Beginning Dec 18, 2016, all clinical trial and nonclinical trial studies must use standards (e.g., CDISC) for submission data and beginning May 5, 2017, NDA, ANDA, and BLA submissions must follow eCTD format for submission documents. In order to enforce these standards mandates, the FDA also released "Technical Rejection Criteria for Study Data" in FDA eCTD website on October 3, 2016. FDA also implemented a rejection process for submissions that do not conform to the required study data standards. The paper will discuss how these new FDA mandates impact the electronic submission and the required preparation for CDISC and eCTD complaint submission package such as SDTM, ADaM, Define.xml, SDTM annotated eCRF, SDRG, ADRG and SAS® programs. The paper will introduce the current FDA submission process, including the current FDA rejection processes – “Technical Rejection” and “Refuse-to-File” and discuss how FDA uses “Technical Rejection” and “Refuse-to-File” to reject submission. The paper will show how FDA rejection of CDISC non-compliant data will impact sponsor’s submission process, and how sponsors should respond to FDA rejections as well as questions throughout the whole submission process. Use cases will demonstrate the key technical rejection criteria that will have the greatest impact on a successful submission process

1. How FDA will reject
non-compliant
eSubmission
Kevin Lee, Data Scientist

2. Electronic Submission vs Offensive
Lineman?
As an offensive lineman, my best game day would
be when my quarterback is always protected and no
one notices me for doing my job.

3. ➢ FDA current Review Process
➢ Technical Rejection vs Refuse
to File
➢ How will FDA reject non-CDISC
submission?
➢ Introduction of Technical
Rejection Criteria for Study
Data
➢ Introduction of Rejection
Process for Submissions
➢ How to prepare and keep up
with FDA updates
➢ Final Thoughts and Q & A
The Agenda

4. eCTD Folder Structures for CDISC / Legacy
Study Submission
ADaM xpt datasets, Define.xml, ADRG
ADaM SAS programs, TFL SAS programs
SDTM xpt datasets, Define.xml, SDTM
annotated blank CRF, SDRG
Legacy xpt datasets, data definition file
SEND xpt datasets, Define.xml, non
Clinical SDRG
Legacy SAS programs, TFL SAS
programs

5. FDA Standard Review Process
Month
0 1 2 3 4 5 6 7 8 9 10
Process
Submissi
on
Plan Review Take Official ActionConduct Review

6. Process Submission
First 14 days
➢ Receive a complete application through ESG.
➢ Perform Technical Validation (< Day 3).
➢ Issue Technical Rejection according to eCTD
Validation Criteria if it fails on Technical
Validation.
➢ Establish review team and distribute submission.
➢ Confirm user fee payment.

7. Plan Review
Day 14 – 60
➢ Assure application completeness and inspect
readiness.
➢ Communicate potential Refuse-to-File and
correctable filing deficiencies.
➢ Make filing decision (Refuse-to-File / File application).
➢ Organize the review tasks, review timelines and
review schedule.
➢ Determine final review classification (Priority or
Standard).

8. Conduct Review
Month 2 - 8
➢ Confirm and validate the sponsor’s
conclusion of the drug (safety and efficacy).
➢ Evaluate the text in the proposed labeling.

9. Take Official Action
Month 9 - 10
➢ Conduct wrap up meeting (outstanding issues,
safety, detailed labeling).
➢ Inform FDA decision to applicants (a regulatory
approval, an approval with conditions, a rejection).

10. FDA Current
Rejection
Process
➢ Technical Rejection
➢ Refuse to File (RTF)

11. FDA Rejection Process
Technical
Rejection
(Day 1 - 3)
RTF
(Day 60)
Month
0 1 2 3 4 5 6 7 8 9 10
Process
Submissi
on
Plan Review Take Official ActionConduct Review

12. Technical
Rejection
Severity of eCTD
Validation Criteria
➢ High
➢ Medium
➢ Low

13. Examples of eCTD Validation Criteria
Number 1734
Group General
Description A Trial Summary (TS) dataset must be presented for each study in
section 4.2 or in section 5.3.
Severity Description High
US DTD Version 2.01 and 3.3
Effective Date TBD
Problem You have not submitted a Trial Summary (TS) dataset for each study
in Module 4, section 4.2 or in Module 5, section 5.3
Corrective Action Resubmit, including a Trial Summary for each study in Module 4,
section 4.2 or in Module 5, section 5.3
Guidance Source Providing Regulatory Submissions in Electronic Format –
Standardized Study; Study Data Technical Conformance Guide

14. Refuse to File
Application
• The application is
incomplete.
• The potentially correctable
deficiencies cannot be
readily rectified or have not
been rectified.
• The application is
inconsistent with regulatory
practice.

15. Current FDA Rejection Process
1. A sponsor
submits electronic
submission
package to FDA.
4. The submission
will be
accepted by
FDA.
2. Does the
submission
pass the
technical
validation?
3. The submission will
be rejected by
FDA for technical
deficiency.Yes
No
8. FDA files the
application and
conducts the
review.
5. FDA reviews the
application.
6. Is the
application
complete for
review?
7. FDA Refuse to
File the
application.
No
Yes

16. According to FDA Data Standards Catalog, all clinical
and nonclinical trial studies starting after December 17th,
2016 with the exception of certain INDs will be required
to have CDISC compliant data.
CDISC Compliant eSubmission

17. Can FDA reject if
submission data
does not follow
CDISC
Standards?
YES
Why
Important?

18. How will FDA Reject non-CDISC
Submission?
Current
Rejection
Process
New
Rejection
Process

19. New FDA
Rejection for
Non-Compliant
CDISC Data
Submission
• Technical Rejection Criteria
for Study Data
• Technical Rejection
Process for Study Data

20. Technical Rejection Criteria for
Study Data
Technical Rejection Criteria for Study Data are added to eCTD validation
criteria.
• A Trial Summary (TS) dataset must be presented for each study. (High
severity)
• The demographic dataset (DM) and Define.xml must be submitted for
SEND and SDTM, also the subject level analysis dataset (ADSL) and
Define.xml must be submitted for ADaM. (High severity)
• The correct Study Tagging File (STF) file-tags must be used for all
standardized datasets. (Medium severity)
• For each study, no more than one dataset of the same type should be
submitted as new. (Medium severity)

21. Why Is TS Domain so Critical?
TS.TSPARMCD=SSTDTC(Study Start Date) and
TS.TSVAL=“yyyy-mm-dd” will tell whether study start before
December 17th, 2016 or after December 17th, 2016.
CDISC DataLegacy / CDISC Data
SSTDTC 2016-12-17
(Study Start Date)

22. Why DM and Define.xml for SDTM and
SEND and ADSL and Define.xml for
ADaM?
• For SDTM and SEND data submission, DM and
Define.xml are the key validations.
• For ADaM data submission, ADSL and Define.xml are the
key validations.

23. How to Respond to Technical
Rejection
• FDA will send “Technical Rejection for Submissions”
through ESG.
• FDA will provide eCTD validation criteria errors number
(e.g., 1734 for missing TS).
• Sponsor corrects the issues (e.g., adding TS domain) and
resubmit the package.

24. Use Case
Submission
without TS on
2017-11-20
Technical
Rejection on
2017-11-21
Resubmission
with TS on
2017-11-28
Pass
Technical
Validation on
2017-11-29
Receipt Date as
of 2017-11-28
Receipt Date as
of 2017-11-20

25. There are a lot more than
2 rejection criteria for
CDISC data.
What About
Other CDISC
Validation
Rules?

26. Questions:
What Will
Be Coming
Next?
• More CDISC rejection rules in eCTD Validation Criteria?
• All other CDISC rejection rules in RTF?
• Additional rejection process?

27. So, What Do We Need to Prepare for Now?
• Whether it is a legacy or CDISC data submission, we need to
prepare TS domains.
Note: Include TS in Define document.
• For CDISC data submission,
• DM and Define.xml should be included in SDTM and SEND.
• ADSL and Define.xml should be included in ADaM.
STUDYID DOMAIN TSSEQ TSPARMCD TSPARM TSVAL
STUDY001 TS 1 SSTDTC Study Start Date 2017-01-20

28. And What Do We Need to Prepare
in the Future?
• Watch out FDA new update
• Keep up with the new update
• Train our team for ongoing new update

29. FDA Pilot Project

30. What is Our Best
Game Day?
• No Rejection due to
CDISC compliance
issues
• No / Less Questions
from FDA related
CDISC compliance
issues

31. Final
Thoughts
Understanding of new
FDA rejection criteria
and process
How to respond and
prepare
Keep up with upcoming
FDA updates

32. Thanks!!!
Please contact
kevin.kyosun.lee@gmail.com
https://www.linkedin.com/in/
HelloKevinLee/