Summary

Sponsors receiving TMFs from CRO partners at the end of a study often experience quality issues when attempting to archive the TMFs. This post provides recommendations for sponsors to help ensure that the TMF deliverable can be archived easily without time-consuming manual steps or the need to accept files that aren’t properly indexed.

Background

Many sponsors delegate responsibility for TMF management to their CRO partners. Often, however, CROs don’t provide a permanent archive for the TMF and sponsors must accept a transfer of TMF records after the end of the trial. The sponsor is then responsible for records management (for 25 years¹ or more), inspectability, and providing availability as needed within their organization.

When the sponsor receives the TMF, there are several options for archiving:

• Storage on a file system or other media (this would require considerable planning to ensure access controls, security, etc.)
• Storage in an Electronic Trial Master File (eTMF)
• Storage in another type of archive system

Often, the sponsor is provided a folder structure containing TMF files and (usually) an Excel manifest of the documents being transferred. This may be done on removable media, via an FTP site, using some other type of secure transfer mechanism.

Often, the sponsor may not attempt to formally archive the TMF until some months after it is delivered. At this point, quality issues often emerge that are difficult to resolve due to the contractual relationship ending, team members moving on, or missing records being inaccessible. Even if the records are examined and archived earlier, the CRO’s specific contractual requirements may be limited.

The TMF Reference Model Exchange Mechanism – A Fast Track to Quality

To avoid archive issues, the sponsor’s agreement with the CRO should include specific information about what should be delivered. The best solution is to provide content and metadata in the TMF Reference Model Exchange Mechanism (EMS) format. This format not only provides a standard for required data and the ability to define system-specific data, but the format includes the ability to validate that the all required data is present and that data is valid according to defined rules.

However, many vendors have not yet implemented the EMS, and CROs often have not committed to supporting it yet. Sponsors can help to promote the standard by talking with their CRO partners about whether they can deliver in this format, and if not, when they will be able to do so. For CROs who can provide an EMS export, contracts should require this and specify that it must be valid according to the DTD provided with the standard.

No EMS: What’s Next?

If the CRO can’t deliver an EMS export, the sponsor will need to take further steps to ensure that a valid export package is provided. Without this, many records may fail on import or require manual intervention to be ready to import. For example, in previsions import projects I’ve worked on, I have experienced:

• Instances where the CRO has insisted that all required information is coded into file names and no other information is needed. Inevitably, most of these filenames are manually and don’t follow consistent standards or contain complete information.
• Missing key information (for example, site level documents where no site is provided)
• Mismatch between Excel indexes and documents, where some rows in the index don’t match a document or vice versa
• Missing audit trail

The contract should state:

• How files will be organized in a folder structure (generally zone/section/artifact or study/country/site)
• Acceptable file formats (for example, will .msg format be accepted for email or must emails be converted to PDF?)
• What metadata will be provided for each file and in what format (could be Excel or XML)
• The requirement to provide the audit trail (sponsors should receive the audit trail back from the vendor)²

Metadata: How much is enough?

At a minimum, sufficient metadata should be provided to archive and retrieve a document, understand its contents, and reconstruct the trial. A recommended minimum set of metadata includes:

• TMF Reference Model ID (this allows the zone, section and artifact to be retrieved)
• Sub-Artifact (if used)
• Study, Country (for country and site level documents) and Site (for site level documents)
• Document Date. Health authorities use the dates of documents to reconstruct the trial. For example, EMA states that “. The documentation should be filed in each appropriate section of the TMF in chronological order³” and MHRA says “It is recommended that the documentation is filed in date sequential order⁴.”
• Expiration Date, if present for the document
• Status. Although only final documents should be present in an archive, it’s possible that they could have been moved to an Obsolete, Superseded or Expired status.
• Any other data that is needed to clarify contents (for example, the subject of email/communication)

Conclusion

TMF transfer standards are a key element of ensuring that a TMF produced by a CRO is completely and accurately transferred to a sponsor at the end of a trial. They should be created and documented as part of an overall program that includes an archiving and records retention strategy and a validated process for completing and confirming TMF transfer. When sponsors establish minimum contractual requirements for the structure and content of the TMF to be delivered, they will avoid not only quality issues but also effort and expense in creating a compliant archive.

[1] EMA, Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic), 06 December 2018, p. 15

[2] MHRA Q&A Document  from ExL TMF Summit, London, October 2018

[3] EMA, Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic), 06 December 2018, p. 6

[4] MHRA Good Clinical Practice Guide, 24 September 2012, page 233