The document outlines the Common Technical Document (CTD) and its electronic variant (eCTD), adopted by the FDA and other global regulatory agencies for drug submissions. It highlights the eCTD's growing adoption in the U.S. and Europe, detailing the structure, submission modules, and challenges faced in transitioning from paper to electronic formats. Key points include the significant increase in eCTD submissions from 2005 to 2008, the technological and procedural requirements for eCTD compliance, and the anticipated shift towards a paperless submission landscape.

1. eCTD Submissions
Saikat Chakraborty

2. WHAT IS COMMON TECHNICAL DOCUMENT?
CTD is an ICH standard that FDA adopted in a consensus process,
as a member of ICH, together with other member regions, Europe
and Japan
Currently global format for regulatory submissions
Consistent data organization
Method to electronically transfer product information and data
Collection of electronic files organized according to guidelines
defining file format, folder/files naming convention, document
specifications etc.
Applies to all NDAs, ANDAs, BLAs, INDs and master files

3. The eCTD challenge
In the US, eCTD-only NDAs, BLAs and INDs are accepted – no
paper necessary
eCTD plus paper still needed for Medical authorities in EU
Paper is still the official archival copy of the EU MA
EU wants eCTD as preferred format for all Marketing
Authorization Applications(MAAs) and variations
Only eCTD for MA for all EU members states by 1 Jan 2010
Health Canada wants eCTD format on CD/DVD plus paper

4. Accepting an Initial Marketing Authorization at the
agency
 100.000 pages represent ~ 250
volumes
 250 volumes represent ~ 80
boxes
 80 boxes represent approx. 3 –
4 palettes
 3 – 4 palettes require a truck
for transportation
The technology and the legislation of today can change this!

5. NEED FOR ELECTRONIC SUBMISSIONS
Designed with consideration that facilitate
Creation
Review
Assists project management and information management
Lifecycle management
(the history of a product application)
Archiving
Drug development planning

6. Current Status of US eCTD Submissions
FDA Office of Chief Information Officer
Quarterly briefing, 12 Dec 2008
During the period 2005 to 2008, eCTD submission volume grew at a
compounded annual growth rate of approximately 300%.

7. Barriers to adoption typically include:
Costs (initial capital: $200K- $300K and annual expense: $100
- $200K) of building, validating and operating an electronic
publishing system.
Effort and time to learn and understand the regulatory
requirements and to develop the organizational competency to
efficiently produce compliant eCTD submissions.
Growth of eCTD as a fraction of total submissions.
In 2007, eCTDs represented 10% of total submissions to CDER.
By February 2009, eCTDs were 20% of the total received.
It is expected that by the end of 2012, eCTD submissions may
represent 40 or 50% of total submissions to CDER.

8. Basics of eCTD
The ICH M4 Expert Working Group (EWG) has defined the
Common Technical Document (CTD).
The ICH M2 EWG has defined, in the current document, the
specification for the Electronic Common Technical Document
(eCTD).
There are 5 modules in the submission report.
A hierarchical cabinet/folder structure containing the electronic
documents (PDF).
An XML backbone that provides a structure to display the PDF
documents in the eCTD format (eCTD viewer)

9. CTD STRUCTURE
NOT Part of the
CTD
Regional
Admin
Information
Module 1
Module 2
Nonclinical Clinical The CTD
Overview Overview
Quality
Overall
Nonclinical Clinical
Summary
Summary Summary
Nonclinical Clinical
Quality Study Reports Study Reports
Module 3 Module 4 Module 5

10. Comparing paper CTD and eCTD

11. eCTD File Structure

12. Example of XML backbone

13. XML Mapping to Folder

14. Document Granularity
All eCTD Submissions Include Module 1
Module 1 Identifies important information
Company Name
Drug Name
Submission Type
Submission Date
Application Number
Sequence Number

15. Module 2 – Summaries

16. Document granularity – Module 3
Module 3 consists of highly granular Quality documents that can
be individually updated
ICH eCTD specification and CTD guidance provides level of
granularity
Module 3 contains hundreds of granules in MA

17. Document Granularity – Module 3

18. Document granularity – Modules 4 and 5
Study report formats
– Legacy report
• Report components published and submitted as a single
PDF with maximum size 100 MB
– Granular report – US eCTD
• Study documents submitted as separate PDF files as originally
published

19. Module 4 contains the Preclinical data

20. Module 5 contains Clinical Study Data

22. Document Publishing
Use tools based on Adobe Acrobat 5.0 or higher
(PDF version 1.4)
Publishing greatly facilitated by use of Word templates
Automate extraction of bookmarks and hyperlinks from Word files
Create PDFs from intelligent source- MS Office—Word, Excel,
PowerPoint or Other word processors, spreadsheets, ASCII text etc.
PDF should be text searchable, however some legacy document
may only be available in scanned form

23. Document Processing
Compare file names with document contents
In PDF
Check page size and orientation
US accepts edocuments as A4 in eCTD
EU MS require A4 paper dossier but you can submit letter- size PDF in an
eCTD

24. Scanned Documents
Avoid scanning unless no other choice
If You Must Scan
Document Type Resolution
Handwritten notes 300 dpi (black ink)
Plotter output graphics 300 dpi
Photographs—b&w 600 dpi (8 bit gray scale)
Photographs—color 600 dpi (24 bit RGB)
Gels and karotypes 600 dpi (8 bit grayscale depth)
High pressure liquid chromatography 300 dpi

25. Hypertext Linking
Navigation improved for PDF documents
Hypertext links for:
„
Annotations
„Related sections
„References
„
Appendices
„Tables or figures
„For anything not located on same page

26. Table of contents and hyperlinks
Hyperlinks designated by blue text or rectangles with thin lines
„Blue text for PDFs from intelligent source
„Thin rectangles only option for scanned documents
„Tables of Contents
„Hyperlinked
„Invisible rectangles and blue text preferred

27. Bookmarks and Hyperlink
Bookmarks
– Match the document TOC
– Bookmarks – Up to level 4, e.g. 1.1.1.1
– For documents with multiple granules, each granule
has its own bookmarks
Provide Bookmarks with Intuitive Names
Incorrect Correct

28. Bookmarks and Hyperlink
One of the important aspect in eCTD reports is to maintain ‘inherit
zoom’ throughout the document.
eCTD publishing system should generate automatically.
It can also be done manually with arcobat.

29. Bookmarks Hierarchy Initial View = Bookmarks & Page
Page Numbering
Document Page = PDF Page

30. File Naming & Folder/File Path
Use lower cases letters
Avoid special characters
except hyphens
File/folder path:
2
„ 30 characters for full
folder/file path
6
„ 4 characters for folder names
eCTD publishing system should generate/truncate automatically

31. Verbally Communicated Requirements
Font size
„12 point font for text
„10 point for tables (9.5 pt)
Font Style:
Arial, Times New Roman, Courier
Optimize for Fast Web View

32. QC of eCTD
Precompilation
QC interdocument links
100% QC that all bookmarks and hyperlinks are live
100% QC that all bookmarks and hyperlinks point to the correct targets
Check all all documents for presence and location
Check document titles in eCTD viewer
Postcompilation
Validate eCTD
Recheck for broken links

33. Submitting the eCTD
Cover letter (From the ICH eCTD spec, v. 3.2.2) as paper copy
with any non-electronic portions and as cover.pdf
A description of the submission including appropriate regulatory
information.
A listing of the sections of the submission filed as paper,
electronic, or both paper and electronic.
A description of the electronic submission including type and
number of electronic media,
Approximate size of the submission, and, if appropriate,
characteristics concerning the media (e.g. Format used for DLT
tapes) based on regional guidance.

34. Submitting an eCTD
A statement that the submission is virus free with a description of
the software used to check the files for viruses.
The regulatory and information technology points of contact for
the submission.
Copy eCTD to CD-ROM, DVD or DLT master
Reload eCTD from CD, DVD or DLT master and revalidate
Create eCTD copies from master
Number of copies determined by each EU MS

35. Points to Remember
1. Files Referenced in the XML Backbone(s)
2. eCTD Submissions Include Module 1
3. Application Numbers are 6 Digits
4. Sequence Numbers are 4 Digits
5. Ensure we receive what you intended
6. Do not send in one submission to be applied to
multiple applications
7. XML must be Standard Components
8. PDF contains Recognizable Text
9. PDF Hyperlinks/Bookmarks are Correct
10.PDF Documents include TOCs

36. Closing Remarks
The end is near for the traditional paper base era for
managing, reviewing, and submitting regulatory submissions.
Successful transtition to eCTD provides competitive advantages:
Increased review efficiency
Decreased risk of refusal to file
Faster time to market
H
„ appier stockholders
G
„ reater employee & management satisfaction
„Lower cost of production
„Simultaneous global submissions
„Healthier patients

37. References
CDER Contact for information on eCTD submissions
esub@fda.hhs.gov
CDER Contact for information on SDTM submission
cder-edata@fda.hhs.gov
Electronic Regulatory Submissions and Review
website
http://www.fda.gov/cder/regulatory/ersr/default.htm
• International Conference on Harmonization
http://www.ich.org
• All FDA Guidances on Electronic Submissions
http://www.fda.gov/cder/guidance/index.htm#electronic_submissions