February 7, 2011 | In June of 2010, an industry coalition under the auspices of the Drug Information Association (DIA) published version 1.0 of the Trial Master File Reference Model. The trial master file (TMF) contains those essential documents that individually and collectively permit the evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of good clinical practice (GCP) and with all applicable regulatory requirements. All sponsors and investigators, as well as those conducting trials in academic research, are required to maintain documentation for each clinical trial. Regulatory guidance, such as ICH E6 section 8, addresses only a sub-set of TMF documents. As a result, until version 1.0 of the Trial Master File Reference Model (TMF RM) was released, no comprehensive common model existed for the TMF.
An outgrowth of the model effort was an industry benchmark survey for trial master files, collecting data on both paper and electronic TMFs. Conducted in the fall of 2010, the intent was to understand our industry’s current processes for collecting, measuring, and quantifying TMF quality, costs, and effectiveness.
The survey gathered data from 103 respondents—60% of which were sponsors—on current TMF practices, identified common problem areas and revealed opportunities for process improvement (see, Figure 1). 50% of the survey respondents maintained inspectable TMFs on paper, while 7% maintained electronic TMFs, and 27% had a combination of electronic and paper TMFs.
The survey provides compelling data on the benefits of an electronic trial master file (eTMF). All of the respondents with eTMFs have standard operating procedures (SOPs) that are consistently followed, while only 58% of the respondents with paper TMFs reported SOPs that are consistently followed. The ability to implement and validate the TMF processes against established SOPs in a predictable and consistent manner provides sponsors with process efficiencies such as on-going process monitoring, establishing well-defined training materials, and the ability to control TMF costs and quality. Table 1 identifies additional areas where eTMF provides significant process advantages.
Process areas that remain problematic for both electronic and paper TMFs are audit preparation and response, ensuring TMF completeness, and maintaining TMF quality.
The survey also indicated an opportunity to reduce overall costs when implementing an electronic trial master file. The estimated average TMF costs for inspectable eTMFs were significantly lower (from 2% to 15% of total study cost) than the respondents with inspectable paper TMFs (from 2% to 40% of total study cost).
In addition to providing an opportunity for industry alignment, defining and standardizing the structure and content of a TMF at study initiation provides a mechanism to monitor the TMF content across the life of the study. Implementation of the TMF RM along with technology to automate monitoring of the TMF documentation could provide a sponsor with an on-demand “dashboard” view of the TMF inventory. In addition, metadata, along with the operational data which is generated by systems such as EDC, CTMS and CDMS systems can provide important key performance indicators, which in turn facilitate the detection of bottlenecks and quality issues.
Information on the TMF RM SIAC can be found at: http://www.diahome.org/en/HomePage/EDM+Corner.htm TMF RM activities can be followed on LinkedIn by joining the TMF Reference Model group. •
Maryanne Quinn is president, Integrated Submission Strategies. Fran Ross is TMF Process Owner, Global Clinical Operations at Genzyme Corporation.
This article also appeared in the January-February 2011 issue of Bio-IT World Magazine. Subscriptions are free for qualifying individuals. Apply today.
