The Real-World Evidence Study Master File Team has received feedback that Notes to File (file notes) are not listed in the artefacts on the RWE SMF Index.

When creating the RWE SMF, the team deliberately focussed on artefacts required by regulation or otherwise considered relevant to RWE studies. There is no regulation that mandates or requires NTF and so the RWE SMF Team decided not to include NTF as an artefact for routine inclusion.

Where so desired, NTF can be added as an artefact in the same way as it is possible to add artefacts to the standard TMF Reference Model. NTF can be useful in exceptional circumstances where required to

• explain exceptional situations;
• define the root cause;
• evaluate the impact;
• describe actions taken to correct the situation; and
• document remedial action(s) taken to prevent recurrence.

However, rather than provide clarity, recording “after-the-fact” matters in NTF potentially

• magnifies sometimes insignificant issues;
• adds confusing, superfluous, or extraneous information;
• highlights ineffective practices, poor performance, and unresolved problems; and
• reveals detrimental evidence regarding inadequate study conduct and monitoring.

And, of course, NTF should never be used to justify

• failure to perform due diligence;
• failure to understand or comply with regulatory requirements or the protocol; or
• missing documents (if an artefact cannot be collected, the NTF does not replace it).

To prevent a culture overly sensitive to- even fearful of- risk, organisations should establish “golden rules” i.e. a framework of SMF policies, standard operating procedures, work instructions, guidelines, or conventions on NTF to

• anticipate (and be prepared for) questions from auditors and regulatory inspectors;
• ensure that NTF are created only in relation to significant issues that have a material impact on the conduct of the trial, the quality of the data produced, or patient safety; and
• avoid being drawn into time-consuming attempts to retrospectively apply “corrections” that might potentially prove counterproductive.

It is important to adopt a pragmatic approach to NTF creation that balances effort required against risks presented: and to guard against hoisting red flags by providing auditors and regulatory inspectors with the rope with which to hang yourself.