On 1st February 2013 the European Medicines Agency (EMA) released for public consultation a draft reflection paper on GCP compliance, including management of trial master files. After a three month consultation period which ended on 30th April 2013, industry has been waiting for finalisation of the reflection paper.
This week – on 15th June 2015 – EMA announced the following:
“It has been decided that the revised version of the TMF document, based on the comments collected during the public consultation, will be incorporated into a guidance on TMF as part of the work related to the implementation of the new Clinical Trial Regulation (EU) 536/2014. A public consultation on the new guidance will follow in due course.”
So, having waited for over 2 years since closure of the initial consultation period, industry has to wait a further period until this important piece of guidance is finalised. In particular, we are keen to see if EMA has responded favourably to the following criticisms of its first draft:
- the suggestion that all correspondence should be maintained “in an appropriate section of the file”, rather than classified according to the content of the correspondence;
- there is no differentiation between “obsolescence” and “deterioration” in relation to digital archiving; this an important distinction to emphasise because both problems require differing preventative and remedial solutions;
- it is important that the documentation generated by the CRO from following its internal procedures is retained as part of the TMF for the required retention period and sponsors must consider this part of the TMF;
- there is no mention of draft documents. As a guidance document, it is recommended that the reflection paper specifically excludes draft documents from being considered TMF content. This is particularly relevant with eTMF systems where documents are created, drafted and reviewed within the same application as the final TMF content. It is important that draft documents are not subject to scrutiny as final documents are;
- electronic correspondence (emails) should be retained electronically, provided the requirements for eTMF and electronic archiving are considered;
- the recommendation to use .pst format rather than pdf is not sound as .pst is a Microsoft proprietary format and is not suitable for preserving content for the period of time required by regulations. Other e-mail formats such as Lotus Notes NSF files, would have to be converted to Outlook before saving. The.pst format is often used informally by staff for saving complete e-mail folders and could lead to irrelevant e-mails being saved in a disorganised manner. Whilst conversion to PDF results in a small loss of metadata related to internet transportation routing, taking a risk-based approach it is recommended that the .pdf format is used for the long-term preservation (archiving) of e-mails;
- it is not clear whether the intention is to use the term “electronic signature” rather than “digital signature”. Electronic signatures are typically created during workflows whereas digital signatures may be used with or without workflow;
- FDA guidance on scanning specifically states that 100% page-by-page QC is not expected. It would be helpful to include a similar statement in this document i.e. a risk-based approach should be used to determine the appropriate level of QC required;
- the requirement to restrict access for archived TMFs to the named archivist only does not take account of the additional protection afforded to electronic records through use of read-only user accounts. If a read-only account is being used, there does not appear to be any justification for restricting access to named archivists only;
- considering the typical retention period for TMF documents is in excess of 25 years, transportable media such as media drives, pen drives and even CD/DVD are not considered to be appropriate for this purpose. This conclusion is supported by The Digital Preservation Consortium and digital preservation specialists such as Tessella and Arkivum. These forms of storage medium are susceptible to media degradation within this time period. In addition, it is likely that hardware to access the content will not be available throughout the retention period (e.g. unavailability of 3.5” floppy disk drives). It is recommended that electronic archiving be carried out as part of a formal digital preservation strategy; and
- the statements and conclusions regarding destruction of scanned originals is considered to be too strong and conflicts with prior advice given. Rather than making a recommendation to retain wet-ink originals, it is recommended that the reflection paper simply provides this as an option in a risk-based approach.
We await with interest publication of the next draft guidance document!