Rammell Consulting Limited

Is the Clinical Database part of the Trial Master File (TMF)?


This was a question posed recently on the MHRA GCP Forum (see http://forums.mhra.gov.uk/showthread.php?1858-Database-and-TMF).  I posted a response (though it wasn’t published by the Forum Moderator) pointing out that for several reasons the clinical database should not be considered an “essential document” and therefore not part of the TMF, though it would be advisable to retain the database for a number of other reasons (not least, for its ongoing research and development value). In my opinion, because the raw data (the CRFs/EDC data) and the derived data (the SAS datasets and the tables, figures and listings) are part of the TMF (and included in the TMF Reference Model), I would not consider the clinical database to be an essential inspectable component of the TMF, with the caveat that all of the supporting database records identified in the TMF Reference Model are retained (programming, specifications, validation records, QA/QC records etc). The MHRA take a different view.

On the Forum, the MHRA state:

“The MHRA will inspect all aspects of the database including the retained essential documents in the TMF and the database itself, which includes the clinical data and all the metadata (audit trails etc.). Direct (and guided) access to the database should be made available along with the TMF for inspection.”

This is a highly significant clarification, considering the retention period for clinical records per EU Regulation 536/2014 is a minimum of 25 years. I have great concerns regarding how a sponsor will be able to maintain all aspects of the clinical database – including “all the metadata (audit trails etc)” for a period of 25 years and provide direct access to the system for this period. Could you provide direct access to an MHRA inspector to the original clinical database from 1990? On the one hand, we’re directed to adopt a risk-based approach and to focus on issues that could potentially have a direct impact on patient safety. On the other hand, we get directives to retain derived/secondary data that has questionable GCP value when taken in the context of all other records that are maintained in the trial master file. I get the feeling we sometimes take one step forward and two steps back!