# Presentation: 187106

## eSUBS and eCTDs:Practical Advice and Pitfalls to Avoid

**Ginny Ventura**
- Regulatory Information Specialist
- CDER, U.S. FDA
- June 21, 2006

## Overview

- CDER’s eCTD processing
- How our tools look and work
- Frequently encountered issues
- Examples
- How to ensure success

## Fewer Technical Issues

- eCTD submissions continue to increase steadily
- Number of technical errors/issues has decreased
- You’re doing a great job!

## How CDER EDR Staff Checks Your eCTD Submission

- Media is loaded to server, validate program is run
- Directory compare tool is run
- If review of your submission cannot proceed, you are contacted
- Otherwise, reviewers are notified that submission is available for review
- Reviewer performs the detailed audit

## General Sample – Module 1 -Risk Management

## Life Cycle Sample – Stability Data Replaced

- Navigation Pane

## Life Cycle Sample – Stability Data Replaced

- Detail Panel

## The Top Technical Issues

- Listed from least to most important
- Most all errors stem from one or more of these items

## Use of Elements

- Not necessary to use every element in the eCTD Specification
- Use only the elements you need
- Placeholder documents are not necessary, and can divert reviewers’ time and attention

## Leaf Titles

- Should be informative and succinct
- Should not include the eCTD numbering
- Should immediately reveal to the reviewer what’s inside

## Clinical Reports – Long and Short Leaf Titles in Navigation

## Always Reference All Files in the XML Backbone(s)

- Unreferenced Files Result from
- Missing/Mislocated Directory references in xlink:href
- “Extra” files
- Failing to Repeat Complete Directory Structure on each media component in a set
- Unreferenced Files may not be located by reviewers

## Include Module 1 in All eCTD Submissions 

- Every eCTD Submission Requires Module 1
- Module 1 Identifies important information
- Company Name
- Drug Name
- Submission Type
- Submission Date
- Application Number
- Sequence Number

## Make Sure All Application Numbers are 6 Digits

- Application-number values must be 6 digits -
- No Alpha Characters
- No “-” “,” or other punctuation
- No spaces
- Six Numbers – pad left “0” if 5 digits are given
- Application number is key - ties all submissions together as an application

## Make Sure All Sequence Numbers are 4 Digits

- Sequence-number values must be 4 digits
- No Alpha Characters
- No “-” “,” or other punctuation
- No spaces
- Sequence number is key and relates all submission components together
- Sequence numbers need not be received/submitted in “sequence”

## Do Not Use Node Extensions

- Node Extensions are Unwanted
- ICH and FDA do not recommend NEs
- At best they are ignored; at worst they defeat the standard headings
- Node Extensions are Unneeded
- Leaf Title can be used to differentiate between documents at the same level

## Verify That All MD5 Checksums are Correct

- MD5 Checksum values should be
- Coded as a leaf attribute in either us-regional.xml or index.xml
- Except
- The MD5 Checksum value is provided in a one-line text file – index-md5.txt - in each sequence number directory

## All Documents Should Conform to eCTD Granularity

- Avoid combining documents at higher parent leaf level (allowed by Module 3)
- Tempting - small initial savings in combining
- Large cost in life cycle complexity
- “Legacy” Study Reports make for life cycle issues down the road

## All XML must use Standard Components

- UTIL Folder
- 3 Standard DTDs
- 3 Standard Styles Sheets in UTIL folder
- Custom components create issues in FDA Processes – Defeat standards efforts
- Avoid GIFs, custom CSS, custom DTDs, custom elements with standard DTDs

## Be Sure All PDF Hyperlinks & Bookmarks are Correct

- Validate all Hyperlinks and Bookmarks
- Broken hyperlinks and bookmarks diminish reviewer confidence in the submission
- Test before you submit

## Book Mark Example to Avoid

## Include TOCs In All PDF Documents 

- For each Document -
- If a paper document needs a TOC, a PDF document needs a hyperlinked TOC
- TOCs should begin a PDF document if possible
- Include both bookmarks and hyperlinks
- Cross Document Links work in an eCTD

## To Summarize

- Correct use of elements and leaf titles
- Always Reference All Files in the XML Backbone(s)
- Include Module 1 in All eCTD Submissions
- Make Sure All Application Numbers are 6 Digits
- Make Sure All Sequence Numbers are 4 Digits
- Do Not Use Node Extensions
- Verify That All MD5 Checksums are CorrectAll Documents Should Conform to eCTD Granularity
- All XML must use standard components
- Be Sure All PDF Hyperlinks & Bookmarks are Correct
- Include TOCs In All PDF Documents

## Ensuring Success

- Submit a Sample eCTD prior to your real eCTD (contact info next slide)
- Follow the specifications and guidances and/or use an experienced consultant
- Follow the advice outlined in this presentation to avoid common problems

## References

**CDER Contact for information on eCTD and CTD submissions:  **eSub@fda.hhs.gov
**Electronic Regulatory Submissions and Review** **website **_**[www.fda.gov/cder/regulatory/ersr/default.htm](http://www.fda.gov/cder/regulatory/ersr/default.htm)**_
**International Conference on Harmonization  **_**[www.ich.org](http://www.ich.org/)**_
**Regulatory Review Support Staff, Office of Business Process Support, CDER **(headed by Gary Gensinger)