Basic information for beginners...

1. eCTD...By,CHANDRAMOHAN

2. • Types of Submission
• What is eCTD?
• Why eCTD?
• History
• eCTD modules
• Components of eCTD
• General considerations
• EU submission
• US submission
• Electronic Submission Gateway
• eCTD growth
• eCTD Challenges

3. Types of Submission
• Paper Submission
• Non-eCTD electronic submission (NeES)
• Electronic submission with eCTD

4. What is eCTD?
Electronic Common Technical Document
• Common format for Quality, Safety, and Efficacy information
• The eCTD is the electronic equivalent to the CTD. [CTD = eCTD]
• An interface for industry to agency transfer of regulatory information
• eCTD in Simple Words:
The eCTD backbone is an XML file representing the structure of the submission, it
includes links to files and other metadata such as check sum.

5. What is eCTD?
Regulatory Perspective
• The eCTD is defined as an interface for
industry, to agency transfer of regulatory
information while at the same time taking
into consideration the facilitation of the
creation,
• Review, lifecycle management and
archival of the electronic
• Submission.
Technical Perspective
• Structured set of folders
• containing PDFs (Portable Document
Format), Word and SAS (Statistical
Analysis System) files.
• Index.xml & us-egional.xml
/euregional.xml.
• Checksum files.
• Study Tagging Files (XML).
• DTD and Style Sheet to support xml
backbone.

6. Why eCTD?
• Quality
Better quality
Entire life cycle of product covered
Easy and rapid call up of information
• Costs
Paper and transportation costs reduced
Storage and archive requirements reduced
Faster, more efficient review, quicker registration
• Environmentally responsible

7. Save a tree!!
• NCE is approx 240,000 pages
Paper for this would be 672 kg
Equivalent to ONE average tree
AN ENTIRE TREE IS REQUIRED TO SUBMIT A SINGLE COPY OF THE
APPLICATION FORM ONE APPLICANT TO ONE HEALTH AUTHORITY

8. Before eCTD

9. After eCTD

10. eSubmissions history
Regional reviewer driven
1980s : Early activities in US in 1980s
1990s : Computer Aided New Drug Application (CANDAs)
eNDA Guideline
DAMOS in Germany, MANSEV in France
Harmonization
1997: M2 EWG start working closely with M4 (CTD)
2003 : ICH eCTD Guideline v3.0
Implementation
2004 : ICH eCTD Guideline v3.2 : implemented in all ICH regions
2008 : ICH eCTD Guideline v3.2.2
All electronic submissions must be in eCTD format in US
2010 : Mandatory eCTD for the Centralised Procedure in EU

11. eSubmissions history
USFDA:
• Jan 1, 2008, eCTD became CDER’s standard for electronic submission.
• FDA has made it mandatory for all ELECTRONIC submissions to be in eCTD
format since 2007-08.
• May 5, 2017: New Drug Applications (NDAs), Abbreviated NDAs (ANDAs), and
Biologics License Applications (BLAs), must be submitted using eCTD format.
• May 5, 2018: Commercial Investigational New Drug Applications (INDs) and
Master Files must be submitted using eCTD format.
EUROPE:
• Since January 2010 the EMA only accepts submissions received in the mandatory
eCTD format

12. eCTD Modules
• When making an electronic submission, each document should be provided as a
separate file.
• The documents, whether for a marketing application, an investigational
application,or a related submission, should be organized based on the five modules
in the CTD:
Module 1: includes administrative information,
Module 2: includes CTD summary,
Module 3: includes information on quality,
Module 4: includes the nonclinical study reports, and
Module 5: includes the clinical study reports.

13. Components of eCTD
• Folder or tree structure
• Set of files (Portable Document Format (.pdf), Microsoft® Word files (.doc) or
Rich Text Format (.rtf) and picture files like jpeg, or png, etc.)
• The eCTD backbone is an XML file (Extensible Markup Language) representing
the structure of the submission, it includes links to files and other metadata such as
check sum information. The schema for the XML is very rigid
• PDF hyperlinks

14. Components of eCTD
The common formats that can be included in an eCTD submission are:
• Narrative: Portable Document Format (PDF)
• Structured: Extensible Markup Language (XML)
• Graphic: Whenever possible, use PDF. When appropriate or when PDF is not
possible, use Joint Photographic Experts Group (JPEG), Portable Network
Graphics (PNG), Scalable Vector Graphics (SVG), and Graphics Interchange
Format (GIF). Special formats for very high resolutions could be appropriate on a
case-by-case basis.

15. Components of eCTD

16. XML Backbone View

17. What is DTD?
Document Type Definition
• Purpose of a DTD is to define the legal building blocks of an XML document.
• It defines the document structure with a list of legal Elements.

18. What is Style Sheet ?
• Style Sheet is a style sheet language used to describe the presentation semantics
(the look and formatting) of a document written in a markup language.
• Its most common application is to style web pages written in HTML and XHTML,
but the language can also be applied to any kind of xml.

19. What is Checksum ?
• A checksum or hash sum is a fixed-size datum computed from an arbitrary block
of digital data for the purpose of detecting accidental errors that may have been
introduced during its transmission or storage. The integrity of the data can be
checked at any later time by recomputing the checksum and comparing it with the
stored one. If the checksums match, the data were almost certainly not altered
(either intentionally or unintentionally).
• The procedure that yields the checksum from the data is called a checksum
function or checksum algorithm. A good checksum algorithm will yield a
different result with high probability when the data is accidentally corrupted; if the
checksums match, the data is very likely to be free of accidental errors.
• Example: fb8fc205-2c3f-4e1e-bfd4-d68ad9994593

20. General Considerations
MODULE 2:
A representative folder hierarchy for module 2

21. MODULE 3:
A representative folder hierarchy for module 3

22. MODULE 4:
A representative folder hierarchy for module 4

23. MODULE 5:
A representative folder hierarchy for module 5

24. Regional / Module 1

26. eCTD Supportive Files

27. Validation Results
The severity levels outline the impact on the official receipt of your submissions.

28. EU eCTD Submission
Eudralink/email
• In order to send the eCTD sequence over Eudralink the entire sequence has to be zipped first.
Some zip formats are not widely readable and therefore a submission could be rejected if the
zipped format cannot be read by the agency. Hence to be checked with agency before submission.
• There is a size limit of 80 MB per file. It is not possible to split an eCTD sequence. Therefore
submission of an initial submission is not recommended over Eudralink as the file size will be
usually over 80 MB.
• When using Eudralink, it is important that the expiry date is set to the maximum of 90 days to
ensure that it can be opened during the process at the receiving authority. In addition, all
information relating to the submission must be contained within the zipped sequence; no formal
information should be included in the body of the Eudralink message.
Portal:
• Generally only small (<100MB) applications can be handled this way. Applicants should check
with individual agencies for details of this process.

29. EU eCTD Submission Procedures
CD/DVD:
• Zipped files should not be used when sending CDs or DVDs.
Labelling of Media
Each CD or DVD submitted with an eCTD should include the following label information clearly presented and printed on the
media:
• Format: eCTD
• The applicant’s name
• The product (invented) name(s)
• The International Non-proprietary Name (INN) of the active substance(s)
• The full application number(s) (if known)
• The sequence number(s) of the eCTD submissions contained on the CD/DVD
• If there are too many sequences to list on the CD/DVD label itself, a separate list should be provided in the cover letter.
• Number of media units per full set and an indication of the place of the individual CD/DVD within this set (e.g. 1(5), 2(5), etc).
• The submission type(s) of each eCTD submission(s) contained on the CD/DVD (e.g. Initial Application, Variation Type II), as
per the eCTD envelope information

30. US eCTD Submission
Submission size Media and format Units
Less than 3.25GB CD-ROM ISO 9660 1 to 5 CDs
Greater than 3.25GB Digital Tape - Digital Equipment
Corp.
DLT 20/40 and 10/20 GB format
using
OPENVMS with VMS backup or NT
server
4.0 with NT backup or backup exec.
No limit

31. US eCTD Submission
Labelling of Media
Label the media with the following:
• Submission identifier (e.g., NDA, BLA number)
• Proprietary and generic name.
• Company name
• Submission serial number, if applicable.
• Submission date: in the format of DD-MMM-YYYY (for example, 01-Jan-1997).
• Disk/CD-ROM/tape number (the number should include the total number submitted such as Disk #
of #)
When sending CD ROMS to CBER, number them from 0.001 through 0.XXX for the original
submission, and 1.001 through 1.XXX for subsequent submissions with additional information.

32. Electronic Submission Gateway (ESG)
FDA ESG Web Interface Electronic Submissions / Gateway to gateway
• Apply for a Test Account
• Test Account Setup and Approval
• Send a Test Submission
• Apply for a Production System Account
• Production System Account Setup and Approval
• Send Submissions to the Production System

33. eCTD Growth
• US

34. eCTD Growth
• EU

35. eCTD Growth
• JP

36. Challenges
• Advantages sometimes perceived as disadvantages
Granularity
PDFs
Hyperlinks
• Requires tools and trained technical experts
• Different implementation approach
• Regional rules vary
• Changes in way of working
• Last minute changes not easy