6 Gaps Between the Investigator Site File and the TMF, and How to Close Them

In MHRA inspections of commercial sponsors across three reporting periods, more than 80% of inspections had at least one TMF finding (MHRA, Trial Master Files presentation). Most TMF programmes focus on the sponsor's side. EMA's TMF guideline is clear that the trial master file has two parts: the sponsor TMF and the investigator TMF, usually called the investigator site file (ISF). Both need to be complete, and the investigator should keep control of the records it generates (EMA TMF guideline).

The two halves are meant to tell the same story from different sides. When they don't, inspectors notice: a protocol version filed at the site but not in the TMF, a safety report sent by the sponsor but never acknowledged by the site, a delegation log that differs between the two. Here are six gaps that come up most often.

Where the two files disagree

1. Version mismatches

The sponsor TMF holds every approved version of the protocol, Investigator's Brochure and consent form. The ISF should hold the versions in use at that site, with dates. A site still holding a superseded consent form is both a TMF gap and a consent risk.

2. Approvals that don't line up

Ethics and regulatory approvals filed in the TMF should match what the site holds, with the same dates and versions. Differences suggest one side was not updated.

3. Safety reports without receipt

Sponsors file the safety reports they send. The site needs to show it received them, and that the PI reviewed them. Without the site's side, the sponsor cannot show the report reached the investigator.

4. Delegation and training copies out of date

Monitors often collect copies of delegation logs and training records for the TMF. If those copies are not refreshed, the TMF shows a different team from the one actually working at the site.

5. Decisions recorded on one side

Important decisions, such as protocol clarifications, are often made by email. If only one side files the correspondence, the other file has a gap.

6. Close-out without confirmed archiving

At close-out, the ISF moves into the site's archive. The TMF should show that the site was told its retention responsibilities and confirmed its archiving arrangements.

ISF and TMF reconciliation checklist

• Compare document versions in the ISF and TMF at each monitoring visit
• Match approval dates and versions per site
• File site acknowledgement and PI review for every safety report
• Refresh delegation log and training copies in the TMF at each visit
• File key correspondence on both sides
• Confirm site archiving arrangements at close-out
• Record reconciliation findings in the monitoring visit report

What this means by role

• eTMF managers: the TMF is only complete when the site side matches it.
• CRAs: ISF and TMF reconciliation is part of every visit, not only close-out.
• CRCs and site regulatory staff: a complete ISF with clear version history makes monitoring visits shorter.
• Principal investigators: your file is your evidence; keep control of it.
• QA and compliance directors: test a sample of sites by comparing both halves.

How Cloudbyz approaches this

Cloudbyz offers eTMF for sponsors and CROs and eRegulatory (eISF) for sites, built natively on Salesforce alongside Cloudbyz CTMS. According to Cloudbyz product materials, eRegulatory covers the ISF binder, start-up and essential documents, IRB approvals, delegation logs and SOPs, with document review and approval, remote monitoring and a sponsor portal. Because the sponsor TMF, the site file and monitoring visits can sit on one platform, version and approval differences can be checked during a visit rather than at close-out. 

See both sides of the TMF

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