ACUTA, ARCS, ARIM, ARIM Publisher, FDA, Software Release, Validator

Getting your STF in order

In 2003, ICH introduced the Study Tagging File (STF) in the electronic Common Technical Document (eCTD) format for electronic submissions to facilitate a way to associate all the documents and data files for a study. Initially the specification included two possible approaches for versioning the study’s items:

  • Cumulative: A complete cumulative STF would be provided in any submission sequence that impacts the study. The study tagging file in each sequence would be updated with a “Replace” operation meaning that each version shows the complete set of files for the study. The new version of the STF contains a complete list of the category metadata, file tags, and leaf IDs for all documents that comprise the documentation for the study.
  • Accumulative: Only changes to the study would be transmitted in subsequent submissions, previous items are not included in later submissions – the “Accumulation” happens in the systems that receive the eCTD message. The Study Tagging File itself will be sent with an “Append” operation, supplementing the previous version. Note that the STF is the only part of the eCTD that currently permits the use of the Append operation.

The Cumulative approach, however, was removed from the specification a couple years later, in 2008 at the request of the FDA, as it was found to be unwieldy, and reviewers had no way to tell what had changed from what was merely carried forward. Since the introduction of the STF, FDA is the only agency that requires its use for clinical and nonclinical study reports.

FDA’s validation criteria include a check to see whether your study tagging files are cumulative or accumulative, and error message #1731 will show up if your STFs appear to be using the cumulative method. This means that when a sponsor submits a subsequent sequence that includes documents for a study that was previously submitted, the STF file must be appended to, and not replace one from a previous sequence.

This all works pretty smoothly, unless your eCTD sequences get out of order, which is perfectly valid: one sequence may get delayed but another one with a higher number gets submitted first. ACUTA’s ARIM system handles this by having a “Submission Order” for each sequence separate from the sequence number.

However, validation systems may see a higher-numbered sequence appending to a Study Tagging File that that was not the most recent, perhaps having been appended to already. This triggers the same Error #1731 – even though the sequences are valid and FDA would not issue an error. Since FDA removed the Submission Date field from the Module 1 Document Type Definition (DTD) version 3.3, there is no other way to track the actual submission order of sequences.

In fact, this failed in the ARIM Validator, but is corrected in ARIM version 3.2.0 Hotfix 1, released in March, 2018. There is no need to panic if you see Error #1731 in your submission. Just use caution and verify the sequence order and lifecycle operations for the Study Tagging File.

In the Hotfix 1 release, the ARIM Validator will not trigger an error when sequence numbers are not the order of submission. However, because the ACUTA Desktop Validator does not have access to the ARIM database to see the order, and can only rely on the sequence number, that error message can still be triggered by out-of-order sequence numbers. Because of that, we have amended the error message to read as follows

1731-Cumulative STF files are not allowed (ACUTA: This criteria may fail even though the submission is valid when the submissions are submitted out of order. Please check for order in which submissions are submitted with STF in question)

Please be assured that this error message only indicates that ARIM Validator is especially vigilant: if your sequences are sent in the correct order, no errors will be generated at FDA.

ACUTA is dedicated to providing the best tools and services for creation of regulatory submissions. Especially with the upcoming requirement to send all Investigational New Drug and Drug Master File submissions in eCTD format as of May 5 (only 3 months away at the time of this writing), getting your eCTDs done correctly is a top priority.  Please contact us to find out how ACUTA ARIM software and ARCS services can help you become eCTD ready.

Fibonacci spiral sequence photo by J Brew

Author: Joel Finkle

Joel became embroiled in electronic submissions when regulatory came downstairs and asked "Can we convert all our clinical study reports to WordPerfect format for the FDA reviewer?" and he didn't say, "No." Since then, he's been involved with custom CANDAs, PDF publishing, eCTD, document template automation, Regulatory Information Management, HL7's RPS, and the ISO IDMP standard. He joined ACUTA in April of 2017. He'd share some of his famous tomatillo salsa with you, but he can't carry it on airplanes.

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