[Eldin Rammell]

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[Eldin Rammell]

Hi Maria,

If included as an annex or supplement to the Trial Agreement, then I agree that 05.02.12 would be the most appropriate classification. You might also consider artifact 05.04.07 Financial Documentation. I’ve seen sponsors use this for trial budgets and payment summaries/reports. Remember that the filing level is for guidance only; if the Reference Model just has an “X” in the site column but an artifact covers the whole trial or just a specific country, there’s no problem filing at the trial level or country level, as appropriate.

Eldin.

[Eldin Rammell]

The SIP initiative from TransCelerate is a great attempt at introducing efficiency. However, from Paula’s query it seems that some investigator’s are adding sponsor-specific details to their common documents in the portal. This breaches confidentiality if those same documents are shared with other sponsors. The CVs uploaded to the SIP by the investigator should not make reference to sponsors for whom they are or have conducted trials for, unless that information is in the public domain e.g. as part of a list of publications on the CV.

Perhaps consider asking that the investigator to replace the CV with one that does not reveal the identity of trial sponsors?

[Eldin Rammell]

Absolutely Sarah. Master versions (templates) of study-specific central trial documents should be in the TMF. But not templates for visit reports, filenotes, etc.

[Eldin Rammell]

Would that be an appropriate location for an MTA that is relevant for transfer within a single country ie no import/export transfers involved?

[Eldin Rammell]

Would 08.02.02 Central & Local Testing\Sample Documentation\Shipment Records be appropriate? This seems the most logical place to me. The only issue is that the “definition/purpose” is not strictly accurate, describing records related to “any one shipment”. I cannot see any other relevant filing location so my personal view is to file in 08.02.02 and update the description of the artifact along the lines of “To capture information related to the shipment of samples”.

An alternative approach for a future revision to the Reference Model (in the absence of a more obvious filing location in the model) might be 08.02.04 Central & Local Testing\Sample Documentation\Sample Import or Export Documentation and amend the artifact name and definition/purpose to cover any kind of record that is required to allow the shipment of samples (not just import/export). This could cover import/export documents but would then also cover MTAs and other shipment agreements or licenses.

Just a suggestion. How have others handled MTAs? What recommendation have the sub-artifact team made on this document?

[Eldin Rammell]

Kathie nailed it!

The EMA TMF guidance document provide quite comprehensive requirements regarding electronic filing systems used for TMF content and those requirements apply to the primary eTMF and to supporting systems that also hold TMF content.

In any event, if IP-related records are held outside the eTMF, they would be subject to GMP requirements for computerized systems…. which mirror those for GCP since inspectors use a common GxP document for computerized systems.

[Eldin Rammell]

When using digital signatures, companies need to be careful about their choice of technology. Whilst all electronic signatures are legally admissible (equivalent to a traditional wet-ink signature), some regulatory agencies have expressed a requirement for specific types of signature. In general, for GCP-regulated activities, digital signatures should be “advanced digital signatures”. A brief overview of the different types of digital signature is provided here: https://www.globalsign.com/en/blog/difference-between-eidas-advanced-and-qualified-electronic-signatures/

A self-certified Adobe signature is not usually considered to be an advanced signature as it is extremely easy to create a false signature. For example, on my laptop I could create a self-certified digital certificate using Adobe Acrobat using the credentials mark.zuckerberg@facebook.com! A document that I sign using Adobe-Sign would look as though it was signed by Mark Zuckerberg and it would be difficult to prove that it hadn’t from the signature. An advanced digital signature on the other hand is uniquely linked to the signatory, usually via a digital certificate that is issued to the signatory based on corroborated evidence of identity (including use of valid email address and password). In some cases, agencies require the next level of signature: a qualified digital signature (e.g. for marketing applications submitted to the FDA or EMA).

Personally, I would not use this requirement as justification to continue with wet-ink; rather to invest a small amount of money in deploying a web-based advanced digital signature solution that meets regulatory requirements. Most advanced digital signature solutions (e.g. DocuSign) show a Return On Investment of 6-12 months, or less.

Eldin.

[Eldin Rammell]

Hi Ish,

My comments would be applicable to any document considered to be part of the TMF but kept outside the main eTMF/TMF.

• The documents must be included on the TMF Plan / TMF Index, together with the identification of the storage location/system
• The documents must be capable of being made readily available in the event of an inspection or audit; this includes being able to easily identify and retrieve relevant documents by study number, site number and/or PI name, as appropriate
• The documents must be accessible to relevant team members to confirm relevant quality standards and completeness requirements have been met
• The documents must be retained in accordance with GCP requirements, including transfer to an archive under the control of an archivist for the period of time required by pertinent regulations
• There must be a reasonable rationale for storing the documents in a system other than the main eTMF/TMF

For documents such as Master Service Agreements that cover multiple studies, sponsors who file these in the TMF usually have a level of filing above study level or file an electronic copy in each applicable TMF. I think there is likely to be a majority of sponsors who file MSA’s outside the TMF, in a contracts management system.

Hope this helps.

Kind regards,
Eldin.

[Eldin Rammell]

I agree with Kathie in that these types of records are not usually managed within a TMF system. They can be requested during inspections – and the MHRA have explicitly stated that GMP batch records are part of the TMF – but are typically managed as part of GMP-regulated manufacturing records.

This is not a recommendation, but if you chose to file in the main TMF and therefore wanted to align them with an existing artifact rather than creating a new one, I suggest 06.02.03 might be the most appropriate….. based on the purpose/description of the artifact rather than the artifact name:
“Any certificate, license OR OTHER DOCUMENTATION that is required by a specific regulation to verify the quality, source, MANUFACTURE, ingredients or other aspect of investigational and/or control product.”

You could perhaps define sub-artifacts for production records / batch records under 06.02.03., though I would still prefer to see them managed outside the TMF system as GMP records.

Kind regards,
Eldin.

[Eldin Rammell]

Hi Sarah,

To the best of my knowledge, none of the GCP/TMF regulations provide an answer to this. Some regulations require documents to be signed using an advanced electronic signature and DocuSign signatures are usually regarded as such.

In my opinion, the issue here is one of trustworthiness. In legal terms, the document is legally acceptable without the Certificate of Completion. And from a regulatory perspective, it meets the requirements without the Certificate; it shows who signed the document, when, requires security to apply the signature, and is linked to the document so that any change is detectable.

The Certificate of Completion simply provides additional evidential weight to the signature, providing additional metadata concerning the signing sequence of events. This information is rarely provided or available for traditional wet-ink signatures (other than those witnessed by a notary, for example) so it does not seem reasonable to expect electronic signatures to have a “higher burden of proof of authenticity”, especially considering digital signatures are typically more robust, secure and trustworthy than wet-ink.

I see some sponsors retain the certificate with the signed document but most are not retaining the certificate.

Kind regards,
Eldin.

[Eldin Rammell]

Hi Maria,

The 2nd option is the one I see most often. This ensures that all TMF for a single country is all located together in a set of folders (or virtual folders in many eTMF systems). It makes it easier to navigate between zones within a country. Similarly, as the site level, you would have all of your zones, sections and artifacts organized within each site folder to allow you to see the full content for the site within a single set of folders.

So:
Study XXX Trial-Level
— Zone 1
— Zone 2 etc
Study XXX Country-Level
— Argentine
— Brazil
—–Zone 1
—–Zone 2 etc
Study XXX Site–Level
—-Brazil Site 001
——Zone 1
——Zone 2 etc

Some systems group all of the countries together and then group all of the sites together. Other systems have the site folders positioned within the respective country folders.

I rarely see the country and site folders underneath the individual artifact folders….I think I’ve only seen this once, where all of the monitoring visit reports, for example, are all filed together, structured first by country and then by site. And then in a different folder the IRB approvals, filed by country and then by site etc.

Hope this helps.

Eldin.

[Eldin Rammell]

Hi Manali,

Column O defines whether or not the artifact is expected in the investigator TMF i.e an investigator document rather than a sponsor document (column N). So for artifact 05.04.08, column O is identified with “No” to signify that this is not a document that is usually expected to be filed in the investigator TMF (ISF).

I hope this helps.

Kind regards,
Eldin.

[Eldin Rammell]

Hi Manali,

In the published Reference Model, this artifact is identified as a site level document only.

Kind regards,
Eldin.

[Eldin Rammell]

I agree with Karen. You can’t beat talking to people who have already made the journey.

One of the primary drivers for using an eTMF that I mention when talking to people is to just think about how we do our work in the 21st century. We create documents using computer software, creating electronic documents. Even when our TMF is allegedly paper, we still collaborate with each other electronically. When we need to see a document, we go to SharePoint, our email, or a network drive to get the information we need. We send around documents electronically by email. And most critically, we rarely work just in one geographic location so we need the ability to access documents from wherever we are located.

So given this working scenario, why would we print everything and retain it using a medium that limits sharing and limits access? A printout is a secondary copy and contains almost none of the metadata generated during the life of the original; best to keep the original e-record in an eTMF!

I’m sure others can provide some additional insights.

Eldin.

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