Data Compliance or Rejection – Are you ready for September 15th?
Author: Melissa Rapp, Manager for Regulatory Operations North America
Until recently sponsors have been able to submit nonclinical and clinical reports without datasets and without fear of rejection. In less than three months, the agency will begin to enforce their Technical Rejection Criteria for Study Data “FDA plans to implement eCTD validation checks when submissions contain content under modules 4 and 5 beginning September 15, 2021. Submissions which fail this validation will be subject to rejection.”  What does this mean for industry and why is it so important to the agency?
Regulatory submissions in previous decades have progressed from the cumbersome and time-consuming paper volume review to electronic document review via computers and eCTD viewers. Such advancements have helped agency reviewers tremendously. The study data requirement seeks to further improve the review process as it aids the agency with organizational data tools. The advantage of using data standards for review is beneficial in several ways. “Having standard, uniform study data enables FDA scientists to explore many new research questions by combining data from multiple studies. Data standards also help FDA receive, process, review, and archive submissions more efficiently and effectively and the scientists at the FDA.  As industry stakeholders, we must keep ahead of the curve for the purpose of achieving important research milestones. A technological hiccup such as a submission rejection can be easily avoided if industry is informed, equipped, and prepared. As the FDA Commissioner Stephen Hahn said in a speech to FDA staff on 30 Jan 2020, “One of the most important resources for our work lies in the power of data. I strongly believe that we need to do everything we can to attain more and better data for the work we’re doing, to be more proactive in gathering data, and to be more creative and thorough in our analysis of it. By harnessing this power, we can improve our regulatory decision-making…” “ Understanding the importance of this initiative to the reviewers is motivation for industry to strive towards data standards innovation.
Now that the priority of data standards has been established, the next inquiry into this matter is determining how to achieve compliance. According to the guidance “Providing Regulatory Submissions in Electronic Format – Standardized Study Data,” NDA, BLA and ANDA submissions with studies that started after Dec. 17, 2016 and Commercial INDs with studies that started after Dec. 17, 2017 are required to be submitted in CDISC format following the FDA Data Standards Catalog “. The agency has already begun to issue warnings like the one below if the correct data has not been submitted along with reports that require them.
The following is a table that outlines the reports that require datasets and the type of datasets involved.
eCTD Technical Rejection Criteria for Study Data Expectations
One prevalent aspect of the table above is the presence of the ts.xpt file. TS.xpt files should be considered as the “gatekeeper” dataset file for nonclinical and clinical study reports. The data provided in these files identifies the categories of data that the agency requires. For example, the ts.xpt file should contain the study start date. In a recent presentation with Pharmalex’s Adair Turner (Director, Regulatory Operations North America), these criteria were explained for a simplified ts.xpt file. The study start date allows FDA to determine that study data is not required to be in a CDISC standardized format. For a simplified ts.xpt file, there should be four variables (STUDYID, TSPARMCD, TSVAL, and TSVALNF) and one row of information.
Table data from DIA RSIDM 2020 FDA Plenary Session – Technical Rejection Criteria for Study Data by Ethan Chen (OBI – CDER)
Datasets consist of three different file formats. In the image below, the SEND dataset contains a define xml file, a Nonclinical Study Data Reviewer’s Guide in PDF format, and datasets in .xpt format. The define file can be viewed by web-browser in html format. The PDF can be opened by Adobe or any PDF viewer. The .xpt file can be viewed and reviewed in a SAS universal viewer that is available for free download 
The amount of information provided and understanding what’s required may appear overwhelming; however, help is available. The agency has provided an “FDA Study Data Prep – Self Checklist” and provides detailed information on their website “Study Data for Submission to CDER and CBER”.
 DIA RSIDM 2020 FDA Plenary Session – Technical Rejection Criteria for Study Data by Ethan Chen (OBI – CDER)