Basic Principles of the eCTD:

What’s it all about?

The Implementation of Electronic
Submission in eCTD Format at Swissmedic

December 10, 2009 and January 19, 2010

Dr. Dorothée Alfonso
sanofi-aventis (suisse) sa
The Basics of eCTD Submissions
What is an eCTD?
te s…
eCTD characteristics u
ttrib
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tion
Granularity… e ra
Op

Meta-data…
NEES…

Xml backbone…

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 What is an eCTD?

The CTD Pyramid

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 What is an eCTD?

Thus, is an eCTD just an electronic version of the CTD?

ICH definition of eCTD

« 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, life cycle
management and archiving of the electronic submission ».
The content is based on the CTD format, which was defined by
the International Conference on Harmonisation (ICH)
The eCTD was also developed by the ICH

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 What is an eCTD?

The ICH further defines the eCTD specification in a

document called ICH eCTD Specification V 3.2.2 (last
version from July 2008):
« The eCTD specification lists the criteria that will make an
electronic submission technically valid. The focus of the
specification is to provide the ability to transfer the registration
application electronically from industry to a regulatory authority ».
« Industry to industry and agency to agency transfer is not
addressed ».

http://estri.ich.org/ectd/eCTD_Specification_v3_2_2.pdf

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 eCTD characteristics

Structure (« Directory structure »)

It is a sort of folder hierarchy, which provides a
« container » for all documents which will be part of a
submission
The ICH eCTD specification includes a directory structure
that must be followed for modules 2 to 5
Regional guidance specifies the directory structure for
module 1

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 eCTD characteristics

Example

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 eCTD characteristics

Documents (1)
In a paper submission, one document is defined as a
set of pages numbered from 1 to n and divided from
the following document by a tab divider

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4 Document 2 (5 pages)
5 3
2
1
Tab divider
3
2
1
Document 1 (3 pages)

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 eCTD characteristics

Documents (2)
Standalone documents
One « document » = one « file »
Most of the documents are pdf files
According to ICH, other formats are possible (see specifications):
xml, gif, jpeg, etc. Agencies may define even other formats
Documents are being created from « source documents », e.g.
word files
Scanned documents shouldn’t be used

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 eCTD characteristics

Documents (3)
Have « hyperlinks » (internal or external hyperlinks) (indicated by
text in blue)
Are paginated with page numbering from 1 to n
Have their own table of contents (with the exception of very small
documents of 1 or 2 pages)
Include « bookmarks » which should reflect the table of contents

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 eCTD characteristics

Example

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 eCTD characteristics

Granularity (breakdown of information) (1)

The information contained in one modul is not contained in one single
document but in several documents => the information is divided

Recommended granularity – one document per lowest granularity

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 eCTD characteristics

Granularity (breakdown of information) (2)

Granularity is used to divide the content of a dossier
In an electronic submission, a new file starts at the same point at
which in a paper submission, a tab divides the documents
The granularity of the paper and electronic submissions should
be equivalent
In deciding whether one or more documents or files are
appropriate, one should bear in mind the Life Cycle Management
(LCM), i.e. the replacement of documents/files to be provided
when information is changed
The higher the granularity, the smaller the files and the more files
there are

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 eCTD characteristics

Meta-data
Meta-data are « data about data » which are contained in a xml
file
Each document contains mandatory meta-data (e.g., title, name
of the file, sequence, operation attribute, etc.)
Each dossier contains mandatory meta-data, with information
about the type of submission, the location of the documents,
navigation aids, etc.

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 eCTD characteristics

Example of meta-data of a file

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 eCTD characteristics

Xml backbone
In the eCTD, the « xml backbone » defines the overall structure
of the submission
It has two purposes:
Manage meta-data for the entire submission and each document
within the submission
Constitute a table of contents
In each sequence, there are two « xml backbones »: one for
module 1 and one for modules 2 to 5 with links between both

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eCTD characteristics

The « xml backbone » in the eCTD corresponds to the

Table of contents (TOC) in the CTD
The xml file is a small database with all information
necessary to play the role of a table of contents
Therefore, no location for a TOC in an eCTD

CTD TOC (pdf) (paper)

eCTD XML Backbone

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 eCTD characteristics

Example

EU xml M1

Index xml
(M2 à M5)

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 eCTD characteristics

Example (colors depend on the tool!)

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 eCTD characteristics

Sequences (1)
To each submission corresponds a sequence number
A sequence number has 4 « digits » and begins with
« 0000 »
Therefore, the first eCTD submission will have the
number « 0000 », the next one « 0001 », then
« 0002 », etc.
Sequence 0001 will often be the answer to the List of
Questions from HA

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 eCTD characteristics

Sequences (2)
The sequences following a given submission may be
related to this submission or may be independent

= initial submission

} = further submissions (related or not)

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 eCTD characteristics

Operation attributes
It is the key element of Life Cycle Management!
In each new sequence, all documents will have an
operation attribute
The attributes give the status of a document in relation
to previous submissions and might be:
New (no relationship with previously submitted documents.
E.g. first submission, additional indication)
Replace (the new file replaces a previously submitted file)
Append (there is an existing file to which this one should be
associated)
Delete (the file is no longer relevant – it is not deleted!)

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 eCTD characteristics

Life Cycle Management (1)

LCM is managed through the xml backbone using meta-data
With an eCTD, it is possible at any time to know the state of a
registration dossier in comparison with the initial dossier, by
means of a « viewing tool ». It is possible to see all the variations
which were submitted (not possible with CTD!)
When is it possible to switch from CTD to eCTD?
Theoretically at any time. However: « once eCTD, always eCTD »
Ideally, a baseline should be established for module 3 (but: added
value? Ressources? What about dossiers in NTA format?)
Practically, it is impossible to switch to the eCTD format for an
entire portefolio at the same time => make priorities

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 eCTD characteristics

Life Cycle Management (2)

Very difficult for « old » products, as documents shouldn’t be
scanned, i.e. they should be completely rewritten
The best case is when the initial dossier for an NCE can be
submitted as an eCTD, because all modules are then in eCTD
What’s going to happen with the hyperlinks from one sequence to
another one ? No solution so far!
It is recommended to set up a tracking table which lists all the
sequences and what they correspond to. This table has to be
added to the cover letter of an application to Swissmedic

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 eCTD characteristics

MD5 Checksum
An eCTD contains a mechanism to guaranty the integrity of a
document and of the whole dossier (checksum)
A unique mathematical sum of each byte in a file
Useful to check the integrity of a dossier and to check that a file
has not been altered (for instance in case of copying or in the
archives of the Health Authority)

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 eCTD characteristics

MD5 Checksum

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 eCTD characteristics

NEES
= Non eCTD Electronic Submission
An electronic submission is not necessarily an eCTD!
A NEES is an eCTD but without the XML component. Therefore,
it has a TOC in pdf format
There is no LCM
Files in pdf format are the same as in an eCTD
= intermediate format between CTD and eCTD which is accepted
by some HAs and which is becoming a standard for several
European HAs

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 eCTD characteristics

The three levels of visualisation

Not defined by ICH
1) Windows Explorer
2) Internet Explorer
3) « review tool »
a) Sequence view
b) Current view
c) Cumulative view
Advantage of the review tool: it enables to see all versions and all
documents submitted to an application and the relationship
between documents and sequences (Life Cycle Management)

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 eCTD characteristics

1) Visualisation with Windows Explorer

Insert your CD / DVD and open the file you are looking for
(usually pdf)
You’ll have the functionalities of a pdf file but nothing more (no
access to meta-data)
= simplest and easiest way to look at a given file and read the
content

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 eCTD characteristics

2) Visualisation with Internet Explorer

Insert your CD / DVD and open the index.xml file via
Internet Explorer (or equivalent) => you’ll have an
overview of the files
Color code: attributes are in red, file names are in
blue, etc.
No Life Cycle Management (no access to meta-data)

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 eCTD characteristics

Example

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 eCTD characteristics

3) Visualisation with a « review tool » (1)

a) Sequence view
Possibility to view an entire sequence, i.e. all files for a given
submission
Life Cycle Management is possible

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 eCTD characteristics

3) Visualisation with a « review tool » (2)

b) Current view
Possibility to see all files currently valid in a dossier
Not possible to see the deleted or replaced files

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 eCTD characteristics

Example

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 eCTD characteristics

3) Visualisation with a « review tool » (3)

c) Cumulative view
Possibility to see at the same time all sequences which were
ever submitted, thus all files ever submitted
Not much used because the longer the LCM, the more files
there are

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 eCTD characteristics

Example

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 eCTD characteristics

« Building tool »
Is needed to « build » an eCTD, as a « viewing tool »
is needed to visualise an eCTD
Helps to place the different documents and
relationships between them, to build the relationship
between the sequences, helps to set up bookmarks
and hyperlinks, and many other features

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Differences Switzerland - other regions

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 Differences Switzerland – other regions

Specification
Specifications of modules 2 to 5 were developped by the ICH
Module 1 is excluded (regional specification)
Each region has its requirements:
Module 1
Other modules might be concerned (e.g. : CRFs in module 5 for the
US; section 2.3.R, etc.)
Swissmedic’s specifications were published end of October as
well as the Guidance for Industry on the homepage
National requirements as well as those in common define the
eCTD structure, the format of the documents, the convention for
the names of files, etc

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 Differences Switzerland – other regions

What about the other regions? (1)

EMEA (centralised procedure)
July 1, 2008: EMEA accepts e-only submissions
January 1, 2009: EMEA strongly recommends e-only
submissions
July 1, 2009: EMEA strongly recommends eCTD
January 1, 2010: EMEA will mandate eCTD format

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 Differences Switzerland – other regions

What about the other regions? (2)

Useful links to EMEA
EMEA site on electronic submisions
http://esubmission.emea.europa.eu/

EMEA implementation of electronic-only submissions and mandatory

eCTD submissions in the centralised procedure: statement of intent
http://www.emea.europa.eu/pdfs/human/regaffair/57245908en.pdf

EMEA implementation of electronic-only submission and eTCD

submissions: questions and answers related to practical and technical
aspects of the implementation
http://www.emea.europa.eu/pdfs/human/regaffair/59688107en.pdf

EMEA implementation of electronic submsissions and eCTD

submissions: statement of intent. Questions and answers relating to
strategic and general aspects of the implementation
http://www.emea.eu/pdfs/human/regaffair/59687007en.pdf

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 Differences Switzerland – other regions

What about the other regions? (3)

HMA (MRP / DCP)
eCTD is highly recommended. However, NEES are
generally also accepted
The « application form » as well as the cover letter must be
submitted in paper with original signature
Module 1 must of course be compliant with EU specifications
Each country may have its own requirements => see internet
sites of the agencies

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 Differences Switzerland – other regions

What about the other regions? (4)

Usuful links to HMA
CMDh site and its links
http://www.hma.eu/225.html
« Best Practice Guide on the use of eCTD in the MRP/DCP »
http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_
h_/procedural_guidance/Application_for_MA/eSubmissions/B
PG_eCTD_MRP_DCP_Rev0.pdf
« Requirements on Electronic submissions for New Applications
within MRP, DCP or National procedures »
http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_
h_/procedural_guidance/Application_for_MA/eSubmissions/eS
ubmissions_NA_Rev0.pdf

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 Differences Switzerland – other regions

What about the other regions? (5)

EU National level
The tendency is to accept eCTD or NEES. Each agency has its
own requirements. See websites
FDA
eCTD is the only electronic format accepted for NDAs and INDs
since December 1, 2007
Health Canada
Implementation in three steps:
Co-submission (eCTD + whole paper CTD)
Hybrid submission (eCTD + modules 1 and 2 in paper CTD)
eCTD (electronic-only submission)
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-
demande/guide-ld/ctd/ectd/prep_ectd_format-eng.php

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 Differences Switzerland – other regions

What about the other regions? (6)

Japan
Two types of acceptance:
Officially: eCTD with paper version
Reference is still pCTD + paper copies + eCTD
Australia
Still paper format

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