What Impact for the Trial Master File (TMF) of ICH E6(R2)?

So we are now extremely close to Step 4 of the ICH E6 process, resulting in a final, approved revision of the guidelines for good clinical practice…. the first revision since the mid-1990’s. The draft was circulated for review (June 2015) and commented upon by regulators and industry (consultation closed January 2016) but we have yet to see the final text put forward by the Expert Group and voted upon most recently. I’m looking forward to seeing what the impact will be for the management of clinical trial records and whether any of the issues that I identified in the 2015 draft document will have been addressed during the final revision of the guideline. Here’s what I noted previously of interest to TMF colleagues:

Certified copy:
The inclusion of a definition for a certified copy is welcomed, especially as it provides for the production of copies via a validated process rather than mandating verification of the copy by use of signatures. However, the definition in the draft requires that a copy has “all of the same attributes” as the original. It must be acknowledged that electronic records contain data other than the information captured within a document (i.e. metadata) and often, this metadata is of inconsequential or no value with regards to trial conduct. Therefore, the requirement to maintain “all of the same attributes” as the original is often not necessary and could require an unnecessary burden and cost. For example, for many years, it was perfectly acceptable to retain printouts of emails in the trial master file despite these not containing all of the same attributes as the original. These retained the information and meaning of the original; retention of the internet metadata was deemed to be unnecessary.

In addition, a certified copy is defined as being a “copy of the original record”. It should be noted that it need not necessarily be a copy of an original. A certified copy could be a copy of an existing copy.

The draft also states: “When a copy is used to replace an original document, the copy should fulfil the requirements for certified copies.” There has been much confusion within industry whether or not it is permissible to destroy original records following copying i.e. whether the certified copies can truly replace the originals. Given this ambiguity, it is recommended to provide explicit clarification here and change the text to: “It is permissible for an original trial record to be replaced with a copy and for the original record to be destroyed if so required, as long as the copy fulfils the requirements for certified copies.”

The draft guideline noted that the “terms clinical trial and clinical study are synonymous” but some jurisdictions (e.g. the EU) have already noted a distinction here. EU Regulation 536/2014 already includes a definition of these two terms so it might be preferable to adopt those definitions and not use the term interchangeably.

Within the guideline, “records”, “data” and “documents” are also used interchangeably. However, typically “documents” and “data” are considered separate entities. For example, subject data within an electronic case report form would be “data” and would not generally be considered to be a “document”, unless converted to PDF for example. It would however be considered to be a “record” and it would also meet the proposed definition of “documentation”. Given that absolute clarity should be the goal within the revised guideline and to remove ambiguity wherever possible, it is recommended that “document” only be used in the traditional meaning of the word…. to mean information that has been recorded in a structured format as a distinct document…. or avoid using the term completely. On this basis, the majority of the references to “documents” within the guideline should be changed to “records”, for example “essential records”.  In the same way, “Source Documents” change to “Source Records” or “Source Documentation”.

Investigator Records:
An assessment of an investigator site for suitable records storage facilities is often overlooked by a sponsor and may not be perceived as an issue until the trial has come to an end and the TMF is ready for archiving. It is recommended that filing/records storage is specifically included and could be accommodated in lines 479-481: “The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely, including storage of essential records during the trial/study and for the whole required retention period.”

Retention Times:
Retention of trial records for an appropriate length of time is critical. However, there are several factors that determine the most appropriate retention time, including ensuring records are available for inspection, potential litigation support and protecting the safety and welfare of subjects. The introduction to the draft guideline states that it “provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.” Therefore, the mandatory, minimum retention period should be consistent with these aims alone, and should not support any business needs or commercial needs of the sponsor. On this basis, a fixed retention period as a number of years following completion of a study/trial would meet the requirement to ensure records were available. Linking the retention period to marketing applications (per the proposed revision and also the original wording) is surely a commercial decision for the sponsor. If a sponsor chooses to destroy records prematurely, it simply impacts the sponsor’s ability to support the marketing application; this is a commercial decision for the sponsor. Whilst most sponsors would in reality retain records for this period, it should not be mandated as part of GCP. Furthermore, it is impractical for an investigator to set a retention period based upon the marketing strategy of the sponsor! Alternative wording should be “Essential documents should be retained for a minimum of 15 years following completion or termination of the clinical study/trial. The sponsor may require the records to be retained for a longer period to support marketing applications.”

An aspect of electronic systems that is frequently over-looked is the long-term retention and preservation of digital content, particularly measures that need to be taken to mitigate against software obsolescence and file format obsolescence. It is recommended that this is addressed in lines 895-911: “(i) Take measures to mitigate against software, hardware and file format obsolescence over the retention period of the trial data and records to ensure their ongoing accessibility, readability and integrity.”

Essential Documents:
Across industry, the minimum list of documents has often been interpreted – incorrectly – as the required content for a trial master file. Although this opinion is decreasing in frequency, the wording here could help provide clarification. The following alternative wording is proposed: “A minimum list of essential records has been developed and is described here. However, this minimum list of records should be supplemented by additional records that collectively permit evaluation of the conduct of a trial and the quality of the data produced.”.

Let’s see what the final document looks like, though I’m not too optimistic that my wish list here will be delivered!


About rammellel

Records management consultant to the life sciences / pharmaceutical industry
This entry was posted in Regulations, TMF. Bookmark the permalink.

One Response to What Impact for the Trial Master File (TMF) of ICH E6(R2)?

  1. Pingback: ICH GCP Guidelines (E6) Addendum Now Available | Rammell Consulting Limited

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