In this blog, I share some experiences we recently had during an FDA submission Cytel performed for a sponsor after September 15, 2021. What is special about this date?
Effective September 15, 2021, the FDA officially implemented the Technical Rejection Criteria (TRCs); this means that the TRC could now block your submission if your Electronic Technical Document (eCTD) package fails any of the TRCs [1,2,3] , that is what happened with our sponsor’s eCTD package for which Cytel had provided the CDISC submission packages.
There were multiple reasons why the eCTD package didn’t pass the TRCs, and the resolution of those issues was not straightforward. It required some interaction with the edata team at the FDA (email@example.com) and some “trial and error”.
TRC for Study Data in a nutshell
The TRCs for Study Data  contain a set of automated validations (technical rejection criteria) implemented in the inbound processing FDA system. The following table provides a quick summary of the three current TRCs for study data:
A dataset named ts.xpt with information on study start date must be present for each study in Module 4^, sections 220.127.116.11, 18.104.22.168, 22.214.171.124, and in Module 5^, sections 126.96.36.199, 188.8.131.52, 184.108.40.206, 220.127.116.11, 18.104.22.168, 22.214.171.124, 5.3.4, 126.96.36.199, 188.8.131.52^
For both SEND and SDTM data package, to verify if FDA Study Data Standards apply e.g., if trial start date is after December 17, 2016
The correct STF file-tags must be used for all standardized datasets and corresponding define.xml files in Module 4, sections 184.108.40.206, 220.127.116.11, 18.104.22.168, and in Module 5, sections 22.214.171.124, 126.96.36.199, 188.8.131.52, 184.108.40.206, 220.127.116.11, 18.104.22.168, 5.3.4, 22.214.171.124, 126.96.36.199
Correct STF file-tags for submitted data package Presence of define-xml
Applicable when trial start date is after December 17, 2016
For Standard for Exchange of Nonclinical Data (SEND) data, a Demographic (DM) dataset and define.xml must be submitted in Module 4, sections 188.8.131.52, 184.108.40.206, 220.127.116.11
For Study Data Tabulation Model (SDTM) data, a DM dataset and define.xml must be submitted Module 5, sections 18.104.22.168, 22.214.171.124, 126.96.36.199, 188.8.131.52, 184.108.40.206, 220.127.116.11, 5.3.4, 18.104.22.168, 22.214.171.124
For Analysis Data Model (ADaM) data, an ADaM Subject level analysis dataset (ADSL) dataset and define.xml must be submitted in Module 5, sections 126.96.36.199, 188.8.131.52, 184.108.40.206, 220.127.116.11, 18.104.22.168, 22.214.171.124, 5.3.4, 126.96.36.199, 188.8.131.52
When submitting SEND and SDTM data packages, DM is a mandatory dataset, while for ADaM packages ADSL is a mandatory dataset
Applicable when trial start date is after December 17, 2016
^ eCTD Module 4 contains information on non-clinical studies. For example, pre-clinical studies in animals; while Module 5 contains information about clinical studies.
Essentially, regardless of whether you submit CDISC datasets or not, you need to have a dataset named ts.xpt in the eCTD datasets folder; the dataset should contain at least a record with a parameter TSPARMCD=STSTDTC, containing the study start date (either the protocol date for module 4 or the first signed informed consent date for module 5). The FDA system will read this dataset and will determine if the FDA data standards requirements apply to your study, or in short whether your study started before or after December 17, 2016. For a study that started before or on December 17, 2016, at least a "simplified” TS is needed. 
Tips and Tricks and Lesson Learned
Despite the requirements seeming straightforward, there are some sort of “traps”.
Multiple Data Packages per Study The reason why our package failed the TRC is because of the two pivotal studies we submitted more than one study data package, one for each interim analysis i.e., different study efficacy endpoint at week 24, 52 and 76 (the sponsor created three different Clinical Study Reports). Each of the three packages were placed by the regulatory vendor into different eCTD locations, each one with a different Study Tagging File (STF), thus not matching the STUDYID variable in the submitted datasets. The issue was solved by working with the regulatory vendor, getting the STF they used in the eCTD and adding an additional TS parameter, SPREFID, containing the same value as the STF (this is as per recommendation provided in the FDA Study Data Technical Conformance Guidance ). See an example below:
Additional ADaM datasets were provided, following the FDA questions
Few weeks later, the FDA requested some additional analyses for which we also provided some new ADaM datasets. The sponsor along with their publishing/regulatory vendor, provided the FDA with the new ADaM datasets in a separate eCTD folder and they again received a rejection because this time the ts.xpt was not provided (considering, the SDTM datasets were already provided to the FDA). The FDA edata team suggested re-submission of the SDTM datasets (duplicate) or alternatively, submit the new ADaM datasets in the same STF but with different leaf title, to distinguish from previously submitted ADaM datasets.
Following a pre-NDA meeting, the FDA agreed with our plan to provide SDTM pooled datasets were some legacy studies, started prior to December 2016, are integrated into the SDTM pool.
This time the question for the FDA edata team was if a ts.xpt, a simplified one, should be submitted with the pooled SDTM datasets, and which STUDYID should be used. The answer was that pooled datasets should be submitted to eCTD section 184.108.40.206 “Reports of Analyses of Data from More than One Study” and ts.xpt is not required for eCTD section 220.127.116.11.
The same is applicable when we integrate study data directly into pooled ADaM datasets; in this case they also confirmed that dm.xpt was also not required.
The FDA TRCs are as of now very basic, and they do not seem to pose any major challenges. It was only with this submission which happened after September 15, that we have been exposed to some technical details that were not clear in the guidance and have become clearer once checked with the FDA edata submission team. It is also extremely important to work closely with the sponsors and their regulatory vendor in case this is not already part of the process in your organization.
The information shared in this blog presents our experience with the agency on this topic, specific to this submission. Hence, I do recommend to always check with the FDA project manager, assigned to your submission, in case of doubts or during any official meeting with the FDA, and eventually contact the edata team.
Angelo Tinazzi is Senior Director, Statistical Programming, Clinical Data Standards and Clinical Data Submission at Cytel. He is a well- published and recognized expert in statistical programming with over 20 years' experience in clinical research. The application of CDISC standards in different therapeutic areas is part of his core expertise since 2003 in particular in the context of data submission to health authorities such as the FDA and PMDA.
Angelo is an authorized CDISC instructor and member of the CDISC ADaM Team as well as the CDISC European Committee where he also manages the Italian-speaking CDISC User Network.