Ten years ago this month, in January 2014, the FDA issued the first version of its Technical Conformance Guide (by chance I also found comments provided by my friend Jozef Aerts already complaining about the use of SAS XPORT).1 The following December, a second version was released after public comments and, on December 16, 2014, the FDA stopped the clock, providing sponsors with a pivotal two-year window to adapt their methods of creating clinical dataset packages to comply with the FDA’s new required data standards for any study commencing after December 16, 2016.
Fast forward through approximately 30 subsequent versions, with the latest version, 5.6, being released in December 2023. The guidance has undergone significant changes, not only in terms of length (from 38 to 88 pages), but also in its content, consequently impacting the requirements for sponsors set forth by the FDA.
More specifically, between 2021 and 2023, the FDA released 13 versions. If you find yourself fatigued from comparing the differences, fear not! In this post, I aim to simplify things for you by highlighting the most substantial changes or new requirements.
Latest Updates: December 2023 Version
Version 5.6 was released while I was completing this article. The major update is in section 5.3, where the FDA lists additional FDA Technical Specification Documents. This includes two new guidances with SDTM and ADaM recommendations: “Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessments (COA) Using Item Response Theory” and “Submitting Patient-Reported Outcome (PRO) Data in Cancer Clinical Trials,” which contains analysis display examples.2
October 2023 Version Updates
Aside from the text additions to enhance clarity in certain sections and various alterations related to SEND (which won’t be discussed here), here are the most significant changes I have identified:
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- In section 4.1.1.3, there are now specific requirements for the PC and PP domains. The agency emphasizes that in both datasets, such as when referencing timepoints like visits, consistency with other domains is crucial. Additionally, there should be coherence between the two datasets when referencing analyte names. PCLLOQ should now also include a lower limit of quantitation.
- Moreover, in section 4.1.1.3, the FDA establishes new requirements for the SV domain, necessitating the inclusion of all scheduled visits, regardless of their occurrence. Additionally, the FDA advocates for the incorporation of new variables that are now standard in SDTM version 2.0 / IG 3.4, namely SVREASOC (Reason for Occur Value), SVEPCHGI (Epi/Pandemic Related Change Indicator), and SVCNTMOD (Contact Mode). The agency strongly prefers these variables to be included in SV and not in SUPPSV, irrespective of the SDTM version in use. Consequently, the VE domain, initially proposed in the CDISC “Guidance for Ongoing Studies Disrupted by COVID-19 Pandemic,”3 is no longer recommended.
- Appendix C lists expected FDA parameters to be included in TS. I strongly recommend regularly assessing any differences and updating your data standards accordingly.
- In Appendix D, the agency provides a list of additional documents not found in the data standards catalogue but encouraged by the FDA. These include the ADaM OCCDS, ADaM Examples of Traceability, ADaM Metadata Submission Guideline v1.0 (note that version 2 has been available since 20214), and “CDISC Documents: Interim User Guide for COVID-19” (of note, last September, CDISC released a consolidated version5) and the “CDISC Guidance for Ongoing Studies Disrupted by COVID-19.”3
June 2023 Version Updates
In the June 2023 version, a significant change was introduced. Notably, the FDA mandated the submission of an additional custom laboratory dataset. This dataset should mirror the structure of LB, with standard results variables (LBSTRESU, LBSTRESC, and LBSTRESN) along with corresponding normal range variables, containing results with US Conventional Unit instead of Standard International Unit (SI).
March 2023 Version Updates
In the March 2023 version, the FDA introduced in section “4.1.1.3 – SDTM Domain Specifications” specific requirements for submitting Immunogenicity data through the IS domain.
March 2022 Version Updates
In the March 2022 version, the FDA formally references the requirement to adhere to additional FDA Technical Specification Documents.6
This version also introduces a new section, “7.2 Electronic File Directory,” providing instructions for sponsors on organizing study datasets and their supporting files within a designated eCTD directory. Within this section, the FDA explicitly clarifies that when datasets are placed in the /split folder, there is no requirement for a second define.xml.
Moreover, this version set the official go-live of the “FDA Technical Rejection Criteria.”7
Other Significant Changes Worth Remembering
It’s been quite some time since October 2018 when the FDA, in section 4.1.1.3, introduced additional requirements regarding the handling of subjects with multiple enrollments in SDTM. Specifically, there was a directive to submit the primary enrollment in the DM domain and any additional enrollments in a demographic custom domain structured similarly to DM. Despite the passage of time, no definitive guidelines have been issued, even with the latest SDTM version (anticipated in SDTM Ig 4.08). Nevertheless, it has become increasingly common practice to submit a custom domain named DC, denoting Demographics as Collected.9 Moreover, for studies with multiple screenings and/or multiple enrollments per subject, the guidance recommends the inclusion of SUBJID in other related domains besides DM even though it may cause validation errors.
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Notes
- Aerts, J. (2014). “Comments to Study Data Technical Conformance Guide (draft) – Technical Specifications Document published by the FDA, February 2014.”
- CenterWatch. (2023). “Two FDA Guidances Present Technical Specifications for Clinical Trial Data.”
- CDISC. (2020). “Guidance for Ongoing Studies Disrupted by COVID-19 Pandemic.”
- CDISC. (2021). “SDTM Metadata Submission Guidelines v2.0.”
- CDISC. (2023). “COVID-19 Therapeutic Area User Guide v2.0.”
- Tinazzi, A. (2022). “Raising the Awareness for Additional FDA Data Submission Recommendations (Part I),” Perspectives on Enquiry and Evidence; and Tinazzi, A. (2022). “Raising Awareness for Additional FDA Data Standards Submission Recommendations (Part II),” Perspectives on Enquiry and Evidence.
- Tinazzi, A. (2022). “Watch out, the FDA Rejection Criteria are Now in Place,” Perspectives on Enquiry and Evidence.
- PharmaSUG China. (2023). “Exploration on Demographic as Collected (DC) Domain to Handle Multiple Screenings in SDTM.”
- Tinazzi, A. (2023). “The Facts in the Case of Subject X,” Perspectives on Enquiry and Evidence.
Read more from Perspectives on Enquiry and Evidence:
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