EMA explains how firms can avoid common problems in drug trial master files
This article was originally published in SRA
The European Medicines Agency is inviting feedback on a draft reflection paper that explains how companies can comply with good clinical practice (GCP) requirements in relation to trial master files, whether these are maintained in paper or electronic formats1.
The reflection paper addresses the common problems found in trials master files during GCP inspections, such as: companies being unable to provide a full trial master file for inspection; improper structuring of the files; failure to fully document and perform effective quality control checks on documents uploaded into an electronic trial master file; poor, repetitive and sometimes incorrect labelling of files; and failure to document activities to allow reconstruction of the trial. All these issues contribute to delays in inspections.
The reflection paper also brings together the EU legislation and related guidance on trial master files; this was deemed necessary by the EU GCP Inspectors' Working Group due to the numerous questions asked by organizations in relation to trial master files, in particular electronic versions of these files. Stakeholders have until 30 April to submit comments on the draft paper, which also addresses issues such as archiving of trial master files, clarifies retention times and offers recommendations on destruction of paper documentation.
A trial master file should allow adequate reconstruction of trial activities undertaken, along with key decisions made concerning the trial, and thus should be prepared and maintained appropriately. The EMA recommends that consideration should be given to preparing the trial master file as a stand-alone document that does not require additional explanation from the associated sponsor or site staff.
As companies have been using electronic trial master files to deal with large, complex trials involving many departments and contract research organizations, the EMA notes that this has "introduced new challenges". Structuring of the file, for example, can be quite difficult in large organizations as it could include documents from across a variety of different departments and systems other than clinical operations, such as data management, statistics, pharmacovigilance, clinical trial supplies, pharmacy, legal, regulatory affairs, etc, as well as those provided or held by CROs.
Also, documents may sometimes need to be located in a separate location from the main trial master file records, for example those that contain information that could "unblind" the study team. The EMA notes that, together, these issues have led to companies being unable to provide trial master files in an appropriate way for management and inspection purposes as required by legislation. The agency clarifies that GCP inspectors are not averse to reviewing an electronic trial file, but sponsors should ensure that the electronic version adequately replicates the paper version in terms of the usability and time taken. As inspectors may need to familiarize themselves with the electronic file, training should be an option for the inspector and should be very brief (taking no more than an hour).
The EMA's reflection paper, when finalized, will cover the use of trial master files in relation to all clinical trials conducted in the EU and in third countries in case the clinical trial reports are submitted as part of marketing authorization applications to EU regulatory authorities.
References
1. Reflection paper on good-clinical-practice compliance in relation to trial master files (paper and / or electronic) for management, audit and inspection of clinical trials (EMA/INS/GCP/3636736/2012EMA/INS/GCP/636736/2012), 18 February 2013, www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/02/WC500138893.pdf