Managing eTMF (electronic trial master file) is a challenge. However, some organizations impose burdens upon themselves by following practices that aren’t consistent with Health Authority guidance. In this blog article, I look at common misconceptions and provide specific agency guidance that debunks these “myths”. Direct quotes from Health Authorities are provided, but I have added bolding in some cases to emphasize important points.

Myth 1: We must do 100% QC on all eTMF documents

While organizations may choose to perform 100% QC on all documents prior to finalization, this is not a Health Authority requirement. For example, EMA guidance states:

In addition to TMF-level QC…, there should be an adequate risk-based document-level QC, as described…  for certified copies.^[i]

EMA and MHRA also describe quality checks needed for confirming accuracy of scanned documents. MHRA GCP states:

Some eTMF systems require a review of each scanned document before it is approved within the eTMF, but all transfers should be certified for accuracy and completeness by someone with appropriate authority example, the trial manager), as part of the quality system. This does not necessarily mean that the individual reviews every document, but that they have approved the validated system that is being used.^[ii]

There are many valid reasons that organizations may choose to perform 100% QC of documents. For example, the organization may be new to eTMF, may not have evidence that less than 100% QC is justified, or may not have technology that allows a risk-based, sampled approach. However, Health Authority expectations of 100% QC should not serve as a rationale for this decision.

Myth 2: As long as the TMF is complete at the end of the study, everything is Ok

Often, those contributing documents to an eTMF may not feel a sense of urgency to submit documents in a timely manner. They may assume that as long as all required documents are filed at the end of the trial, the sponsor’s obligations have been fulfilled. In general, Health Authorities do not agree with this position, as seen in these quotes from MHRA GCP:

Documentation in the TMF that is relied upon for subsequent activities should therefore be in the TMF before these activities take place; for example, monitoring visits rely on the information in the previous report, so the previous report should be completed and filed in the TMF prior to the next visit.

It may raise concerns on inspection if the TMF appeared so out of date that the organisation’s ability to manage and oversee the trial conduct was questionable. It should be remembered that MHRA GCP inspections can be unannounced or performed at short notice and even routine inspections may not contain a notification of the trials to be inspected until shortly before the inspection, thus the TMF must be maintained in an ‘inspection-ready state‘. This particularly applies to TMFs after the trial has completed, as these TMFs must be ‘complete and legible’.^[iii]

If you have attended presentations from the MHRA, you have probably seen a graph they generated showing that a sponsor had uploaded a significant number of documents in the weeks before the inspection, and had thus not been maintaining the TMF in a contemporaneous state. 

Best practices to address this issue include education of contributors on the importance of timely submissions, and procedures for monitoring TMF completeness and timeliness for ongoing trials.

Want to learn about about timeliness? Read the White Paper: Completeness, Quality and Timeliness: A Deep Dive

Myth 3: We don’t have to validate a commercial eTMF

Encouraged by some vendors, some sponsors and CROs have been assuming that a commercial eTMF is completely “pre-validate” and does not need any validation or User Acceptance Test (UAT) by the organization. However, this is not the expectation of the Health Authorities.

When asked to comment on “UAT and test scripts created by vendor”, Andy Fisher of MHRA stated:

Sponsor should be testing requirements for the trial and executing UAT scripts – looking at failures and how they are fixed. Vendors should have an oversight approach to the sponsor’s UAT.^[iv]

The FDA has also commented on this:

What should sponsors and other regulated entities consider when deciding to validate outsourced electronic services that are used in clinical investigations? A risk-based approach to validation similar to that described in section IV.A.Q1 should be taken for outsourced electronic services. It is ultimately the responsibility of the sponsor or other regulated entity to ensure that the outsourced electronic service is validated as appropriate. Sponsors and other regulated entities should obtain documentation from the electronic service vendor that includes, but is not limited to, a description of standard operating procedures and results of testing and validation to establish that the outsourced electronic service functions in the manner intended.^[v]

And finally, the EMA advises:

The eTMF systems should be validated to demonstrate that the functionality is fit for purpose, with formal procedures in place to manage this process.^[vi]

Therefore, a sponsor or CRO needs to design and document a risk-based process for User Acceptance Test that ensures the commercial system meets the user requirements and is fit for purpose. It’s fine to use materials provided by the vendor, but there must be evidence that they fulfill user requirements and that the risk-based approach is justified.

Myth 4: Everything has to be kept in the primary eTMF

The TMF contains many records and documents that might not need to be stored in the primary eTMF, especially if they are records or data rather than documents.

MHRA has often raised the issue of whether it is  sensible to convert everything to a pdf or move files into the eTMF system or whether long term retention (archive) and direct access are better off maintained in original systems. Andy Fisher of MHRA commented on this at the TMF Summit in 2018:

24. How many systems are too many?

A reasonable number! It depends. Not 47 as was presented at one inspection. Recommend to place as many documents in the primary TMF system as possible and reduce the number of systems holding TMF documents. The protocol could be kept in a different system, as long as its location is defined.^[vii]

EMA guidance stresses the need to retain dynamic data, which may not be possible in an eTMF:

The appropriateness of the storage system should be evaluated based on the file format used, e.g. whether the eTMF-document-management system is appropriate for the storage of dynamic data files (e.g. Excel files and SAS datasets), where needed and does not require such files to be rendered as a PDF. Within the eTMF-document-management system, PDF files generated from dynamic data files in other systems (e.g. IMP shipping reports generated from IRT datasets and monitoring visit reports generated from the clinical-trial-management system (CTMS) datasets) might be uploaded to the primary TMF system; if so, the original dynamic file should be retained in the original system.^[viii]

Myth 5: “All you need is the documents” – when archiving an eTMF from a CRO

21 CFR Part 11 clearly states that audit trails need to be retained for the life of the associated records.  This also applies when an eTMF is transferred from CRO to sponsor, as Andy Fisher of the MHRA has stated on many occasions.

Sponsors need to ensure all data and metadata is archived. Examples have been seen of only the flat pdfs with no audit trails being retained therefore the trial cannot be fully reconstructed.^[ix]

Where to keep the audit trails if you import them?

TMF is defined by a lot of different systems. So if you have a massive dataset you have to look at what is the best system to store in, you need to define that for yourself and just ensure that you are able to find them. Sponsors should receive the audit trail back with the eTMF from the vendor.^[x]

Most eTMFs cannot merge imported audit trail entries with their own, so it’s important to define how the audit trail for a migrated eTMF will be managed and retained.

Questions? Contact our team of experts.

^{[i] Guideline on the content, management and archiving of the trial master file (paper and/or electronic), EMA, 06 December 2018
[ii] Good Clinical Practice Guide, Medicines and Healthcare products Regulatory Agency (MHRA), 2012
[iii] Good Clinical Practice Guide
[iv] Andrew Fisher, MHRA Inspector, TMF Questions & Answers from ExL TMF Summit, October 2018
[v] Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Questions and Answers Guidance for Industry, FDA, June 2017
[vi] Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)
[vii] Andrew Fisher, MHRA Inspector, TMF Questions & Answers
[viii] Guideline on the content, management and archiving of the trial master file (paper and/or electronic)
[ix] Minutes of the Stakeholder Engagement Meeting (StEM), MHRA 18 March 2016
[x] Andrew Fisher, MHRA Inspector, TMF Questions & Answers}