixture of hardware, software, people, and processes. It is essential to establish procedures that take the random documentation and channel it into a structured TMF that meets the standards demanded by the pharmaceutical industry.
Drawbacks to Paper
eTMFs can sit inside or outside the IT environment of a company. They can be as simple as documentation scanned or electronically transferred to a centralized repository for PDF images, or they can be as complex as being part of a document management system for the creation, review, modification, and version control of documents.
Ideally, eTMFs should use the concept of metadata or indexing (attaching a virtual label to the document to allow for two-dimensional searching) to drill down through studies and centers or slice and dice across them. Imagine having online access to your TMF documentation, allowing reporting and comparison of CRO or even CRA activity.
The features of an eTMF offer significant benefit to all stakeholders in the clinical trial process. These benefits support excellence in clinical research.
The added value from using an eTMF is a dual benefit of process enhancements coupled with enhanced data security. Through user profile log-in, restrictions can be put in place if certain sections of the TMF should have limited visibility. Audit trails also show viewing and downloading activity, thereby enhancing security around TMF documentation.
To get the maximum benefit of an eTMF, including significant cost savings, it has to be considered as a management tool rather than just an electronic document repository. As all documents are date and time stamped as they enter the system, the flow of documentation is much more visible to the study manager. For example, once a monitoring report is completed and uploaded onto the system, an automatic trigger could be put in place to generate payment to the CRO performing the visit.
Using CROs can often complicate matters, and in the unfortunate scenario that the decision is made to change the CRO midstudy, extracting the TMFs from the initial organization can often be challenging. By centralizing the TMF electronically from the start, this worry is alleviated and the potential problem totally avoided.
EDC has taken a considerable time to take hold of the pharmaceutical industry. The initial golden nugget with EDC of faster database lock was soon overshadowed by the apparent increase in costs. However, it was only when process reengineering really took hold that EDC was successful. eTMFs face the same challenge to their success. Workflow changes are required to gain maximum benefit from the advantages offered by eTMFs.
Sponsors need to understand the power of the eTMF tool. No longer can a CRO hide its documentation until an audit, or even the end of the study. The sponsor can assess the flow of documentation into the TMF and the quality of the documentation (down to an individual level), and they can do this any time of day with no time-zone restrictions.
Project teams need to consider carefully what is included in the TMF (ICH talks about relevant information) and they need to send it centrally on a regular basis, or the visibility benefit becomes less powerful. They also need to check their TMFs online regularly to avoid the end-of-study panic.
Even CRAs need to change their working practices. If they are at a site and documentation is missing from a file, they can download and print the documentation and file it themselves, avoiding the repeating circle of lost paperwork.
An eTMF is a combination of hardware, software, processes, and people. Therefore, when implementing a system, consideration needs to be given to the system itself and the supporting services around it.
In most cases, an eTMF will require TMF documentation preparation, scanning, and indexing, with regulatory compliance being an underlying feature of all of these processes, especially if the documents are ultimately going to be used in an eCTD. The people undertaking these tasks will need training, SOPs, user guides—to name but a few.
The challenge is implementing a system that really takes into account all the processes and TMF stakeholders and provides them with a tool to make their job more efficient.
Karen Roy is the executive director and global head of Business Development at Phlexglobal Ltd, Mandeville House, 62 The Broadway, Amersham, Bucks HP7 0HJ, United Kingdom, email: KRoy@phlexglobal.com
1. ICH/ GCP Topic E6, 1 May 1996, CPMP/ICH/135/95.
2. European Directive 2001/20/EC.
3. European Directive 2005/28/EC.