Electronic Trial Master FilesMar 2, 2009By: Karen RoyApplied Clinical Trials In Europe today, each studys 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 theattention it deserves. Document managers may use all their efforts to create a perfect andup-to-date TMF, but the project team is always more focused on the key projectmilestones, such as first patient first visit, end of recruitment, database lock, and finalreport production.The TMF, however, relates the story of the trial. According to ICHSection 8, it "individually and collectively permits the evaluation ofthe conduct of the trial and the quality of the data produced" and itserves to "demonstrate the compliance of the investigator, sponsor,and monitor with the standards of GCP and the regulatoryrequirements." PHOTOGRAPHY:By law, we have to have TMFs—The European Directives of 2001 GETTY IMAGESand 2005 and National Laws demand it, but also ICH GCP, the ILLUSTRATION:Declaration of Helsinki, and Company SOPs require a TMF to be PAUL A. BELCImaintained. ICH GCP 8.3.11 requires the retention of "relevantcommunications that document any agreement or significant discussions regarding trialadministration, protocol violations, trial conduct, or adverse event reporting."The TMF world as we know itWhat is the reality of the TMF today? The majority of European companies still operateon paper TMFs, especially when studies are contracted out to CROs. While somepharmaceutical companies do have active eTMFs in place, other companies have eTMFinitiatives, but often these do not capture the entire TMF, rather just the more essentialdocuments.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 evenmore locations. Storage facilities vary, from environmentally protected rooms to thehome offices of clinical research associates (CRAs). Inevitably, this multiple locationTMF ends up containing a huge amount of duplication (everyone wants a copy of allimportant documents) and consists of multiple and variable filing systems that areisolated.What is potentially more worrying is whether everyone is working from the samedocuments. There is nothing worse than reaching an investigator site and realizing thatthey havent received the most recent protocol amendment. Or doing some last minuteaudit preparation and finding a key document is missing.Being so spread out and entirely paper-based means that the TMF fails to be themanagement tool it could potentially be. Instead, it is viewed as a huge paper burden atstudy close-out, when the various clumps of documentation need to be consolidated intoone clean, concise, and legible TMF. Also, by relying on a paper TMF you unnecessarilymake yourself vulnerable to emergencies, such as a flooded or burned warehouse. Iftheres no backup, when its gone, its 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). eClinical has landedPaper vs.Electronic Eclinical is firmly embedded in the clinical research industry. ElectronicTMFs data capture (EDC) has finally taken hold, and the majority of major pharma companies have an eClinical program, with EDC an integralpart of their workflows. The final destination of all successful trial results is a regulatorysubmission. The electronic Common Technical Document (eCTD) has been themandatory method of electronic submissions since 2008 in the United States and will befor Europe by the end of 2009. And the starting point for much of eCTD documentationis 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 paperTMF. But the stumbling block is the diversity ofdocumentation sources, so an eTMF has to become abundled mixture of hardware, software, people, andprocesses. It is essential to establish procedures that takethe random documentation and channel it into astructured TMF that meets the standards demanded bythe pharmaceutical industry. Drawbacks to PapereTMFs can sit inside or outside the IT environment of a company. They can be as simpleas documentation scanned or electronically transferred to a centralized repository forPDF images, or they can be as complex as being part of a document management systemfor the creation, review, modification, and version control of documents.Ideally, eTMFs should use the concept of metadata or indexing (attaching a virtual labelto the document to allow for two-dimensional searching) to drill down through studiesand centers or slice and dice across them. Imagine having online access to your TMFdocumentation, allowing reporting and comparison of CRO or even CRA activity.Why an eTMF?The features of an eTMF offer significant benefit to all stakeholders in the clinical trialprocess. These benefits support excellence in clinical research.The added value from using an eTMF is a dual benefit of process enhancements coupledwith enhanced data security. Through user profile log-in, restrictions can be put in placeif certain sections of the TMF should have limited visibility. Audit trails also showviewing and downloading activity, thereby enhancing security around TMFdocumentation.To get the maximum benefit of an eTMF, including significant cost savings, it has to beconsidered as a management tool rather than just an electronic document repository. Asall documents are date and time stamped as they enter the system, the flow ofdocumentation is much more visible to the study manager. For example, once amonitoring report is completed and uploaded onto the system, an automatic trigger couldbe put in place to generate payment to the CRO performing the visit.Using CROs can often complicate matters, and in the unfortunate scenario that thedecision is made to change the CRO midstudy, extracting the TMFs from the initialorganization can often be challenging. By centralizing the TMF electronically from thestart, this worry is alleviated and the potential problem totally avoided.No change no gain
EDC has taken a considerable time to take hold of the pharmaceutical industry. Theinitial golden nugget with EDC of faster database lock was soon overshadowed by theapparent increase in costs. However, it was only when process reengineering really tookhold that EDC was successful. eTMFs face the same challenge to their success.Workflow changes are required to gain maximum benefit from the advantages offered byeTMFs.Sponsors need to understand the power of the eTMF tool. No longer can a CRO hide itsdocumentation until an audit, or even the end of the study. The sponsor can assess theflow of documentation into the TMF and the quality of the documentation (down to anindividual 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 aboutrelevant information) and they need to send it centrally on a regular basis, or the visibilitybenefit becomes less powerful. They also need to check their TMFs online regularly toavoid the end-of-study panic.Even CRAs need to change their working practices. If they are at a site anddocumentation is missing from a file, they can download and print the documentation andfile it themselves, avoiding the repeating circle of lost paperwork.Ultimate successAn 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 thesupporting services around it.In most cases, an eTMF will require TMF documentation preparation, scanning, andindexing, with regulatory compliance being an underlying feature of all of theseprocesses, especially if the documents are ultimately going to be used in an eCTD. Thepeople 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 processesand 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 atPhlexglobal Ltd, Mandeville House, 62 The Broadway, Amersham, Bucks HP7 0HJ,United Kingdom, email: KRoy@phlexglobal.comReferences1. ICH/ GCP Topic E6, 1 May 1996, CPMP/ICH/135/95.2. European Directive 2001/20/EC.3. European Directive 2005/28/EC.