You’ve Got Mail: Correspondence and the eTMF

February 18, 2013

  • eTMF Resources

Certain correspondence clearly falls into the category of essential documents that must be managed in the TMF.  For example, ICH E6 in section 8.3. RELEVANT COMMUNICATIONS OTHER THAN SITE VISITS requires that the TMF include “letters… To document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, adverse event (AE) reporting.”  The TMF Reference Model reserves a location in each zone for “Relevant Communications.”  But unlike many other TMF documents, most correspondence is not planned in advance.  So what is relevant?

Until recently, the authorities have not provided a great deal of published guidance.  However, in the recently issued MHRA “Good Clinical Practice Guide”, the MHRA states:

“Only relevant correspondence that is necessary for reconstruction of key activities and decisions (for example, the medical advisor allows a subject to remain in the trial who has taken a banned concomitant medication, or confirmation that the IMP can continue to be used after a temperature excursion), or correspondence that contains other significant information, must be retained.

If some correspondence is not retained (particularly certain emails which may not add any value by being retained, such as email correspondence between investigator site staff and the trial monitor discussing holidays or suitable hotels to stay in near the site), then there should be a formal process to assist individuals in the evaluation of whether it contributes to the reconstruction of the trial or not.”

Although not highly specific, this guidance does provide sponsors, CROs and investigators with a framework for managing inclusion of correspondence in the TMF:

• A responsible person or persons who has been assigned this responsibility should examine each piece of correspondence associated with the trial

• Based on a documented rationale, the decision should be made as to whether it is needed for reconstruction of key activities or decisions

• If so, standard procedures should be used for inclusion in a paper TMF or uploading to an eTMF

MHRA goes on to discuss the implications for correspondence received or stored in electronic form:

Electronic correspondence may be retained electronically, provided the requirements for eTMF are considered. It is recommended that correspondence is effectively organised; this could be done by segregating correspondence into topic area (for example, protocol development) or into relevant sections (for example, correspondence with the MHRA and REC). It is also recommended that correspondence is always filed in chronological order and that duplication of documentation (for example, chain emails) is avoided. Electronically attached documents that are not present elsewhere within the TMF must be included where necessary for reconstruction (for example, reports/data reviewed in dose escalation meetings).

The takeaways from this guidance include:

• It’s not helpful to store everything under a major heading of correspondence – items should be organized under useful headings (for example, as suggested by the TMF reference model)

• Correspondence should be viewable in chronological order

• The eTMF should be able to handle email message formats. If it does not, a validated method is needed for converting them into other formats.

• A strategy is needed for how to store and view responses and follow ups. Since keeping the TMF up to date at all times is an important requirement, how will sponsors handle email chains that occur over a period of time? Once the first email has been received and uploaded, will a later email be treated as a new version or a separate document? Will the original be purged?

• A strategy is needed for how to handle email attachments. Some documents will already be in the system, for example, protocols. In this case, it should be possible to attach or associate the correspondence to the referenced document or documents. In other cases, if the attachment is not already present, it would have to be uploaded as part of the correspondence or as a separate document.

The MHRA GCP guide provides valuable insight into the role correspondence plays in a TMF as perceived by the agency. TMF planning and work practices should be reviewed in light of this advice.